Table 1

Biochemical markers analysed in the APPROACH cohort sampled from serum (S) and urine (U)

NameInter- and intra-CVDetection rangeDescription
S_C3M<15%1–85 ng/mLMatrix metalloproteinase (MMP)-mediated type III collagen degradation fragment. Type III collagen is a major collagen of connective tissues, including synovial membrane. C3M has been shown to be released from synovial membranes in the presence of proinflammatory cytokines which activate MMPs.43
S_CRPM<15%1–110 ng/mLMMP-mediated C reactive protein (CRP) degradation fragment. CRP is an acute reactant elevated in chronic inflammatory diseases. CRPM is a metabolite of CRP.44
S_ARGS<15%0.01–0.40 pmol/mLADAMTS-mediated aggrecan degradation products. Aggrecan is the major proteoglycan of articular cartilage. Like MMPs, ADAMTS are expressed and activated in the presence of proinflammatory cytokines.45
S_C10C<15%500–7500 ng/mLCathepsin K-mediated type X collagen degradation fragment. Type X collagen is a minor collagen expressed by the cartilage cells called chondrocytes.46
S_C2M<15%0–10 ng/mLMMP-mediated type II collagen degradation fragment. Type 2 collagen is the major fibrillar protein of cartilage and C2M is released on activation of MMPs.47
S_COLL2_1<15%200–2200 nMType II collagen degradation fragment similar, but from a different domain compared with C2M.48
S_COLL2_1NO2<15%150–6000 pg/mLInflammation-related (nitrated) type-II collagen degradation fragment. Nitrosylation is a post-translational modification induced by an increase in oxidative stress associated with inflammation.48
S_COMP<15%1–50 units/LCartilage oligomeric matrix protein. COMP is articular cartilage protein, which is released when cartilage is turned over.49
S_CTXI<10%0–3 ng/mLCross-linked, isomerised and cathepsin K-generated fragment of type I collagen C-terminal telopeptide. Type I collagen is the major fibrillar protein of bone and some connective tissues. Cathepsin K is mainly expressed by osteoclast, making CTX-I a marker of bone resorption.50
S_HA<15%10–800 ng/mLHyaluronic acid is a glycosaminoglycan distributed widely across connective, epithelial and neural tissues, including articular cartilage. It is released as part of tissue remodelling and turnover induced by, for example, inflammation.50
S_hsCRP<10%0–60 mg/LHigh-sensitive C reactive protein (hsCRP) is an acute reactant elevated in chronic inflammatory diseases and used as a diagnostic marker in different rheumatic diseases.51
S_PRO_C2<10%5–1000 ng/mLType IIB collagen propeptide (synthesis). When new type II collagen is expressed by cartilage cells, PRO-C2 is released and is a reflection of cartilage formation.12
S_NMID<10%1–180 ng/mLBone gamma-carboxyglutamic acid-containing protein.52
S_RE_C1M<15%10–500 ng/mLMMP-mediated type I collagen degradation. See S_C3M and S_CTX-I.53
U_CTXI_ALPHA<15%0–10 μg/mmolCathepsin K-generated fragment of type I collagen C-terminal telopeptide (corrected for creatinine) is a non-isomerised version of S_CTX-I and therefore believed to reflect degradation of young bone in contrast to the isomerised which measures old bone.54
U-CTXII<15%10–2500 ng/mmolMMP- and cathepsin K-mediated type II collagen degradation fragment (corrected for creatinine). See CTX-I and C2M as well.50
  • Coefficient of variation (CV) and detection range are shown; for further assay validation, see references.