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Serum Biomarkers in Healthy, Injured, and Osteoarthritic Knees: A Critical Review

Open AccessPublished:November 17, 2022DOI:https://doi.org/10.1016/j.jcjp.2022.100091

      Abstract

      Purpose

      The purpose of this critical review is to summarize and evaluate the existing serum biomarkers currently proposed for the identification and evaluation of osteoarthritis onset and progression in three populations: healthy-, anterior cruciate ligament reconstructed- and osteoarthritic knees using the BIPED classification.

      Methods

      Articles that reported on serum biomarkers in individuals with healthy, anterior cruciate ligament reconstructed and osteoarthritic knees were collected from peer-reviewed sources available on Medline (2000 through March 2020). Search terms included the following: serum AND biomarker AND knee AND osteoarthritis AND healthy AND (“anterior cruciate ligament” OR “anterior cruciate ligament reconstruction” OR “ACLR”). Articles were limited to studies in humans, written in English and full text accessible. All serum biomarkers evaluated in the gathered manuscripts were classified according to the BIPED classification.

      Results

      A total of 164 unique serum biomarkers were identified across healthy individuals, 18 reported on patients after knee injury (commonly ACLR), 71 reported on patients with diagnosed OA and 5 reported mixed populations. Biomarkers studied most frequently include serum COMP, interleukin-6, C2C, CPII, hyaluronic acid, tumor necrosis factor- alpha, c-reactive protein, MMP-3, high sensitivity-CRP, IL-8 and IL-1B, CS846, YKL-40, and C1,2C.

      Discussion

      The results highlight large variations in how these biomarkers respond to different stimuli across multiple populations. The most frequently studied biomarkers were those categorized under the BIPEDs criteria as diagnostic, burden of disease and prognostic biomarkers. More robust and longitudinal research on serum biomarkers needs to be conducted in these 3 populations.

      Keywords

      Introduction

      Osteoarthritis (OA) is defined as a “chronic, progressive disease” characterized by systemic changes to the affected joint including deterioration and loss of articular cartilage, subchondral bone, synovium, ligaments and integrity of the neuromuscular system.
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      OA is generally accepted to be a whole-organ disease with inflammatory, biochemical and biomechanical components.
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      Together, these systemic alterations lead to significant health and economic burdens.
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      Early diagnosis to enable early treatment of pre-osteoarthritis.
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      Although OA is often considered to be an aging disorder affecting older individuals, the incidence of knee OA in younger adults is rising. About 50% of osteoarthritis cases are now occurring in individuals younger than 5583, with many of these individuals developing OA following a traumatic knee injury.
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      Upwards of 50% of young adolescents who sustain anterior cruciate ligament (ACL) injuries will develop posttraumatic OA within 10-20 years
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      Joint injury causes knee osteoarthritis in young adults.
      due to unfavorable biomechanical and biochemical environments within the knee joint. Thus, it is evident that a significant number of young active individuals will be burdened with premature joint degeneration and poorer quality of life. Understanding the early changes in the development of OA is imperative for prevention and identification treatment approaches to halt or reverse OA progression.
      OA has deleterious effects on the joint and there have been many targeted strategies to identify OA onset and progression prior to presentation of clinical symptoms and radiographic changes (e.g. joint space narrowing, osteophyte development).
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      As biochemical alterations have been reported to precede structural changes related to OA onset
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      An update on the pathophysiology of osteoarthritis.
      , emerging research has focused on the utility of certain biochemical markers (biomarkers) as potential precursors of OA. Such biomarkers are commonly obtained from the serum, synovial fluid and urine and can capture aspects of joint metabolism, including cartilage and bone synthesis and degradation (i.e. turnover) as well as inflammatory and cytokine responses, all of which have been shown to be altered in patients with various stages of OA.
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      Serum and urine biomarkers provide a systemic, non-localized measure of these biochemical alterations, and they are often more clinically feasible and less invasive than obtaining intraarticular synovial fluid samples. Although these are “systemic” markers, they often also coincide with local joint injury. For example, previous work has reported that elevated levels of serum cartilage oligomeric matrix protein (COMP) occur after knee injury and in the early stages of OA.
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      Small fragments of cartilage oligomeric matrix protein in synovial fluid and serum as markers for cartilage degradation.
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      Relationship between serum cartilage oligomeric matrix protein levels and disease progression in osteoarthritis of the knee joint.
      Further, Svoboda et al reported altered levels of serum C2C and C1,2C (cartilage degradation markers) in patients after ACL injury compared to healthy controls.
      • Svoboda SJ
      • Harvey TM
      • Owens BD
      • et al.
      Changes in serum biomarkers of cartilage turnover after anterior cruciate ligament injury.
      For these reasons, serum biomarkers have been widely studied across disease spectrums for their ability to classify the following characteristics: cartilage damage during early pre-radiographic stages, disease activity, severity or burden of disease, prognosis prediction and response to certain treatment approaches. Using serum characteristics to schematically classify joint health, also known as the BIPEDs classification, was proposed by the Osteoarthritis Biomarkers Network in 2006 to identify important parameters surrounding the evaluation and qualification of biomarkers related to OA.
      • Bauer DC
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      Classification of osteoarthritis biomarkers: a proposed approach.
      Over the last several decades, significant strides have been made towards better understanding serum biomarker dynamics in response to certain physical activity bouts across multiple disease states. Importantly many of these serum biomarkers have been studied not only in patients with OA or following traumatic knee injury but also in healthy populations during various physical tasks, often with conflicting findings. Joint loading is important for maintaining cartilage health, however, excessive joint loading may initiate an intraarticular inflammatory process leading to the premature degeneration of articular cartilage and underlying subchondral bone.
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      Recent studies have also proposed the use of serum cartilage turnover biomarker panels to potentially identify healthy individuals at a high risk of injury as specific biomarkers are not abundant in healthy joints and thus could indicate early pathology. Individuals who demonstrate elevated cartilage turnover levels may already be exhibiting faulty biomechanical strategies affecting the internal biochemical processes occurring within the joint. Thus, an imbalance in underlying metabolic processes associated with the maintenance of cartilage turnover or cumulative tissue load affecting collagen synthesis and degradation may serve as a precursor to early degenerative changes and injury.
      • Svoboda SJ
      • Owens BD
      • Harvey TM
      • et al.
      The Association Between Serum Biomarkers of Collagen Turnover and Subsequent Anterior Cruciate Ligament Rupture.
      For example, a recent prospective study
      • Svoboda SJ
      • Owens BD
      • Harvey TM
      • et al.
      The Association Between Serum Biomarkers of Collagen Turnover and Subsequent Anterior Cruciate Ligament Rupture.
      indicated that pre-injury differences in serum biomarker levels of cartilage turnover may be reflective of certain risk profiles for ACL injury. Notably, cartilage degradation (C1,2C and C2C) and synthesis (CPII, CS846) biomarkers were significantly associated with the subsequent likelihood of sustaining an ACL injury.
      • Svoboda SJ
      • Owens BD
      • Harvey TM
      • et al.
      The Association Between Serum Biomarkers of Collagen Turnover and Subsequent Anterior Cruciate Ligament Rupture.
      Multiple studies also support that biomarker fluctuations observed after ACL injury
      • Catterall JB
      • Stabler TV
      • Flannery CR
      • Kraus VB.
      Changes in serum and synovial fluid biomarkers after acute injury (NCT00332254).
      ,
      • Svoboda SJ
      • Harvey TM
      • Owens BD
      • et al.
      Changes in serum biomarkers of cartilage turnover after anterior cruciate ligament injury.
      ,
      • Svoboda SJ
      • Owens BD
      • Harvey TM
      • et al.
      The Association Between Serum Biomarkers of Collagen Turnover and Subsequent Anterior Cruciate Ligament Rupture.
      and after some forms of long duration exercise in healthy individuals
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      • Best TM
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      • Toumi H.
      Osteoarthritis biomarker responses and cartilage adaptation to exercise: A review of animal and human models.
      may negatively influence long term joint health and increase the risk for OA development. While it is important to point out that a correlation does not indicate causality, an altered biomarker profile may indicate early adaptive changes that can serve as a potential indicator for early joint damage.
      Therefore, the purpose of this critical review is to summarize and evaluate the current state of the science regarding serum biomarkers and their potential clinical usefulness. This work is based upon those markers, currently proposed for the identification and evaluation of osteoarthritis onset and progression in three populations: healthy-, anterior cruciate ligament reconstructed- and osteoarthritic knees. This will allow us to provide a comprehensive overview of the current evidence surrounding serum biomarkers across disease state spectrums (healthy to osteoarthritic) and their potential uses within the BIPED classification.

      Materials and Methods

      Search strategy

      A systematic literature search was performed on articles reporting about serum biomarkers related to OA in healthy individuals, those with traumatic knee injuries such as ACL injury and reconstruction (ACLR), and those diagnosed with OA. The articles were collected from peer-reviewed sources available on Medline and PubMed between January 1, 2000 and March 31, 2020. The following search parameters were used to locate appropriate articles: serum AND biomarker AND knee AND osteoarthritis AND healthy AND (“anterior cruciate ligament” OR “anterior cruciate ligament reconstruction” OR “ACLR” OR “knee injury”). The initial literature search results were screened by the primary author. Articles and abstracts screened were limited to studies in humans, written in English, involved patients with knee OA, reported serum biomarkers and were full text accessible. Articles were excluded if they were written in languages other than English, animal studies, those not evaluating serum biomarkers, joints other than the knee (i.e. hip, ankle) and reviews. Following initial screening, the articles that met the aforementioned inclusion criteria were then critically reviewed by two authors. Additionally, reference lists and reviews were hand searched for applicable articles. Figure 1 outlines the screening and inclusion process for all articles. There were 120 articles that were included for the final critical analysis and a total of 164 unique serum biomarkers were identified. All serum biomarkers evaluated in these final articles were classified independently by two authors according to the BIPED classification (burden of disease, investigative, prognostic, efficacy of intervention and diagnostic).
      Fig 1
      Fig. 1Article screening and inclusion process

      Biomarker classification

      The BIPEDs classification schema was developed in order to facilitate consistency in research terminology and for the use in future clinical trials.
      • Bauer DC
      • Hunter DJ
      • Abramson SB
      • et al.
      Classification of osteoarthritis biomarkers: a proposed approach.
      ,
      • Kraus VB
      • Burnett B
      • Coindreau J
      • et al.
      Application of biomarkers in the development of drugs intended for the treatment of osteoarthritis.
      Originally the BIPEDs system classifies potential OA biomarkers into five categories including the following: burden of disease, diagnostic, investigative, prognosis and efficacy of intervention. A sixth category, biomarker safety was added in 2011.
      • Kraus VB
      • Burnett B
      • Coindreau J
      • et al.
      Application of biomarkers in the development of drugs intended for the treatment of osteoarthritis.
      Based on this classification strategy
      • Bauer DC
      • Hunter DJ
      • Abramson SB
      • et al.
      Classification of osteoarthritis biomarkers: a proposed approach.
      ,
      • Kraus VB
      • Burnett B
      • Coindreau J
      • et al.
      Application of biomarkers in the development of drugs intended for the treatment of osteoarthritis.
      , a single biomarker may fall into one or more categories, detailed below, across different studies.

      Burden of disease biomarkers

      Biomarkers classified under ‘burden of disease’ can be used to indicate the extent or severity of disease and also reflect the state of the disease at the time of assessment but may not be able to predict continued progression. Articles evaluating burden of disease markers typically provide a comparison of the biomarker levels to a clinically recognized gold standard assessment (i.e. Kellgren-Lawrence (K-L) classification). K-L classification falls into a category between 0 and 4, with grade 0 indicating no radiographic evidence of osteoarthritis, grade 1 indicating doubtful narrowing of the joint space with possible osteophyte formation, grade 2 indicating possible narrowing of the joint space with definite osteophyte formation, grade 3 indicating definite narrowing of joint space, moderate osteophyte formation, some sclerosis, and possible deformity of bony ends and grade 4 indicating severe osteoarthritic changes demonstrated by large osteophyte formation, severe narrowing of the joint space with marked sclerosis, and definite deformity of bone ends.
      • Kellgren JH
      • Lawrence JS.
      Radiological assessment of osteo-arthrosis.

      Investigative biomarkers

      Investigative biomarkers are those that may not yet have enough evidence accumulated to be assigned to a particular BIPEDS category show promise for future incorporation.

      Prognostic biomarkers

      Prognostic biomarkers serve as important indicators for who is at risk for developing symptomatic OA and in those already diagnosed with OA, whether a patient's disease is likely to progress and how quickly the progression will occur. These markers require long term serial evaluations.

      Efficacy of intervention biomarkers

      These biomarkers are important to demonstrate that a drug is having the desired immediate downstream biochemical effect and/or an impact on the clinical manifestations of the disease. Markers classified under this category may be indicative of longer-term treatment efficacy.

      Diagnostic biomarkers

      Biomarkers with diagnostic properties differentiates between those with OA and those without, but may not reflect disease severity. These markers also may be able to identify people at risk for OA. Biochemical biomarkers could detect the process leading to OA before it is detectable by radiography or other imaging modalities, highlighting the potential utility for prevention efforts.

      Safety biomarkers

      Safety biomarkers were introduced in 2011 into the BIPED(S) classification to assist in preclinical and clinical monitoring the health of the joint tissues, the whole joint organ, or the musculoskeletal system. instance, biomarkers reflecting the synthesis of the main proteins of the joint might provide an index of the “joint-protective” effect of a potential treatment.

      Results

      Following article screening, a total of 120 articles were identified as eligible and included in the final critical analysis. Sixty-four of these articles were cross-sectional and 56 were longitudinal studies. Twenty-three of these articles reported on healthy, active individuals, 18 reported on patients after knee injury (commonly ACLR), 71 reported on patients with diagnosed OA and 5 reported mixed populations containing healthy individuals, knee injury and OA patients. The studies included a total of 17,372 patients. Of these patients, 10,952 were diagnosed with knee OA, 1,103 had sustained a knee injury (most commonly ACL injury), and 5,317 were healthy controls. From these 120 articles, a total of 164 unique serum biomarkers were identified. Several biomarkers were studied multiple times. Biomarkers studied the most frequently (5 articles or more) included the following: serum COMP (61 articles), interleukin-6 (16 articles), C2C (14 articles), CPII (12 articles), hyaluronic acid (14 articles), tumor necrosis factor- alpha (12 articles), c-reactive protein (11 articles), MMP-3 (10 articles), high sensitivity-CRP (8 articles), IL-8 and IL-1B (6 articles), CS846 (6 articles), YKL-40 (5 articles), and C1,2C (5 articles).

      BIPEDs classification

      Each biomarker was classified according to the BIPEDs classification schema into 5 categories: burden of disease, investigative, prognostic, efficacy of intervention, or diagnostic. No studies investigating the safety of serum biomarkers were included in this review. Biomarkers may fall into multiple categories across different studies based on the study design.

      Burden of disease biomarkers

      A total of 80 unique biomarkers reported across 30 studies were categorized under burden of disease classification, for a total of 101 analyses on burden of disease serum biomarkers. Burden of disease markers assess the severity or the extent of OA and thus are often compared with gold standard metrics for determining severity. The most commonly utilized radiographic criteria assessing severity was the Kellgren-Lawrence classification, utilized in 23 studies. Additional, but less commonly used magnetic resonance imaging (MRI) criteria, included the Whole-Organ Magnetic Resonance Imaging Score (WORMS) which was assessed in 2 articles, the Koshino, Ahlback and Recht
      • Recht MP
      • Kramer J
      • Marcelis S
      • et al.
      Abnormalities of articular cartilage in the knee: analysis of available MR techniques.
      classification schema (1 article each), and an ultrasound assessment to identify osteophytes (1 article). Clinical criteria used to determine severity of OA most commonly cited was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), used in 9 studies, the visual analog scale (VAS) (4 articles), the index of severity (1 article), Lequesne algofunctional index (1 article), knee injury and osteoarthritis outcomes score (KOOS) (1 article) and the health assessment questionnaire disability index (1 article).
      Forty-three burden of disease biomarkers demonstrated a positive relationship with knee OA severity based on radiographic classifications, and 8 demonstrated a positive relationship with clinical markers of knee OA (i.e. self-reported or functional outcomes) (Figure 2a, Table 1). A negative relationship with radiographic knee OA severity was found for 24 biomarkers, and 4 biomarkers demonstrated a negative relationship with clinical burden of disease measures (WOMAC, KOOS scores) (Figure 2b, Table 1). No relationship was found for 23 serum biomarkers for either imaging or clinical metrics of burden of disease.
      Table. 1Burden of Disease Biomarkers
      BiomarkerPositive Association to Radiographic AssessmentRefBiomarkerPositive Association to Clinical AssessmentRef
      COMPKL grade >2 demonstrated higher COMP levels than <1
      • Azukizawa M
      • Ito H
      • Hamamoto Y
      • et al.
      The Effects of Well-Rounded Exercise Program on Systemic Biomarkers Related to Cartilage Metabolism.
      HAHA at T3 (8 hours after ADLs) associated with morning knee stiffness & total WOMAC
      • Criscione LG
      • Elliott AL
      • Stabler T
      • et al.
      Variation of serum hyaluronan with activity in individuals with knee osteoarthritis.
      COMPCOMP + associated with WORMS; KL grade II & III patients had ↑ COMP levels than KL I
      • Georgiev T
      • Ivanova M
      • Kopchev A
      • et al.
      Cartilage oligomeric protein, matrix metalloproteinase-3, and Coll2-1 as serum biomarkers in knee osteoarthritis: a cross-sectional study.
      HA↑ HA + associated with ↑ circulatory problems & gout
      • Elliott AL
      • Kraus VB
      • Luta G
      • et al.
      Serum hyaluronan levels and radiographic knee and hip osteoarthritis in African Americans and Caucasians in the Johnston County Osteoarthritis Project.
      COMP1 unit ↑in COMP, ↑ odds of cartilage loss on MRI by 6.09 times.
      • Hunter DJ
      • Li J
      • LaValley M
      • et al.
      Cartilage markers and their association with cartilage loss on magnetic resonance imaging in knee osteoarthritis: the Boston Osteoarthritis Knee Study.
      IL-16↑IL-16 + correlated with WOMAC scores
      • Das Gupta E
      • Ng WR
      • Wong SF
      • Bhurhanudeen AK
      • Yeap SS
      Correlation of serum cartilage oligomeric matrix protein (COMP) and interleukin-16 (IL-16) levels with disease severity in primary knee osteoarthritis: A pilot study in a Malaysian population.
      HAHA + associated with KL scores
      • Chua Jr, SD
      • Messier SP
      • Legault C
      • et al.
      Effect of an exercise and dietary intervention on serum biomarkers in overweight and obese adults with osteoarthritis of the knee.
      IL-6↑ IL-6 associated with ↓ walking speed
      • Penninx B
      • Abbas H
      • Ambrosius W
      • et al.
      Inflammatory markers and physical function among older adults with knee osteoarthritis.
      HAHA at T3 (8 hours after ADLs) associated weakly with KL grade sum score (not significant when accounting for BMI)
      • Criscione LG
      • Elliott AL
      • Stabler T
      • et al.
      Variation of serum hyaluronan with activity in individuals with knee osteoarthritis.
      TNF-α↑ TNFα (-) correlated with WOMAC physical function
      • Penninx B
      • Abbas H
      • Ambrosius W
      • et al.
      Inflammatory markers and physical function among older adults with knee osteoarthritis.
      HA↑ HA + associated with ↑KL grade
      • Elliott AL
      • Kraus VB
      • Luta G
      • et al.
      Serum hyaluronan levels and radiographic knee and hip osteoarthritis in African Americans and Caucasians in the Johnston County Osteoarthritis Project.
      TNF-sR1↑TNF-sR1 correlated with ↑ WOMAC physical function & higher pain & greater stiffness
      • Penninx B
      • Abbas H
      • Ambrosius W
      • et al.
      Inflammatory markers and physical function among older adults with knee osteoarthritis.
      CRP↑ CRP + correlated with higher KL grades
      • Livshits G
      • Zhai G
      • Hart DJ
      • et al.
      Interleukin-6 is a significant predictor of radiographic knee osteoarthritis: The Chingford Study.
      TNF-sR2↑TNF-sR2 correlated with ↑ WOMAC physical function & higher pain
      • Penninx B
      • Abbas H
      • Ambrosius W
      • et al.
      Inflammatory markers and physical function among older adults with knee osteoarthritis.
      CRP↑ CRP levels + correlated with KL grades
      • Mao Y
      • Xu W
      • Xie Z
      • Dong Q.
      Association of Irisin and CRP Levels with the Radiographic Severity of Knee Osteoarthritis.
      CRPCRP + associated with VAS & WOMAC
      • Georgiev T
      • Ivanova M
      • Kopchev A
      • et al.
      Cartilage oligomeric protein, matrix metalloproteinase-3, and Coll2-1 as serum biomarkers in knee osteoarthritis: a cross-sectional study.
      hs-CRP↑hsCRP with ↑ of KL grade (TKR) compared to lower KL grades (mild and moderate OA)
      • Siebuhr AS
      • Petersen KK
      • Arendt-Nielsen L
      • et al.
      Identification and characterisation of osteoarthritis patients with inflammation derived tissue turnover.
      4E-BP14E-BP1 + associated with KOOS pain
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      MMP-1MMP-1 levels ↑ in patients with Recht scores III & IV
      • Li W
      • Du C
      • Wang H
      • Zhang C.
      Increased serum ADAMTS-4 in knee osteoarthritis: a potential indicator for the diagnosis of osteoarthritis in early stages.
      YKL-40Duration of disease (years) + correlated with YKL-40 values
      • Zivanovic S
      • Rackov LP
      • Vojvodic D
      • Vucetic D.
      Human cartilage glycoprotein 39–biomarker of joint damage in knee osteoarthritis.
      MMP-3MMP-3 levels ↑ in patients with Recht scores III & IV
      • Li W
      • Du C
      • Wang H
      • Zhang C.
      Increased serum ADAMTS-4 in knee osteoarthritis: a potential indicator for the diagnosis of osteoarthritis in early stages.
      AdiponectinAdiponectin levels were + associated with VAS & WOMAC scores
      • Coskun NC
      • AY S
      • Evcik FD
      • Oztuna D
      Adiponectin is it a biomarker for assessing the disease severity in knee osteoarthritis patients?.
      DKK-1↑ DKK1 correlated with ↑ KL grade
      • Min S
      • Wang C
      • Lu W
      • et al.
      Serum levels of the bone turnover markers dickkopf-1, osteoprotegerin, and TNF-alpha in knee osteoarthritis patients.
      BMP-2↑BMP-2 + correlated with WOMAC scores
      • Liu Y
      • Hou R
      • Yin R
      • Yin W.
      Correlation of bone morphogenetic protein-2 levels in serum and synovial fluid with disease severity of knee osteoarthritis.
      DKK-1↑ Dkk-1 levels correlated with ↑KL grade
      • Theologis T
      • Efstathopoulos N
      • Nikolaou V
      • et al.
      Association between serum and synovial fluid Dickkopf-1 levels with radiographic severity in primary knee osteoarthritis patients.
      CGRPCGRP + associated with total WOMAC & subscales
      • Dong T
      • Chang H
      • Zhang F
      • et al.
      Calcitonin gene-related peptide can be selected as a predictive biomarker on progression and prognosis of knee osteoarthritis.
      ADAMTS-4ADAMTs-4 levels ↑ with Recht scores I and II, compared to III or IV & controls.
      • Li W
      • Du C
      • Wang H
      • Zhang C.
      Increased serum ADAMTS-4 in knee osteoarthritis: a potential indicator for the diagnosis of osteoarthritis in early stages.
      CSF-1CSF + associated with KOOS pain
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      ADAMTS-5ADAMTS-5 levels ↑ in patients with Recht scores III & IV
      • Li W
      • Du C
      • Wang H
      • Zhang C.
      Increased serum ADAMTS-4 in knee osteoarthritis: a potential indicator for the diagnosis of osteoarthritis in early stages.
      FGF-21FGF-21 + associated with KOOS pain
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      AdiponectinAdiponectin levels were + associated with KL grades
      • Coskun NC
      • AY S
      • Evcik FD
      • Oztuna D
      Adiponectin is it a biomarker for assessing the disease severity in knee osteoarthritis patients?.
      Resistin+ association with WOMAC scores
      • Alissa EM
      • Alzughaibi LS
      • Marzouki ZM.
      Relationship between serum resistin, body fat and inflammatory markers in females with clinical knee osteoarthritis.
      APOH↑ with KL IV
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      BMP-2↑BMP-2 + correlated with ↑KL grades
      • Liu Y
      • Hou R
      • Yin R
      • Yin W.
      Correlation of bone morphogenetic protein-2 levels in serum and synovial fluid with disease severity of knee osteoarthritis.
      C1M↑C1M with ↑ of KL grade (TKR) compared to moderate and severe grades.
      • Siebuhr AS
      • Petersen KK
      • Arendt-Nielsen L
      • et al.
      Identification and characterisation of osteoarthritis patients with inflammation derived tissue turnover.
      C2M↑C2M with ↑ of KL grade (TKR) compared to moderate and severe grades.
      • Siebuhr AS
      • Petersen KK
      • Arendt-Nielsen L
      • et al.
      Identification and characterisation of osteoarthritis patients with inflammation derived tissue turnover.
      CFAD↑with KL II and KL IV
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      CGRPCGRP + associated with KL grades
      • Dong T
      • Chang H
      • Zhang F
      • et al.
      Calcitonin gene-related peptide can be selected as a predictive biomarker on progression and prognosis of knee osteoarthritis.
      CO3↑ with KL IV
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      CO4A↑with KL IV
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      CO6↑ in KL II &IV
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      CO8A↑ with KL II
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      CO9↑ with KL IV
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      CRPM↑CRPM with ↑ of KL grade (TKR) compared to moderate KL grades.
      • Siebuhr AS
      • Petersen KK
      • Arendt-Nielsen L
      • et al.
      Identification and characterisation of osteoarthritis patients with inflammation derived tissue turnover.
      CSF-1CSF-1 was ↑ in OA versus healthy controls
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      F13B↑ with KL IV
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      FETUB↑ with KL IV
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      FGF-21FGF-21 was ↑ in OA versus healthy controls
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      HGFA↑with KL IV
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      HIF-1a↑HIF-1a associated with KL grade >4
      • Chu H
      • Xu ZM
      • Yu H
      • Zhu KJ
      • Huang H.
      Association between hypoxia-inducible factor-1a levels in serum and synovial fluid with the radiographic severity of knee osteoarthritis.
      IL-6IL-6 was ↑ in OA versus healthy controls
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      LAP TGF-B1LAP TGF-B1 was ↑ in OA versus healthy controls
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      LG3BP↑ with KL II
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      LUM↑ with KL IV
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      MCP-3MCP-3 was ↑ in OA versus healthy controls
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      PTNPTN levels ↑ in OA patients graded Ahlback II to III.
      • Kaspiris A
      • Mikelis C
      • Heroult M
      • et al.
      Expression of the growth factor pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta in the serum, cartilage and subchondral bone of patients with osteoarthritis.
      PZP↑with KL IV
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      RET4↑with KL II, KL IV
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      RPTPB/ZRPTPB/Z levels ↑ in OA patients with Ahlback III.
      • Kaspiris A
      • Mikelis C
      • Heroult M
      • et al.
      Expression of the growth factor pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta in the serum, cartilage and subchondral bone of patients with osteoarthritis.
      TETN↑ with KL IV
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      TNF-sR1↑TNF-sR1 weakly associated with worse Altman scores
      • Penninx B
      • Abbas H
      • Ambrosius W
      • et al.
      Inflammatory markers and physical function among older adults with knee osteoarthritis.
      TNF-sR2↑TNF-sR2 weakly associated with worse Altman scores
      • Penninx B
      • Abbas H
      • Ambrosius W
      • et al.
      Inflammatory markers and physical function among older adults with knee osteoarthritis.
      TNF-α↑ TNF-alpha level with ↑ KL grade
      • Gundogdu G
      • Gundogdu K.
      A novel biomarker in patients with knee osteoarthritis: adropin.
      TSP1↑ with KL IV
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      VWF↑ with KL II, KL IV
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      BiomarkerNegative Association to Radiographical AssessmentRefBiomarkerNegative Association to Clinical AssessmentRef
      4E-BP14E- BP1 was ↓ in OA versus healthy controls
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      COMP↓ in COMP levels after glucosamine treatment
      • Petersen SG
      • Saxne T
      • Heinegard D
      • et al.
      Glucosamine but not ibuprofen alters cartilage turnover in osteoarthritis patients in response to physical training.
      A2MG↓in KL II and KL IV
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      IL-6IL-6 (-) associated with KOOS pain
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      ACTB↓ in KL II and KL IV
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      Fetuin-A↓fetuin-A (-) correlated with WOMAC scores
      • Xiao J
      • Wang XR
      • Hu KZ
      • et al.
      Serum fetuin-A levels are inversely associated with clinical severity in patients with primary knee osteoarthritis.
      Adropin↓ adropin level with ↑ KL grade
      • Gundogdu G
      • Gundogdu K.
      A novel biomarker in patients with knee osteoarthritis: adropin.
      TWEAKTWEAK (-) associated with KOOS pain
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      APOB↓ in KL II and KL IV
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      TGF-B1TGF-B1 (-) associated with KL scores
      • Chua Jr, SD
      • Messier SP
      • Legault C
      • et al.
      Effect of an exercise and dietary intervention on serum biomarkers in overweight and obese adults with osteoarthritis of the knee.
      APOM↓in KL IV
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      AXIN-1AXIN-1 was ↓ in OA versus healthy controls
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      C1S↓in KL II
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      CASP-8CASP-8 was ↓ in OA versus healthy controls
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      DNERDNER was ↓ in OA versus healthy controls
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      DOPO↓ in KL II
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      EN-RAGEEN-RAGE was ↓ in OA versus healthy controls
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      Fetuin-A↓fetuin-A (-) correlated with KL grades
      • Xiao J
      • Wang XR
      • Hu KZ
      • et al.
      Serum fetuin-A levels are inversely associated with clinical severity in patients with primary knee osteoarthritis.
      Irisin↓ irisin levels (-) correlated with KL grades
      • Mao Y
      • Xu W
      • Xie Z
      • Dong Q.
      Association of Irisin and CRP Levels with the Radiographic Severity of Knee Osteoarthritis.
      LAMP↓ in KL II
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      PHLD↓ in KL II
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      PIICP↓ PIICP levels in KL grade <1 compared with >2 grade
      • Azukizawa M
      • Ito H
      • Hamamoto Y
      • et al.
      The Effects of Well-Rounded Exercise Program on Systemic Biomarkers Related to Cartilage Metabolism.
      SCFSCF was ↓ in OA versus healthy controls
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      SIRT2SIRT2 was ↓ in OA versus healthy controls
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      STAMBPSTAMBP was ↓ in OA versus healthy controls
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      TWEAKTWEAK was ↓ in OA versus healthy controls
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      uPAuPA was ↓ in OA versus healthy controls
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      YKL-40(-) correlation between YKL-40 levels and cartilage thickness on medial femoral condyle
      • Zivanovic S
      • Rackov LP
      • Vojvodic D
      • Vucetic D.
      Human cartilage glycoprotein 39–biomarker of joint damage in knee osteoarthritis.
      BiomarkerNo Association with Radiographical AssessmentRef
      COMPNo association
      • Chua Jr, SD
      • Messier SP
      • Legault C
      • et al.
      Effect of an exercise and dietary intervention on serum biomarkers in overweight and obese adults with osteoarthritis of the knee.
      COMPNo differences reported
      • Fernandez-Puente P
      • Mateos J
      • Fernandez-Costa C
      • et al.
      Identification of a panel of novel serum osteoarthritis biomarkers.
      COMPNot evaluated
      • Petersen SG
      • Saxne T
      • Heinegard D
      • et al.
      Glucosamine but not ibuprofen alters cartilage turnover in osteoarthritis patients in response to physical training.
      COMPNo differences reported
      • Das Gupta E
      • Ng WR
      • Wong SF
      • Bhurhanudeen AK
      • Yeap SS
      Correlation of serum cartilage oligomeric matrix protein (COMP) and interleukin-16 (IL-16) levels with disease severity in primary knee osteoarthritis: A pilot study in a Malaysian population.
      CRPNo association
      • Coskun NC
      • AY S
      • Evcik FD
      • Oztuna D
      Adiponectin is it a biomarker for assessing the disease severity in knee osteoarthritis patients?.
      CRPNo association
      • Georgiev T
      • Ivanova M
      • Kopchev A
      • et al.
      Cartilage oligomeric protein, matrix metalloproteinase-3, and Coll2-1 as serum biomarkers in knee osteoarthritis: a cross-sectional study.
      CRPNo association
      • Penninx B
      • Abbas H
      • Ambrosius W
      • et al.
      Inflammatory markers and physical function among older adults with knee osteoarthritis.
      hs-CRPNo association
      • Alissa EM
      • Alzughaibi LS
      • Marzouki ZM.
      Relationship between serum resistin, body fat and inflammatory markers in females with clinical knee osteoarthritis.
      IL-16No differences reported
      • Das Gupta E
      • Ng WR
      • Wong SF
      • Bhurhanudeen AK
      • Yeap SS
      Correlation of serum cartilage oligomeric matrix protein (COMP) and interleukin-16 (IL-16) levels with disease severity in primary knee osteoarthritis: A pilot study in a Malaysian population.
      IL-1sRNo association
      • Penninx B
      • Abbas H
      • Ambrosius W
      • et al.
      Inflammatory markers and physical function among older adults with knee osteoarthritis.
      IL-6No association
      • Kaneko S
      • Satoh T
      • Chiba J
      • et al.
      Interleukin-6 and interleukin-8 levels in serum and synovial fluid of patients with osteoarthritis.
      IL-6No association
      • Penninx B
      • Abbas H
      • Ambrosius W
      • et al.
      Inflammatory markers and physical function among older adults with knee osteoarthritis.
      IL-6sRNo association
      • Penninx B
      • Abbas H
      • Ambrosius W
      • et al.
      Inflammatory markers and physical function among older adults with knee osteoarthritis.
      IL-8No association
      • Kaneko S
      • Satoh T
      • Chiba J
      • et al.
      Interleukin-6 and interleukin-8 levels in serum and synovial fluid of patients with osteoarthritis.
      TNF-αNo association
      • Min S
      • Wang C
      • Lu W
      • et al.
      Serum levels of the bone turnover markers dickkopf-1, osteoprotegerin, and TNF-alpha in knee osteoarthritis patients.
      TNF-αNo association
      • Penninx B
      • Abbas H
      • Ambrosius W
      • et al.
      Inflammatory markers and physical function among older adults with knee osteoarthritis.
      AgKSNo association
      • Chua Jr, SD
      • Messier SP
      • Legault C
      • et al.
      Effect of an exercise and dietary intervention on serum biomarkers in overweight and obese adults with osteoarthritis of the knee.
      B2MNo association
      • Melikoglu MA
      • Yildirim K
      • Senel K.
      Relationship between radiographic grading of osteoarthritis and serum beta-2 microglobulin.
      C1,2CNo differences reported
      • Hunter DJ
      • Li J
      • LaValley M
      • et al.
      Cartilage markers and their association with cartilage loss on magnetic resonance imaging in knee osteoarthritis: the Boston Osteoarthritis Knee Study.
      C2CNo differences reported
      • Hunter DJ
      • Li J
      • LaValley M
      • et al.
      Cartilage markers and their association with cartilage loss on magnetic resonance imaging in knee osteoarthritis: the Boston Osteoarthritis Knee Study.
      C3MNo differences reported
      • Siebuhr AS
      • Petersen KK
      • Arendt-Nielsen L
      • et al.
      Identification and characterisation of osteoarthritis patients with inflammation derived tissue turnover.
      CCL2No association
      • Li L
      • Jiang B.
      Serum and synovial fluid chemokine ligand 2/monocyte chemoattractant protein 1 concentrations correlates with symptomatic severity in patients with knee osteoarthritis.
      CCL20No differences reported
      • Guan J
      • Li Y
      • Ding LB
      • et al.
      Relationship between serum and synovial fluid CCL20 concentrations with disease severity in primary knee osteoarthritis.
      Coll 2-1No association
      • Georgiev T
      • Ivanova M
      • Kopchev A
      • et al.
      Cartilage oligomeric protein, matrix metalloproteinase-3, and Coll2-1 as serum biomarkers in knee osteoarthritis: a cross-sectional study.
      CPIIINo differences reported
      • Hunter DJ
      • Li J
      • LaValley M
      • et al.
      Cartilage markers and their association with cartilage loss on magnetic resonance imaging in knee osteoarthritis: the Boston Osteoarthritis Knee Study.
      CS846No differences reported
      • Hunter DJ
      • Li J
      • LaValley M
      • et al.
      Cartilage markers and their association with cartilage loss on magnetic resonance imaging in knee osteoarthritis: the Boston Osteoarthritis Knee Study.
      MMP-3No association
      • Georgiev T
      • Ivanova M
      • Kopchev A
      • et al.
      Cartilage oligomeric protein, matrix metalloproteinase-3, and Coll2-1 as serum biomarkers in knee osteoarthritis: a cross-sectional study.
      OPGNo association
      • Min S
      • Wang C
      • Lu W
      • et al.
      Serum levels of the bone turnover markers dickkopf-1, osteoprotegerin, and TNF-alpha in knee osteoarthritis patients.
      ResistinNo association
      • Alissa EM
      • Alzughaibi LS
      • Marzouki ZM.
      Relationship between serum resistin, body fat and inflammatory markers in females with clinical knee osteoarthritis.
      SclerostinNo differences reported
      • Theologis T
      • Efstathopoulos N
      • Nikolaou V
      • et al.
      Association between serum and synovial fluid Dickkopf-1 levels with radiographic severity in primary knee osteoarthritis patients.
      Abbreviations: Biomarker abbreviations see Key in Supplementary Material; Ref, Reference

      Investigative biomarkers

      A total of 11 unique biomarkers reported across 6 articles were classified as investigative biomarkers (Table 2). A single study evaluated the diurnal variation of two biomarkers, PIIANP and HELIXII, in response to physical activity and food intake. Two studies evaluated the influence of running on cartilage serum biomarkers in healthy populations. Firner et al
      • Firner S
      • Willwacher S
      • de Marees M
      • et al.
      Effect of increased mechanical knee joint loading during running on the serum concentration of cartilage oligomeric matrix protein (COMP).
      evaluated a 30-minute running bout on serum COMP levels finding high inter-individual variability in serum COMP levels after running bouts. Henrotin et al
      • Henrotin Y
      • Labasse A
      • Franck T
      • et al.
      Collagen catabolism through Coll2-1 and Coll2-1NO2 and myeloperoxidase activity in marathon runners.
      evaluated the influence of marathon running on cartilage degradation markers Coll 2-1, Coll2-1NO2 and MPO and found that serum levels of Coll 2-1 and Coll 2-1NO2 were decreased after the marathon indicating reduced cartilage catabolism. The remaining studies evaluated atropine, TNF-alpha and Fib 3-1 and Fib 3-2 as potential biomarkers to identify OA. These studies did not have further sufficient information included within the manuscript to warrant the classification under additional BIPEDs criteria.
      Table. 2Investigative Biomarkers
      BiomarkerReference (Article Number)Patient populationResults
      COMP
      • Firner S
      • Willwacher S
      • de Marees M
      • et al.
      Effect of increased mechanical knee joint loading during running on the serum concentration of cartilage oligomeric matrix protein (COMP).
      Healthy runners (n=20)COMP levels increased immediately after a 30-minute bout of running using both passive and active knee orthoses. The active knee orthoses increased the external knee flexion moments using a pneumatically driven device built into the brace. Using active orthoses caused individuals to adopt greater joint flexion strategies during movement, increasing areas of cartilage unaccustomed to load.
      CCL20
      • Guan J
      • Li Y
      • Ding LB
      • et al.
      Relationship between serum and synovial fluid CCL20 concentrations with disease severity in primary knee osteoarthritis.
      OA population (n=99)Serum levels of CCL20 were not indicative of those with OA compared to healthy controls. No correlation between serum levels of CCL20 and synovial fluid levels.
      Adropin
      • Gundogdu G
      • Gundogdu K.
      A novel biomarker in patients with knee osteoarthritis: adropin.
      OA populationAdropin level significantly decreased as KL grade/severity increased. Adropin level was negatively correlated with TNF-alpha
      TNF-alpha
      TNF-alpha level increased as KL grade/severity increased.
      Coll2-1
      • Henrotin Y
      • Labasse A
      • Franck T
      • et al.
      Collagen catabolism through Coll2-1 and Coll2-1NO2 and myeloperoxidase activity in marathon runners.
      HealthyAfter completion of a marathon, levels of Coll2-1 and Coll2-1NO2 concentrations were slightly, but systemically decreased, indicating intensive running could reduce cartilage metabolism. Conversely, MPO concentrations increased 2-3-fold after marathon.
      Coll2-1NO2
      MPO
      Fib3-1
      • Henrotin Y
      • Gharbi M
      • Mazzucchelli G
      • et al.
      Fibulin 3 peptides Fib3-1 and Fib3-2 are potential biomarkers of osteoarthritis.
      OA populationLevels of serum Fib3-1 and Fib3-2 were elevated in patients with OA compared with healthy controls.
      Fib3-2
      PIIANP
      • Quintana DJ
      • Garnero P
      • Huebner JL
      • Charni-Ben Tabassi N
      • Kraus VB
      PIIANP and HELIXII diurnal variation.
      OA populationPIIANP and HELIXII mean concentrations increased from prior to rising from bed and one hour after rising.
      HELIXII

      Prognostic biomarkers

      A total of 39 unique biomarkers reported across 28 studies were classified under prognosis, for a total of 83 analyses on prognostic serum biomarkers. Eighteen prognostic biomarkers demonstrated a significant relationship with markers of OA progression during the study period duration (Table 3). Twenty-seven biomarkers across various studies (Table 3) reported no prognostic ability to identify individuals at higher risk of OA development.
      Table. 3Prognostic Biomarkers
      Studies with 5-10 year follow up
      BiomarkerRefPatient populationResults
      Aggrecan
      • Blumenfeld O
      • Williams FM
      • Hart DJ
      • et al.
      Association between cartilage and bone biomarkers and incidence of radiographic knee osteoarthritis (RKOA) in UK females: a prospective study.
      865 patients with no diagnosis of OAAggrecan at baseline were found inversely associated with JSN in medial compartment after 10 years
      Aggrecan ARGS
      • Struglics A
      • Larsson S
      • Kumahashi N
      • Frobell R
      • Lohmander LS.
      Changes in Cytokines and Aggrecan ARGS Neoepitope in Synovial Fluid and Serum and in C-Terminal Crosslinking Telopeptide of Type II Collagen and N-Terminal Crosslinking Telopeptide of Type I Collagen in Urine Over Five Years After Anterior Cruciate Ligament Rupture: An Exploratory Analysis in the Knee Anterior Cruciate Ligament, Nonsurgical Versus Surgical Treatment Trial.
      121 patients after acute ACL injuryAggrecan ARGS levels shortly after ACL injury were ↑ 1.4-fold compared to control levels.
      C2C
      • Kumahashi N
      • Sward P
      • Larsson S
      • et al.
      Type II collagen C2C epitope in human synovial fluid and serum after knee injury–associations with molecular and structural markers of injury.
      71 knee injury patientsNo differences reported
      cIAP
      • Blumenfeld O
      • Williams FM
      • Hart DJ
      • et al.
      Association between cartilage and bone biomarkers and incidence of radiographic knee osteoarthritis (RKOA) in UK females: a prospective study.
      865 patients with no diagnosis of OANo differences reported
      COMP
      • Golightly YM
      • Marshall SW
      • Kraus VB
      • et al.
      Biomarkers of incident radiographic knee osteoarthritis: do they vary by chronic knee symptoms?.
      353 individuals without baseline osteophyte formation, 446 knees without JSN↑ COMP levels ↑ risk of osteophyte formation and joint space narrowing (JSN)
      COMP
      • Sharif M
      • Kirwan JR
      • Elson CJ
      • Granell R
      • Clarke S.
      Suggestion of nonlinear or phasic progression of knee osteoarthritis based on measurements of serum cartilage oligomeric matrix protein levels over five years.
      115 patients with knee OACOMP at baseline was ↑in progressors compared to the non-progressors. COMP levels ↑ after TKR; more so in the progressors.
      COMP
      • Kumm J
      • Tamm A
      • Lintrop M
      • Tamm A.
      The value of cartilage biomarkers in progressive knee osteoarthritis: cross-sectional and 6-year follow-up study in middle-aged subjects.
      129 with knee complaintsFor every unit ↑ in COMP level, there was 33 % ↑ risk for tibiofemoral osteophyte progression.
      COMP
      • Erhart-Hledik JC
      • Favre J
      • Asay JL
      • et al.
      A relationship between mechanically-induced changes in serum cartilage oligomeric matrix protein (COMP) and changes in cartilage thickness after 5 years.
      17 individuals with medial knee OAΔs in COMP occurring at 3.5 and 5.5 hours after activity correlated with Δs in cartilage thickness in medial femur and tibia at 5-year f/u. Baseline pre activity COMP levels nor changes post exercise were correlated with thickness changes.
      COMP
      • Kluzek S
      • Bay-Jensen AC
      • Judge A
      • et al.
      Serum cartilage oligomeric matrix protein and development of radiographic and painful knee osteoarthritis. A community-based cohort of middle-aged women.
      593 women with no knee OA↑ COMP was associated with ↑ risk of RKOA with odds ratio of 1.97 (95% CI: 1.33–2.91) over 20 years.
      COMP
      • Streich NA
      • Zimmermann D
      • Schmitt H
      • Bode G.
      Biochemical markers in the diagnosis of chondral defects following anterior cruciate ligament insufficiency.
      38 patients with previous ACL injuryCOMP levels within normal limits. No differences reported
      COMP
      • Blumenfeld O
      • Williams FM
      • Hart DJ
      • et al.
      Association between cartilage and bone biomarkers and incidence of radiographic knee osteoarthritis (RKOA) in UK females: a prospective study.
      865 patients with no diagnosis of OA↑COMP at baseline predicted ↑risk of K/L 2 appearance after 10 years
      HA
      • Golightly YM
      • Marshall SW
      • Kraus VB
      • et al.
      Biomarkers of incident radiographic knee osteoarthritis: do they vary by chronic knee symptoms?.
      353 individuals without baseline osteophyte formation, 446 knees without JSN↑ levels of HA ↑knee JSN risk
      hs-CRP
      • Golightly YM
      • Marshall SW
      • Kraus VB
      • et al.
      Biomarkers of incident radiographic knee osteoarthritis: do they vary by chronic knee symptoms?.
      353 individuals without baseline osteophyte formation, 446 knees without JSNBaseline hsCRP levels did not predict knee outcomes
      IFNgamma
      • Struglics A
      • Larsson S
      • Kumahashi N
      • Frobell R
      • Lohmander LS.
      Changes in Cytokines and Aggrecan ARGS Neoepitope in Synovial Fluid and Serum and in C-Terminal Crosslinking Telopeptide of Type II Collagen and N-Terminal Crosslinking Telopeptide of Type I Collagen in Urine Over Five Years After Anterior Cruciate Ligament Rupture: An Exploratory Analysis in the Knee Anterior Cruciate Ligament, Nonsurgical Versus Surgical Treatment Trial.
      121 patients after acute ACL injuryNo differences reported
      IFNgamma
      • Roemer FW
      • Englund M
      • Turkiewicz A
      • et al.
      Molecular and Structural Biomarkers of Inflammation at Two Years After Acute Anterior Cruciate Ligament Injury Do Not Predict Structural Knee Osteoarthritis at Five Years.
      113 patients after ACL injuryNo predictive value
      IL-10
      • Roemer FW
      • Englund M
      • Turkiewicz A
      • et al.
      Molecular and Structural Biomarkers of Inflammation at Two Years After Acute Anterior Cruciate Ligament Injury Do Not Predict Structural Knee Osteoarthritis at Five Years.
      113 patients after ACL injuryNo predictive value
      IL-10
      • Struglics A
      • Larsson S
      • Kumahashi N
      • Frobell R
      • Lohmander LS.
      Changes in Cytokines and Aggrecan ARGS Neoepitope in Synovial Fluid and Serum and in C-Terminal Crosslinking Telopeptide of Type II Collagen and N-Terminal Crosslinking Telopeptide of Type I Collagen in Urine Over Five Years After Anterior Cruciate Ligament Rupture: An Exploratory Analysis in the Knee Anterior Cruciate Ligament, Nonsurgical Versus Surgical Treatment Trial.
      121 patients after acute ACL injuryNo differences reported
      IL-12p70
      • Roemer FW
      • Englund M
      • Turkiewicz A
      • et al.
      Molecular and Structural Biomarkers of Inflammation at Two Years After Acute Anterior Cruciate Ligament Injury Do Not Predict Structural Knee Osteoarthritis at Five Years.
      113 patients after ACL injuryNo predictive value
      IL-12p70
      • Struglics A
      • Larsson S
      • Kumahashi N
      • Frobell R
      • Lohmander LS.
      Changes in Cytokines and Aggrecan ARGS Neoepitope in Synovial Fluid and Serum and in C-Terminal Crosslinking Telopeptide of Type II Collagen and N-Terminal Crosslinking Telopeptide of Type I Collagen in Urine Over Five Years After Anterior Cruciate Ligament Rupture: An Exploratory Analysis in the Knee Anterior Cruciate Ligament, Nonsurgical Versus Surgical Treatment Trial.
      121 patients after acute ACL injuryNo differences reported
      IL-1B
      • Roemer FW
      • Englund M
      • Turkiewicz A
      • et al.
      Molecular and Structural Biomarkers of Inflammation at Two Years After Acute Anterior Cruciate Ligament Injury Do Not Predict Structural Knee Osteoarthritis at Five Years.
      113 patients after ACL injuryNo predictive value
      IL-1B
      • Struglics A
      • Larsson S
      • Kumahashi N
      • Frobell R
      • Lohmander LS.
      Changes in Cytokines and Aggrecan ARGS Neoepitope in Synovial Fluid and Serum and in C-Terminal Crosslinking Telopeptide of Type II Collagen and N-Terminal Crosslinking Telopeptide of Type I Collagen in Urine Over Five Years After Anterior Cruciate Ligament Rupture: An Exploratory Analysis in the Knee Anterior Cruciate Ligament, Nonsurgical Versus Surgical Treatment Trial.
      121 patients after acute ACL injuryNo differences reported
      IL-6
      • Roemer FW
      • Englund M
      • Turkiewicz A
      • et al.
      Molecular and Structural Biomarkers of Inflammation at Two Years After Acute Anterior Cruciate Ligament Injury Do Not Predict Structural Knee Osteoarthritis at Five Years.
      113 patients after ACL injuryNo predictive value
      IL-6
      • Struglics A
      • Larsson S
      • Kumahashi N
      • Frobell R
      • Lohmander LS.
      Changes in Cytokines and Aggrecan ARGS Neoepitope in Synovial Fluid and Serum and in C-Terminal Crosslinking Telopeptide of Type II Collagen and N-Terminal Crosslinking Telopeptide of Type I Collagen in Urine Over Five Years After Anterior Cruciate Ligament Rupture: An Exploratory Analysis in the Knee Anterior Cruciate Ligament, Nonsurgical Versus Surgical Treatment Trial.
      121 patients after acute ACL injuryNo differences reported
      IL-8
      • Roemer FW
      • Englund M
      • Turkiewicz A
      • et al.
      Molecular and Structural Biomarkers of Inflammation at Two Years After Acute Anterior Cruciate Ligament Injury Do Not Predict Structural Knee Osteoarthritis at Five Years.
      113 patients after ACL injuryNo predictive value
      IL-8
      • Struglics A
      • Larsson S
      • Kumahashi N
      • Frobell R
      • Lohmander LS.
      Changes in Cytokines and Aggrecan ARGS Neoepitope in Synovial Fluid and Serum and in C-Terminal Crosslinking Telopeptide of Type II Collagen and N-Terminal Crosslinking Telopeptide of Type I Collagen in Urine Over Five Years After Anterior Cruciate Ligament Rupture: An Exploratory Analysis in the Knee Anterior Cruciate Ligament, Nonsurgical Versus Surgical Treatment Trial.
      121 patients after acute ACL injuryNo differences reported
      KS
      • Golightly YM
      • Marshall SW
      • Kraus VB
      • et al.
      Biomarkers of incident radiographic knee osteoarthritis: do they vary by chronic knee symptoms?.
      353 individuals without baseline osteophyte formation, 446 knees without JSNBaseline KS levels did not predict knee outcomes
      NTx
      • Blumenfeld O
      • Williams FM
      • Hart DJ
      • et al.
      Association between cartilage and bone biomarkers and incidence of radiographic knee osteoarthritis (RKOA) in UK females: a prospective study.
      865 patients with no diagnosis of OANo differences reported
      PIIANP
      • Kumm J
      • Tamm A
      • Lintrop M
      • Tamm A.
      The value of cartilage biomarkers in progressive knee osteoarthritis: cross-sectional and 6-year follow-up study in middle-aged subjects.
      129 with knee complaintsNo differences reported
      TNF
      • Roemer FW
      • Englund M
      • Turkiewicz A
      • et al.
      Molecular and Structural Biomarkers of Inflammation at Two Years After Acute Anterior Cruciate Ligament Injury Do Not Predict Structural Knee Osteoarthritis at Five Years.
      113 patients after ACL injuryNo predictive value
      TNF
      • Struglics A
      • Larsson S
      • Kumahashi N
      • Frobell R
      • Lohmander LS.
      Changes in Cytokines and Aggrecan ARGS Neoepitope in Synovial Fluid and Serum and in C-Terminal Crosslinking Telopeptide of Type II Collagen and N-Terminal Crosslinking Telopeptide of Type I Collagen in Urine Over Five Years After Anterior Cruciate Ligament Rupture: An Exploratory Analysis in the Knee Anterior Cruciate Ligament, Nonsurgical Versus Surgical Treatment Trial.
      121 patients after acute ACL injuryNo differences reported
      Studies with 1-4 year follow up
      C1,2C
      • Hunter DJ
      • Li J
      • LaValley M
      • et al.
      Cartilage markers and their association with cartilage loss on magnetic resonance imaging in knee osteoarthritis: the Boston Osteoarthritis Knee Study.
      137 individuals with symptomatic knee OANo differences reported
      C2C
      • Hunter DJ
      • Li J
      • LaValley M
      • et al.
      Cartilage markers and their association with cartilage loss on magnetic resonance imaging in knee osteoarthritis: the Boston Osteoarthritis Knee Study.
      137 individuals with symptomatic knee OANo differences reported
      C2C
      • Boeth H
      • MacMahon A
      • Poole AR
      • et al.
      Differences in biomarkers of cartilage matrix turnover and their changes over 2 years in adolescent and adult volleyball athletes.
      18 adolescents & 19 adult volleyball players (healthy)No differences reported
      CILP-2
      • Boeth H
      • MacMahon A
      • Poole AR
      • et al.
      Differences in biomarkers of cartilage matrix turnover and their changes over 2 years in adolescent and adult volleyball athletes.
      18 adolescents & 19 adult volleyball players (healthy)↑ of CILP-2 in adults
      Clusterin
      • Fukuda I
      • Takeshi I
      • Ohmachi S
      • et al.
      Potential plasma biomarkers for progression of knee osteoarthritis using glycoproteomic analysis coupled with a 2D-LC-MALDI system.
      68 individuals with knee OANo differences reported
      COMP
      • Hunter DJ
      • Li J
      • LaValley M
      • et al.
      Cartilage markers and their association with cartilage loss on magnetic resonance imaging in knee osteoarthritis: the Boston Osteoarthritis Knee Study.
      137 individuals with symptomatic knee OA1 unit ↑in COMP, ↑ odds of cartilage loss by 6.09 times.
      COMP
      • Hunter DJ
      • Li J
      • LaValley M
      • et al.
      Cartilage markers and their association with cartilage loss on magnetic resonance imaging in knee osteoarthritis: the Boston Osteoarthritis Knee Study.
      137 individuals with symptomatic knee OANo differences reported
      COMP
      • Bruyere O
      • Collette J
      • Ethgen O
      • et al.
      Biochemical markers of bone and cartilage remodeling in prediction of longterm progression of knee osteoarthritis.
      212 patients with knee OANo associations reported
      COMP
      • Vilim V
      • Olejarova M
      • Machacek S
      • et al.
      Serum levels of cartilage oligomeric matrix protein (COMP) correlate with radiographic progression of knee osteoarthritis.
      48 patients with symptomatic knee OAThe change in JSW over 3 years was + associated with COMP level at baseline & study end.
      COMP
      • Eckstein F
      • Le Graverand MP
      • Charles HC
      • et al.
      Clinical, radiographic, molecular and MRI-based predictors of cartilage loss in knee osteoarthritis.
      75 individuals with knee OA, 77 healthy controlsNo differences reported
      COMP
      • Eckstein F
      • Le Graverand MP
      • Charles HC
      • et al.
      Clinical, radiographic, molecular and MRI-based predictors of cartilage loss in knee osteoarthritis.
      75 individuals with knee OA, 77 healthy controlsOA patients had ↓CPII markers,
      COMP
      • Boeth H
      • MacMahon A
      • Poole AR
      • et al.
      Differences in biomarkers of cartilage matrix turnover and their changes over 2 years in adolescent and adult volleyball athletes.
      18 adolescents & 19 adult volleyball players (healthy)COMP changes were associated with SF 36 physical component scores in adults
      COMP
      • Pavelka K
      • Forejtova S
      • Olejarova M
      • et al.
      Hyaluronic acid levels may have predictive value for the progression of knee osteoarthritis.
      89 individuals with knee OA, 20 healthy↑COMP in KOA compared with controls
      COMP
      • Boeth H
      • MacMahon A
      • Poole AR
      • et al.
      Differences in biomarkers of cartilage matrix turnover and their changes over 2 years in adolescent and adult volleyball athletes.
      18 adolescents & 19 adult volleyball players (healthy)↓of CPII in adolescents; CPII changes associated with IKDC scores in adolescents.
      COMP
      • Sowers MF
      • Karvonen-Gutierrez CA
      • Yosef M
      • et al.
      Longitudinal changes of serum COMP and urinary CTX-II predict X-ray defined knee osteoarthritis severity and stiffness in women.
      72 women with OA↑levels of COMP were associated with ↑OA severity and body size.
      CS846
      • Hunter DJ
      • Li J
      • LaValley M
      • et al.
      Cartilage markers and their association with cartilage loss on magnetic resonance imaging in knee osteoarthritis: the Boston Osteoarthritis Knee Study.
      137 individuals with symptomatic knee OANo differences reported
      DPD
      • Bruyere O
      • Collette J
      • Ethgen O
      • et al.
      Biochemical markers of bone and cartilage remodeling in prediction of longterm progression of knee osteoarthritis.
      212 patients with knee OANo associations reported
      HA
      • Bruyere O
      • Collette J
      • Ethgen O
      • et al.
      Biochemical markers of bone and cartilage remodeling in prediction of longterm progression of knee osteoarthritis.
      212 patients with knee OA↓in HA levels over one year were associated with 3-year progression in JSW in patients with OA
      HA
      • Pavelka K
      • Forejtova S
      • Olejarova M
      • et al.
      Hyaluronic acid levels may have predictive value for the progression of knee osteoarthritis.
      89 individuals with knee OA, 20 healthy↑ HA had faster radiological progression
      Hemopexin
      • Fukuda I
      • Takeshi I
      • Ohmachi S
      • et al.
      Potential plasma biomarkers for progression of knee osteoarthritis using glycoproteomic analysis coupled with a 2D-LC-MALDI system.
      68 individuals with knee OANo differences reported
      KS
      • Bruyere O
      • Collette J
      • Ethgen O
      • et al.
      Biochemical markers of bone and cartilage remodeling in prediction of longterm progression of knee osteoarthritis.
      212 patients with knee OANo associations reported
      MMP-9
      • Pavelka K
      • Forejtova S
      • Olejarova M
      • et al.
      Hyaluronic acid levels may have predictive value for the progression of knee osteoarthritis.
      89 individuals with knee OA, 20 healthy↑MMP-9 in KOA compared with controls
      OC
      • Bruyere O
      • Collette J
      • Ethgen O
      • et al.
      Biochemical markers of bone and cartilage remodeling in prediction of longterm progression of knee osteoarthritis.
      212 patients with knee OA↑in OC levels over one year were associated with 3-year progression in JSW in patients with OA
      pentosidine
      • Pavelka K
      • Forejtova S
      • Olejarova M
      • et al.
      Hyaluronic acid levels may have predictive value for the progression of knee osteoarthritis.
      89 individuals with knee OA, 20 healthy↑ pentosidine in KOA compared with controls; ↑ pentosidine had faster radiological progression
      PIIANP
      • Garnero P
      • Ayral X
      • Rousseau JC
      • et al.
      Uncoupling of type II collagen synthesis and degradation predicts progression of joint damage in patients with knee osteoarthritis.
      75 patients with medial knee OAOA patients had ↓PIIANP
      PIIINP
      • Eckstein F
      • Le Graverand MP
      • Charles HC
      • et al.
      Clinical, radiographic, molecular and MRI-based predictors of cartilage loss in knee osteoarthritis.
      75 individuals with knee OA, 77 healthyOA patients had ↑ PIIINP levels.
      PINP
      • Eckstein F
      • Le Graverand MP
      • Charles HC
      • et al.
      Clinical, radiographic, molecular and MRI-based predictors of cartilage loss in knee osteoarthritis.
      75 individuals with knee OA, 77 healthyNo differences reported
      PYD
      • Bruyere O
      • Collette J
      • Ethgen O
      • et al.
      Biochemical markers of bone and cartilage remodeling in prediction of longterm progression of knee osteoarthritis.
      212 patients with knee OANo associations reported
      TIMP
      • Pavelka K
      • Forejtova S
      • Olejarova M
      • et al.
      Hyaluronic acid levels may have predictive value for the progression of knee osteoarthritis.
      89 individuals with knee OA, 20 healthy↑ TIMP in KOA compared with controls
      YKL-40
      • Pavelka K
      • Forejtova S
      • Olejarova M
      • et al.
      Hyaluronic acid levels may have predictive value for the progression of knee osteoarthritis.
      89 individuals with knee OA, 20 healthyNo differences reported
      Studies with under 1 year follow up
      C2C
      • Pietrosimone B
      • Loeser RF
      • Blackburn JT
      • et al.
      Biochemical markers of cartilage metabolism are associated with walking biomechanics 6-months following anterior cruciate ligament reconstruction.
      18 ACL reconstruction patients↓vGRF limb symmetry associated with ↑C2C:CPII after ACL injury (not significant accounting for walking speed)
      COMP
      • Hoch JM
      • Mattacola CG
      • Bush HM
      • et al.
      Longitudinal documentation of serum cartilage oligomeric matrix protein and patient-reported outcomes in collegiate soccer athletes over the course of an athletic season.
      29 soccer athletes↑ in COMP were seen at T2 and T3 compared with T1 (non-significant). COMP↑ athletes reported an increased level of function.
      COMP
      • Pietrosimone B
      • Loeser RF
      • Blackburn JT
      • et al.
      Biochemical markers of cartilage metabolism are associated with walking biomechanics 6-months following anterior cruciate ligament reconstruction.
      18 ACL reconstruction patients↓vGRF limb symmetry associated with ↑C2C:CPII after ACL injury (not significant accounting for walking speed)
      COMP
      • Celik O
      • Salci Y
      • Ak E
      • Kalaci A
      • Korkusuz F.
      Serum cartilage oligomeric matrix protein accumulation decreases significantly after 12 weeks of running but not swimming and cycling training - a randomised controlled trial.
      44 healthy malesPre-test showed that 30 min of walking ↑COMP levels in all groups. The post-tests revealed ↑ COMP level of all groups, except running, after a 30-min walking activity.
      COMP
      • Hunt M
      • Pollock C
      • Kraus V
      • et al.
      Relationships amongst osteoarthritis biomarkers, dynamic knee joint load, and exercise: results from a randomized controlled pilot study.
      17 individuals with medial knee OACOMP changes were greater in exercise group compared to controls. Control group had slight ↑in COMP where those in exercise group ↓
      COMP
      • Hunt M
      • Pollock C
      • Kraus V
      • et al.
      Relationships amongst osteoarthritis biomarkers, dynamic knee joint load, and exercise: results from a randomized controlled pilot study.
      17 individuals with medial knee OANo differences reported
      CTX-I
      • Eckstein F
      • Le Graverand MP
      • Charles HC
      • et al.
      Clinical, radiographic, molecular and MRI-based predictors of cartilage loss in knee osteoarthritis.
      75 individuals with knee OA, 77 healthy↓ levels of CTXI but not statistically significant
      HA
      • Hunt M
      • Pollock C
      • Kraus V
      • et al.
      Relationships amongst osteoarthritis biomarkers, dynamic knee joint load, and exercise: results from a randomized controlled pilot study.
      17 individuals with medial knee OANo differences reported
      IL-6
      • Pietrosimone B
      • Loeser RF
      • Blackburn JT
      • et al.
      Biochemical markers of cartilage metabolism are associated with walking biomechanics 6-months following anterior cruciate ligament reconstruction.
      18 ACL reconstruction patients↓IL-6 associated with lesser KAM
      MMP-3
      • Pietrosimone B
      • Loeser RF
      • Blackburn JT
      • et al.
      Biochemical markers of cartilage metabolism are associated with walking biomechanics 6-months following anterior cruciate ligament reconstruction.
      18 ACL reconstruction patients↑ MMP-3 levels associated with less KAM limb symmetry
      Studies with under 8 week follow up
      COMP
      • Bobacz K
      • Maier R
      • Fialka C
      • et al.
      Is pro-matrix metalloproteinase-3 a marker for posttraumatic cartilage degradation?.
      259 patients after knee injuryNo differences reported.
      C2C
      • Rego-Perez I
      • Fernandez-Moreno M
      • Deberg M
      • et al.
      Mitochondrial DNA haplogroups modulate the serum levels of biomarkers in patients with osteoarthritis.
      73 patients with OA, 77 healthy controls↑ C2C and C2C/CPII in the healthy controls.
      COMP
      • Herger S
      • Vach W
      • Liphardt AM
      • et al.
      Dose-response relationship between ambulatory load magnitude and load-induced changes in COMP in young healthy adults.
      24 healthy individualsLoad induced ↑ in COMP ↑ with load magnitude. Mean COMP ↑immediately after walking stress test.
      COMP
      • Rego-Perez I
      • Fernandez-Moreno M
      • Deberg M
      • et al.
      Mitochondrial DNA haplogroups modulate the serum levels of biomarkers in patients with osteoarthritis.
      73 patients with OA, 77 healthy controls↑ C2C and C2C/CPII in the healthy controls
      Fibulin-3
      • Atef Nassif M.
      Fibulin-3 serum and urine levels in the diagnosis and severity assessment of primary knee osteoarthritis.
      50 females with knee OA, 25 healthyFibulin-3 levels were ↑ in patients with OA compared to healthy controls.
      HA
      • Criscione LG
      • Elliott AL
      • Stabler T
      • et al.
      Variation of serum hyaluronan with activity in individuals with knee osteoarthritis.
      20 individuals with knee OAHA ↑from T0 to T1.
      HA
      • Rego-Perez I
      • Fernandez-Moreno M
      • Deberg M
      • et al.
      Mitochondrial DNA haplogroups modulate the serum levels of biomarkers in patients with osteoarthritis.
      73 patients with OA, 77 healthy controls↑HA in OA patients
      CRP
      • Bobacz K
      • Maier R
      • Fialka C
      • et al.
      Is pro-matrix metalloproteinase-3 a marker for posttraumatic cartilage degradation?.
      259 patients after knee injuryNo differences reported.
      MMP-3
      • Bobacz K
      • Maier R
      • Fialka C
      • et al.
      Is pro-matrix metalloproteinase-3 a marker for posttraumatic cartilage degradation?.
      259 patients after knee injuryproMMP3 correlated to MMP3 levels.
      ProMMP-3
      • Bobacz K
      • Maier R
      • Fialka C
      • et al.
      Is pro-matrix metalloproteinase-3 a marker for posttraumatic cartilage degradation?.
      259 patients after knee injuryProMMP3 levels ↑ compared to controls. ProMMP3 ↑ early after trauma. proMMP3 correlated to MMP3 levels.
      TIMP1
      • Bobacz K
      • Maier R
      • Fialka C
      • et al.
      Is pro-matrix metalloproteinase-3 a marker for posttraumatic cartilage degradation?.
      259 patients after knee injuryNo differences reported.
      TIMP2
      • Bobacz K
      • Maier R
      • Fialka C
      • et al.
      Is pro-matrix metalloproteinase-3 a marker for posttraumatic cartilage degradation?.
      259 patients after knee injuryNo differences reported.
      YKL-40
      • Rego-Perez I
      • Fernandez-Moreno M
      • Deberg M
      • et al.
      Mitochondrial DNA haplogroups modulate the serum levels of biomarkers in patients with osteoarthritis.
      73 patients with OA, 77 healthy controlsNo differences reported
      In populations with existing knee pain or OA diagnoses, increased levels of COMP occurred following an increase in activity level and duration of activity
      • Celik O
      • Salci Y
      • Ak E
      • Kalaci A
      • Korkusuz F.
      Serum cartilage oligomeric matrix protein accumulation decreases significantly after 12 weeks of running but not swimming and cycling training - a randomised controlled trial.
      ,
      • Erhart-Hledik JC
      • Favre J
      • Asay JL
      • et al.
      A relationship between mechanically-induced changes in serum cartilage oligomeric matrix protein (COMP) and changes in cartilage thickness after 5 years.
      ,
      • Hunt M
      • Pollock C
      • Kraus V
      • et al.
      Relationships amongst osteoarthritis biomarkers, dynamic knee joint load, and exercise: results from a randomized controlled pilot study.
      as well as increased risk of joint space narrowing, cartilage loss and radiographic knee OA.
      • Blumenfeld O
      • Williams FM
      • Hart DJ
      • et al.
      Association between cartilage and bone biomarkers and incidence of radiographic knee osteoarthritis (RKOA) in UK females: a prospective study.
      ,
      • Erhart-Hledik JC
      • Favre J
      • Asay JL
      • et al.
      A relationship between mechanically-induced changes in serum cartilage oligomeric matrix protein (COMP) and changes in cartilage thickness after 5 years.
      ,
      • Golightly YM
      • Marshall SW
      • Kraus VB
      • et al.
      Biomarkers of incident radiographic knee osteoarthritis: do they vary by chronic knee symptoms?.
      ,
      • Hunter DJ
      • Li J
      • LaValley M
      • et al.
      Cartilage markers and their association with cartilage loss on magnetic resonance imaging in knee osteoarthritis: the Boston Osteoarthritis Knee Study.
      ,
      • Kluzek S
      • Bay-Jensen AC
      • Judge A
      • et al.
      Serum cartilage oligomeric matrix protein and development of radiographic and painful knee osteoarthritis. A community-based cohort of middle-aged women.
      ,
      • Kumm J
      • Tamm A
      • Lintrop M
      • Tamm A.
      The value of cartilage biomarkers in progressive knee osteoarthritis: cross-sectional and 6-year follow-up study in middle-aged subjects.
      ,
      • Pavelka K
      • Forejtova S
      • Olejarova M
      • et al.
      Hyaluronic acid levels may have predictive value for the progression of knee osteoarthritis.
      ,
      • Sharif M
      • Kirwan JR
      • Elson CJ
      • Granell R
      • Clarke S.
      Suggestion of nonlinear or phasic progression of knee osteoarthritis based on measurements of serum cartilage oligomeric matrix protein levels over five years.
      ,
      • Sowers MF
      • Karvonen-Gutierrez CA
      • Yosef M
      • et al.
      Longitudinal changes of serum COMP and urinary CTX-II predict X-ray defined knee osteoarthritis severity and stiffness in women.
      ,
      • Vilim V
      • Olejarova M
      • Machacek S
      • et al.
      Serum levels of cartilage oligomeric matrix protein (COMP) correlate with radiographic progression of knee osteoarthritis.
      Four studies
      • Criscione LG
      • Elliott AL
      • Stabler T
      • et al.
      Variation of serum hyaluronan with activity in individuals with knee osteoarthritis.
      ,
      • Golightly YM
      • Marshall SW
      • Kraus VB
      • et al.
      Biomarkers of incident radiographic knee osteoarthritis: do they vary by chronic knee symptoms?.
      ,
      • Pavelka K
      • Forejtova S
      • Olejarova M
      • et al.
      Hyaluronic acid levels may have predictive value for the progression of knee osteoarthritis.
      ,
      • Rego-Perez I
      • Fernandez-Moreno M
      • Deberg M
      • et al.
      Mitochondrial DNA haplogroups modulate the serum levels of biomarkers in patients with osteoarthritis.
      demonstrated that increased levels of hyaluronic acid were associated with increased radiological progression and joint space narrowing risk; a single study demonstrated that reduction in HA levels over the course of one year was associated with a 3-year progression in joint space width narrowing in patients with OA.
      • Bruyere O
      • Collette J
      • Ethgen O
      • et al.
      Biochemical markers of bone and cartilage remodeling in prediction of longterm progression of knee osteoarthritis.
      After ACL injury, decreased IL-6107 levels and increased MMP-3107 were associated with lesser knee adduction moment symmetry and ARGS levels
      • Streich NA
      • Zimmermann D
      • Schmitt H
      • Bode G.
      Biochemical markers in the diagnosis of chondral defects following anterior cruciate ligament insufficiency.
      were increased 1.4-fold compared to healthy controls. Two studies evaluated a host of inflammatory markers including IFNy, IL-10, IL-12p70, IL-1B, IL-8 and found no predictive value in these markers over the course of 5 years.
      • Roemer FW
      • Englund M
      • Turkiewicz A
      • et al.
      Molecular and Structural Biomarkers of Inflammation at Two Years After Acute Anterior Cruciate Ligament Injury Do Not Predict Structural Knee Osteoarthritis at Five Years.
      ,
      • Streich NA
      • Zimmermann D
      • Schmitt H
      • Bode G.
      Biochemical markers in the diagnosis of chondral defects following anterior cruciate ligament insufficiency.
      No changes were found in COMP level fluctuations after ACL injury.
      • Bobacz K
      • Maier R
      • Fialka C
      • et al.
      Is pro-matrix metalloproteinase-3 a marker for posttraumatic cartilage degradation?.
      ,
      • Streich NA
      • Zimmermann D
      • Schmitt H
      • Bode G.
      Biochemical markers in the diagnosis of chondral defects following anterior cruciate ligament insufficiency.
      There were significant differences between C2C, CPII and C2C:CPII ratios in several populations. Increased C2C levels and C2C:CPII ratios were increased in heathy controls compared to those with OA
      • Rego-Perez I
      • Fernandez-Moreno M
      • Deberg M
      • et al.
      Mitochondrial DNA haplogroups modulate the serum levels of biomarkers in patients with osteoarthritis.
      and with reduced loading after ACL injury.
      • Pietrosimone B
      • Loeser RF
      • Blackburn JT
      • et al.
      Biochemical markers of cartilage metabolism are associated with walking biomechanics 6-months following anterior cruciate ligament reconstruction.
      Additionally, decreases in CPII was seen in both OA patients and healthy adolescents with no injury. In a strictly healthy population, 4 studies
      • Boeth H
      • MacMahon A
      • Poole AR
      • et al.
      Differences in biomarkers of cartilage matrix turnover and their changes over 2 years in adolescent and adult volleyball athletes.
      ,
      • Celik O
      • Salci Y
      • Ak E
      • Kalaci A
      • Korkusuz F.
      Serum cartilage oligomeric matrix protein accumulation decreases significantly after 12 weeks of running but not swimming and cycling training - a randomised controlled trial.
      ,
      • Firner S
      • Willwacher S
      • de Marees M
      • et al.
      Effect of increased mechanical knee joint loading during running on the serum concentration of cartilage oligomeric matrix protein (COMP).
      ,
      • Germaschewski FM
      • Matheny CJ
      • Larkin J
      • et al.
      Quantitation OF ARGS aggrecan fragments in synovial fluid, serum and urine from osteoarthritis patients.
      evaluating COMP concentrations demonstrated that increased levels of COMP were observed as a result of participation in physical activity, increases in activity duration and load magnitude.

      Efficacy of Intervention

      A total of 13 unique biomarkers reported across 6 studies were classified under efficacy of intervention, for a total of 18 analyses regarding the efficacy of an intervention on serum biomarker changes (Table 4). IL-6 levels were significantly reduced following an exercise protocol
      • Aguiar GC
      • Do Nascimento MR
      • De Miranda AS
      • et al.
      Effects of an exercise therapy protocol on inflammatory markers, perception of pain, and physical performance in individuals with knee osteoarthritis.
      coupled with consumption of Licofelone and Naproxen treatments.
      • Pelletier JP
      • Raynauld JP
      • Caron J
      • et al.
      Decrease in serum level of matrix metalloproteinases is predictive of the disease-modifying effect of osteoarthritis drugs assessed by quantitative MRI in patients with knee osteoarthritis.
      Individuals with higher levels of IL-6 during the drug treatment studies had a greater risk for cartilage loss.
      • Pelletier JP
      • Raynauld JP
      • Caron J
      • et al.
      Decrease in serum level of matrix metalloproteinases is predictive of the disease-modifying effect of osteoarthritis drugs assessed by quantitative MRI in patients with knee osteoarthritis.
      In the same study, increases in MMP-1 and MMP-3 were inversely predictive of cartilage volume loss. Three studies evaluated COMP fluctuations in response to exercise protocols and found various results. One study
      • Andersson ML
      • Thorstensson CA
      • Roos EM
      • et al.
      Serum levels of cartilage oligomeric matrix protein (COMP) increase temporarily after physical exercise in patients with knee osteoarthritis.
      reported no increase in COMP over a 6-week exercise program, another reported a weak but significant difference between exercise groups
      • Chua Jr, SD
      • Messier SP
      • Legault C
      • et al.
      Effect of an exercise and dietary intervention on serum biomarkers in overweight and obese adults with osteoarthritis of the knee.
      , and the third reported an increase in COMP levels in both pre-OA and OA diagnosed individuals.
      • Azukizawa M
      • Ito H
      • Hamamoto Y
      • et al.
      The Effects of Well-Rounded Exercise Program on Systemic Biomarkers Related to Cartilage Metabolism.
      Participation in a weight loss protocol demonstrated reductions in COMP levels in obese patients with radiographic knee OA.
      • Bartels EM
      • Christensen R
      • Christensen P
      • et al.
      Effect of a 16 weeks weight loss program on osteoarthritis biomarkers in obese patients with knee osteoarthritis: a prospective cohort study.
      Further a single weight loss study
      • Chua Jr, SD
      • Messier SP
      • Legault C
      • et al.
      Effect of an exercise and dietary intervention on serum biomarkers in overweight and obese adults with osteoarthritis of the knee.
      demonstrated that HA and TGF-B1 were positively and negatively correlated with K-L scores, respectively. AgKS levels also decreased in interventions groups across the study period.
      • Chua Jr, SD
      • Messier SP
      • Legault C
      • et al.
      Effect of an exercise and dietary intervention on serum biomarkers in overweight and obese adults with osteoarthritis of the knee.
      Table. 4Efficacy of Intervention Biomarkers
      BiomarkerReferenceType of treatmentResults
      COMP
      • Andersson ML
      • Thorstensson CA
      • Roos EM
      • et al.
      Serum levels of cartilage oligomeric matrix protein (COMP) increase temporarily after physical exercise in patients with knee osteoarthritis.
      Exercise protocolNo sig differences in COMP before intervention. COMP levels increased after 60 minutes of exercise and decreased in group after 60 minutes of rest. In 2nd study, COMP increased immediately after exercise and decreased to baseline after 30 minutes. Overall, no increase in COMP after 6-week exercise program.
      COMP
      • Azukizawa M
      • Ito H
      • Hamamoto Y
      • et al.
      The Effects of Well-Rounded Exercise Program on Systemic Biomarkers Related to Cartilage Metabolism.
      Exercise protocolCOMP levels increased in both pre-OA and OA groups. KL group >2 had higher levels than those with KL scores <1
      COMP
      • Bartels EM
      • Christensen R
      • Christensen P
      • et al.
      Effect of a 16 weeks weight loss program on osteoarthritis biomarkers in obese patients with knee osteoarthritis: a prospective cohort study.
      Weight lossCOMP concentration decreased on average 1.1 u/L with a correlation to weight loss. Rapid weight loss in obese KOA patients associated (weakly) with reduction in COMP.
      COMP
      • Chua Jr, SD
      • Messier SP
      • Legault C
      • et al.
      Effect of an exercise and dietary intervention on serum biomarkers in overweight and obese adults with osteoarthritis of the knee.
      Exercise protocol and weight lossWeak but significant differences between intervention groups were present for mean levels of COMP
      COMP
      • Pelletier JP
      • Raynauld JP
      • Caron J
      • et al.
      Decrease in serum level of matrix metalloproteinases is predictive of the disease-modifying effect of osteoarthritis drugs assessed by quantitative MRI in patients with knee osteoarthritis.
      Licofelone (200 mg twice daily) versus naproxen (500 mg twice daily).Over time an increase occurred in COMP levels. Baseline levels of COMP were a predictor of lateral compartment loss. Higher baseline values of COMP are predictive of greater risk of cartilage loss in OA
      IL-6
      • Aguiar GC
      • Do Nascimento MR
      • De Miranda AS
      • et al.
      Effects of an exercise therapy protocol on inflammatory markers, perception of pain, and physical performance in individuals with knee osteoarthritis.
      Exercise protocolThere was significant reduction in serum levels of IL-6.
      IL-6
      • Pelletier JP
      • Raynauld JP
      • Caron J
      • et al.
      Decrease in serum level of matrix metalloproteinases is predictive of the disease-modifying effect of osteoarthritis drugs assessed by quantitative MRI in patients with knee osteoarthritis.
      Licofelone (200 mg twice daily) versus naproxen (500 mg twice daily).IL-6 levels decreased over the study period. Baseline levels of IL-6 showed relationship with cartilage volume loss. Higher levels of Il-6 were predictive of greater risk for cartilage loss.
      TNF-alpha
      • Aguiar GC
      • Do Nascimento MR
      • De Miranda AS
      • et al.
      Effects of an exercise therapy protocol on inflammatory markers, perception of pain, and physical performance in individuals with knee osteoarthritis.
      Exercise protocolA decrease in the perception of pain was evident on VAS (p < 0.001) and pain sub- scale of the WOMAC. No significant changes in the levels of the TNF-α and its soluble receptor. Physical function subscale score and the WOMAC global score improved.
      TNFR1
      • Aguiar GC
      • Do Nascimento MR
      • De Miranda AS
      • et al.
      Effects of an exercise therapy protocol on inflammatory markers, perception of pain, and physical performance in individuals with knee osteoarthritis.
      Exercise protocolA decrease in the perception of pain was evident on VAS (p < 0.001) and pain sub- scale of the WOMAC. No significant changes in the levels of the TNF-α and its soluble receptor. Physical function subscale score and the WOMAC global score improved.
      TNFR2
      • Aguiar GC
      • Do Nascimento MR
      • De Miranda AS
      • et al.
      Effects of an exercise therapy protocol on inflammatory markers, perception of pain, and physical performance in individuals with knee osteoarthritis.
      Exercise protocolA decrease in the perception of pain was evident on VAS (p < 0.001) and pain sub- scale of the WOMAC. No significant changes in the levels of the TNF-α and its soluble receptor. Physical function subscale score and the WOMAC global score improved.
      MMP-1
      • Pelletier JP
      • Raynauld JP
      • Caron J
      • et al.
      Decrease in serum level of matrix metalloproteinases is predictive of the disease-modifying effect of osteoarthritis drugs assessed by quantitative MRI in patients with knee osteoarthritis.
      Licofelone (200 mg twice daily) versus naproxen (500 mg twice daily).Over time there was an increase in MMP-1. Increase in MMP1 was significantly less in the licofelone group. Baseline MMP 1 level was significantly but inversely predictive of cartilage volume loss.
      MMP-3
      • Pelletier JP
      • Raynauld JP
      • Caron J
      • et al.
      Decrease in serum level of matrix metalloproteinases is predictive of the disease-modifying effect of osteoarthritis drugs assessed by quantitative MRI in patients with knee osteoarthritis.
      Licofelone (200 mg twice daily) versus naproxen (500 mg twice daily).Over time there was an increase in MMP-3. Increase in MMP3 was significantly less in the licofelone group.
      PIICP
      • Azukizawa M
      • Ito H
      • Hamamoto Y
      • et al.
      The Effects of Well-Rounded Exercise Program on Systemic Biomarkers Related to Cartilage Metabolism.
      Exercise protocolPre-OA (x-ray determination) showed significant increase in PIICP (cartilage synthesis) with improved physical performance. Knee OA severity <1 demonstrated lower PIICP levels compared with >2 group.
      HA
      • Chua Jr, SD
      • Messier SP
      • Legault C
      • et al.
      Effect of an exercise and dietary intervention on serum biomarkers in overweight and obese adults with osteoarthritis of the knee.
      Weight lossHA levels were found to be negatively correlated with medial joint space width and positively correlated with Kellgren- Lawrence scores (K-L scores).
      CRP
      • Pelletier JP
      • Raynauld JP
      • Caron J
      • et al.
      Decrease in serum level of matrix metalloproteinases is predictive of the disease-modifying effect of osteoarthritis drugs assessed by quantitative MRI in patients with knee osteoarthritis.
      Licofelone (200 mg twice daily) versus naproxen (500 mg twice daily).Baseline CRP levels were associated with worsening WOMAC scores. Higher baseline CRP levels were predictive of greater risk for cartilage loss.
      CTX-I
      • Pelletier JP
      • Raynauld JP
      • Caron J
      • et al.
      Decrease in serum level of matrix metalloproteinases is predictive of the disease-modifying effect of osteoarthritis drugs assessed by quantitative MRI in patients with knee osteoarthritis.
      Licofelone (200 mg twice daily) versus naproxen (500 mg twice daily).Baseline levels of CTX1 were associated with an increase in the size of bone marrow lesion in the medial compartment
      AgKS
      • Chua Jr, SD
      • Messier SP
      • Legault C
      • et al.
      Effect of an exercise and dietary intervention on serum biomarkers in overweight and obese adults with osteoarthritis of the knee.
      Weight lossAgKS levels averaged over all intervention groups decreased study period.
      TGF-B1
      • Chua Jr, SD
      • Messier SP
      • Legault C
      • et al.
      Effect of an exercise and dietary intervention on serum biomarkers in overweight and obese adults with osteoarthritis of the knee.
      Weight lossTGF-β1 levels negatively correlated with K-L scores. When biomarker levels measured at 6 and 18-months were adjusted for baseline values, age, gender, and body mass index (BMI), weak but significant differences between intervention groups were present for mean levels of TGF-β1.

      Diagnostic

      A total of 109 unique biomarkers were reported across 70 studies and classified as diagnostic biomarkers. This totaled 238 analyses on serum biomarkers used for diagnostic purposes across multiple populations. Seventy of these biomarkers demonstrated concentration levels that were significantly different in OA patients compared to control populations. In OA patients, COMP levels were increased significantly compared to healthy controls in 9 studies
      • El-Arman MM
      • El-Fayoumi G
      • El-Shal E
      • El-Boghdady I
      • El-Ghaweet A.
      Aggrecan and cartilage oligomeric matrix protein in serum and synovial fluid of patients with knee osteoarthritis.
      ,
      • Fernandes FA
      • Pucinelli ML
      • da Silva NP
      • Feldman D.
      Serum cartilage oligomeric matrix protein (COMP) levels in knee osteoarthritis in a Brazilian population: clinical and radiological correlation.
      ,
      • Garnero P
      • Piperno M
      • Gineyts E
      • et al.
      Cross sectional evaluation of biochemical markers of bone, cartilage, and synovial tissue metabolism in patients with knee osteoarthritis: relations with disease activity and joint damage.
      ,
      • Georgiev T
      • Ivanova M
      • Kopchev A
      • et al.
      Cartilage oligomeric protein, matrix metalloproteinase-3, and Coll2-1 as serum biomarkers in knee osteoarthritis: a cross-sectional study.
      ,
      • Herger S
      • Vach W
      • Liphardt AM
      • et al.
      Dose-response relationship between ambulatory load magnitude and load-induced changes in COMP in young healthy adults.
      ,
      • Kumm J
      • Tamm A
      • Lintrop M
      • Tamm A.
      The value of cartilage biomarkers in progressive knee osteoarthritis: cross-sectional and 6-year follow-up study in middle-aged subjects.
      ,
      • Mundermann A
      • King KB
      • Smith RL
      • Andriacchi TP.
      Change in serum COMP concentration due to ambulatory load is not related to knee OA status.
      ,
      • Sowers MF
      • Karvonen-Gutierrez CA
      • Yosef M
      • et al.
      Longitudinal changes of serum COMP and urinary CTX-II predict X-ray defined knee osteoarthritis severity and stiffness in women.
      ,
      • Verma P
      • Dalal K.
      Serum cartilage oligomeric matrix protein (COMP) in knee osteoarthritis: a novel diagnostic and prognostic biomarker.
      , increased levels of HA (concentration range, 25.0 − 304.0 ng/mL) were observed in patients with higher K-L grades compared to healthy controls
      • Catterall JB
      • Stabler TV
      • Flannery CR
      • Kraus VB.
      Changes in serum and synovial fluid biomarkers after acute injury (NCT00332254).
      ,
      • Sasaki E
      • Tsuda E
      • Yamamoto Y
      • et al.
      Serum hyaluronic acid concentration predicts the progression of joint space narrowing in normal knees and established knee osteoarthritis - a five-year prospective cohort study.
      ,
      • Turan Y
      • Bal S
      • Gurgan A
      • Topac H
      • Koseoglu M.
      Serum hyaluronan levels in patients with knee osteoarthritis.
      ,
      • Wakitani S
      • Nawata M
      • Kawaguchi A
      • et al.
      Serum keratan sulfate is a promising marker of early articular cartilage breakdown.
      and levels of inflammatory markers (IL-17A, 1L-21, IFN-gamma, IL-6) were significantly increased in patients with OA compared to healthy controls.
      • de Seny D
      • Sharif M
      • Fillet M
      • et al.
      Discovery and biochemical characterisation of four novel biomarkers for osteoarthritis.
      ,
      • Giordano R
      • Petersen KK
      • Andersen HH
      • Simonsen O
      • Arendt-Nielsen L.
      Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.
      Furthermore, higher levels of CRP (concentration range, 1.22, 53.01 mg/L) were observed in patients with knee OA compared with control populations.
      • Mao Y
      • Xu W
      • Xie Z
      • Dong Q.
      Association of Irisin and CRP Levels with the Radiographic Severity of Knee Osteoarthritis.
      ,
      • Shan Y
      • Qi C
      • Liu Y
      • et al.
      Increased frequency of peripheral blood follicular helper T cells and elevated serum IL21 levels in patients with knee osteoarthritis.
      The remaining biomarker results can be found in Table 5.
      Table 5Diagnostic Biomarkers
      BiomarkerArticleResults
      Biomarkers with Upward Trends
      COMP
      • Garnero P
      • Piperno M
      • Gineyts E
      • et al.
      Cross sectional evaluation of biochemical markers of bone, cartilage, and synovial tissue metabolism in patients with knee osteoarthritis: relations with disease activity and joint damage.
      COMP was ↑ compared to healthy controls.
      COMP
      • Georgiev T
      • Ivanova M
      • Kopchev A
      • et al.
      Cartilage oligomeric protein, matrix metalloproteinase-3, and Coll2-1 as serum biomarkers in knee osteoarthritis: a cross-sectional study.
      OA patients had ↑ COMP compared to controls. Patients with KLII/III knee OA had ↑COMP levels than KLI patients.
      COMP
      • Herger S
      • Vach W
      • Liphardt AM
      • et al.
      Dose-response relationship between ambulatory load magnitude and load-induced changes in COMP in young healthy adults.
      Load induced increases in COMP ↑ with load magnitude. COMP ↑ immediately after walking stress test.
      COMP
      • Jayabalan P
      • Gustafson J
      • Sowa GA
      • Piva SR
      • Farrokhi S.
      A Stimulus-Response Framework to Investigate the Influence of Continuous Versus Interval Walking Exercise on Select Serum Biomarkers in Knee Osteoarthritis.
      Continuous walking ↑ COMP up to 45 mins; interval walking was associated with return of COMP back to baseline at 45 mins.
      COMP
      • Kersting UG
      • Stubendorff JJ
      • Schmidt MC
      • Bruggemann GP.
      Changes in knee cartilage volume and serum COMP concentration after running exercise.
      Cartilage volume change caused by running was correlated with resting COMP levels and with relative change of COMP after run. Resting COMP levels, COMP change after run and time of co-activation of flexor/extensor muscles explain variance in volume changes.
      COMP
      • Kim HJ
      • Lee YH
      • Kim CK.
      Changes in serum cartilage oligomeric matrix protein (COMP), plasma CPK and plasma hs-CRP in relation to running distance in a marathon (42.195 km) and an ultra-marathon (200 km) race.
      COMP ↑1.6x at 10 km during a marathon race and ↓ to the pre-race level after 2 days recovery. COMP ↑ 1.9x after a 200-km race and maintained until day 3 of recovery; returning to the pre-race level on day 6
      COMP
      • Kim HJ
      • Lee YH
      • Kim CK.
      Biomarkers of muscle and cartilage damage and inflammation during a 200 km run.
      COMP ↑3x between timepoints
      COMP
      • Kumm J
      • Tamm A
      • Lintrop M
      • Tamm A.
      The value of cartilage biomarkers in progressive knee osteoarthritis: cross-sectional and 6-year follow-up study in middle-aged subjects.
      For every unit ↑ in COMP level, there was 33 % ↑ risk for tibiofemoral osteophyte progression.
      COMP
      • Mateer JL
      • Hoch JM
      • Mattacola CG
      • Butterfield TA
      • Lattermann C.
      Serum Cartilage Oligomeric Matrix Protein Levels in Collegiate Soccer Athletes over the Duration of an Athletic Season: A Pilot Study.
      No significant differences between baseline and practice or postseason COMP levels. A qualitative analysis indicated ↑ COMP levels occurred when minutes of activity ↑ across season.
      COMP
      • Mundermann A
      • King KB
      • Smith RL
      • Andriacchi TP.
      Change in serum COMP concentration due to ambulatory load is not related to knee OA status.
      COMP ↑ immediately after the walking exercise. Difference in ↑ after exercise did not differ between groups.
      COMP
      • Mundermann A
      • Klenk C
      • Billich C
      • et al.
      Changes in Cartilage Biomarker Levels During a Transcontinental Multistage Footrace Over 4486 km.
      COMP Δ significantly throughout ultramarathon. Concentrations ↑ during the first measurement interval for COMP.
      COMP
      • Mundermann A
      • Geurts J
      • Hugle T
      • et al.
      Marathon performance but not BMI affects post-marathon pro-inflammatory and cartilage biomarkers.
      COMP ↑ 39% during the marathon race and remained elevated 24 h after the marathon race. Differences in marathon finishing time explained 28% of variability in Δs in COMP during the 24 h recovery after the marathon race.
      COMP
      • Mundermann A
      • Dyrby CO
      • Andriacchi TP
      • King KB.
      Serum concentration of cartilage oligomeric matrix protein (COMP) is sensitive to physiological cyclic loading in healthy adults.
      After exercise protocol, ↑ in COMP occurred immediately after walking. Second ↑in COMP occurred 5.5 hours after walking. In resting protocol, baseline COMP was ↑ compared to all other timepoints. COMP ↓ from 3.5 hour to 5.5 hour after rest.
      COMP
      • Neidhart M
      • Hauser N
      • Paulsson M
      • et al.
      Small fragments of cartilage oligomeric matrix protein in synovial fluid and serum as markers for cartilage degradation.
      COMP levels in runners were ↑ compared with controls. COMP levels were ↑ than upper normal limits and were found in 7 and 5 of the 8 runners. ↑ levels of COMP were similar to those found in joint injury or osteoarthritis. COMP ↑ during the run and returned to baseline w/in 24 hours.
      COMP
      • Niehoff A
      • Muller M
      • Bruggemann L
      • et al.
      Deformational behaviour of knee cartilage and changes in serum cartilage oligomeric matrix protein (COMP) after running and drop landing.
      COMP levels ↑ immediately after the running and landing activity.
      COMP
      • Niehoff A
      • Kersting UG
      • Helling S
      • et al.
      Different mechanical loading protocols influence serum cartilage oligomeric matrix protein levels in young healthy humans.
      COMP ↑ was detected immediately after 30 minutes running exercise. No changes to COMP with deep knee bends. Lymphatic drainage also had no effect on COMP. After 30 minutes of rest COMP level↓
      COMP
      • Palmieri-Smith RM
      • Wojtys EM
      • Potter HG.
      Early Cartilage Changes After Anterior Cruciate Ligament Injury: Evaluation With Imaging and Serum Biomarkers-A Pilot Study.
      Circulating COMP levels were greater in ACL patients compared with the control subjects.
      COMP
      • Shin KA
      • Kim AC
      • Kim YJ
      • et al.
      Effect of Ultra-marathon (308 km) Race on Bone Metabolism and Cartilage Damage Biomarkers.
      COMP was ↑ by 194% over duration of marathon.
      COMP
      • Wakitani S
      • Nawata M
      • Kawaguchi A
      • et al.
      Serum keratan sulfate is a promising marker of early articular cartilage breakdown.
      COMP in recent knee trauma group tended to be ↑ compared with old knee trauma group. COMP levels in healthy subjects ↓ compared with KL grades 0-IV
      COMP
      • El-Arman MM
      • El-Fayoumi G
      • El-Shal E
      • El-Boghdady I
      • El-Ghaweet A.
      Aggrecan and cartilage oligomeric matrix protein in serum and synovial fluid of patients with knee osteoarthritis.
      COMP levels in OA patients were↑ compared to controls.
      COMP
      • Jordan JM
      • Luta G
      • Stabler T
      • et al.
      Ethnic and sex differences in serum levels of cartilage oligomeric matrix protein: the Johnston County Osteoarthritis Project.
      COMP was ↑ in African American women compared to Caucasian women. COMP was ↑ in Caucasian men compared to Caucasian women. No differences in COMP between African American men and women.
      COMP
      • Senolt L
      • Braun M
      • Olejarova M
      • et al.
      Increased pentosidine, an advanced glycation end product, in serum and synovial fluid from patients with knee osteoarthritis and its relation with cartilage oligomeric matrix protein.
      COMP levels were ↑ in patients with OA compared with controls.
      COMP
      • Fernandes FA
      • Pucinelli ML
      • da Silva NP
      • Feldman D.
      Serum cartilage oligomeric matrix protein (COMP) levels in knee osteoarthritis in a Brazilian population: clinical and radiological correlation.
      COMP levels were ↑ in patients with OA compared to healthy controls and to those with non-symptomatic narrowing of the articular space. Patients with clinical evidence of KOA and without radiological abnormalities (K/L grade 0 or 1) had intermediate serum COMP levels, higher than those in healthy.
      COMP
      • Verma P
      • Dalal K.
      Serum cartilage oligomeric matrix protein (COMP) in knee osteoarthritis: a novel diagnostic and prognostic biomarker.
      COMP level was ↑ in OA group compared with controls.
      CPII
      • Cattano NM
      • Driban JB
      • Barbe MF
      • et al.
      Physical activity levels and quality of life relate to collagen turnover and inflammation changes after running.
      ↓tegner activity levels were related to ↑ CTX-II/CPII ratio changes after the run . ↓
      CPII
      • Svoboda SJ
      • Owens BD
      • Harvey TM
      • et al.
      The Association Between Serum Biomarkers of Collagen Turnover and Subsequent Anterior Cruciate Ligament Rupture.
      ↑ CPII levels at baseline were associated with odds ratios of 4.41 for sustaining ACL injury
      CPII
      • Tourville TW
      • Jarrell KM
      • Naud S
      • et al.
      Relationship between isokinetic strength and tibiofemoral joint space width changes after anterior cruciate ligament reconstruction.
      ACL-injured patients with an abnormal tibiofemoral JSW had diminished quality of life, increased pain, and increased type II collagen uCTX-II/sCPII ratios compared with healthy controls
      CPII
      • Cibere J
      • Zhang H
      • Garnero P
      • et al.
      Association of biomarkers with pre-radiographically defined and radiographically defined knee osteoarthritis in a population-based study.
      ↑ CPII reduced the risk of ROA versus no OA.
      CPII
      • Ishijima M
      • Watari T
      • Naito K
      • et al.
      Relationships between biomarkers of cartilage, bone, synovial metabolism and knee pain provide insights into the origins of pain in early knee osteoarthritis.
      CPII ↓ with onset of OA (KL 2 versus KL 1), regardless of joint pain. CPII ↑in patients with KL grades 1 and 2 with knee pain. In grade 1 patients both C2C and CPII ↑in those with knee pain.
      C2C
      • Svoboda SJ
      • Owens BD
      • Harvey TM
      • et al.
      The Association Between Serum Biomarkers of Collagen Turnover and Subsequent Anterior Cruciate Ligament Rupture.
      ↑ C2C levels at baseline were associated with odds ratios of 2.05 for sustaining ACL injury
      C2C
      • Ishijima M
      • Watari T
      • Naito K
      • et al.
      Relationships between biomarkers of cartilage, bone, synovial metabolism and knee pain provide insights into the origins of pain in early knee osteoarthritis.