Table 4.
Representative Osteoarthritis Biomarkers.
| Biomarker | Process | Description | Examples of Clinical Associations |
|---|---|---|---|
| Bone | |||
| C1M | Matrix destruction | MMP mediated tissue destruction. MMP-cleaved fragment of the interhelical region of Col1 and destroyed by cathepsin K 42 | C1M are associated with pain outcomes 43 and pharmacodynamic responses to diet/exercise 44 and anti-inflammatory interventions 45 |
| CTX-I | Bone resorption | A C-terminal crosslinked and isomerized fragment of collagen type I generated by cathepsin K cleavage during osteoclast-mediated bone resorption of mature collagen | Reflects Cathepsin K and MMP mediated bone resorption 46; in FNIH OA consortium, CTX-I was associated with disease progression 47; also modified with anti-resorptive treatment in OA 48,49 |
| αCTX-I | Bone resorption | A C-terminal crosslinked fragment of Col1 generated by cathepsin K cleavage during osteoclast-mediated bone resorption of newly synthesized collagen. A measurement of young bone resorption such as woven bone in cancer 50 and subchondral remodeling on OA | Associated with subchondral bone turnover, JSN, osteophyte progression 51 and prognostic for knee OA progression in the important FNIH study 47 |
| ICTP | Matrix destruction | MMP-cleaved type I collagen generated by many cell types including osteoclasts | Associated with JSN in hip OA 52 |
| NTX-1 | Bone resorption | An N-terminal crosslinked fragment of type I collagen generated by cathepsin K during osteoclastic bone resorption | OAI-FNIH, NTX was associated with disease progression 47 |
| OPG | Osteoclast function | OPG is the natural ligand to RANK-L and is important for bone turnover in combination with RANK-L, SOST and DKK-1 | Osteoclast activity is often investigated in osteoporosis studies 53 |
| Osteocalcin | Bone formation or resorption | More bone specific than type I collagen; synthesized by osteoblasts, odontoblasts, and hypertrophic chondrocytes 54; intact protein indicative of bone formation; fragments indicative of bone resorption 46 | Associated with progression of knee OA and severity of hand OA (reviewed in 46; used in most bone pharmacology studies 55 |
| PICP | Bone formation | The C-terminal pro-peptide is enzymatically released from newly synthesized pre-pro-collagen prior to incorporation of the collagen molecule into the extracellular bone matrix. A measurement of bone and soft tissue formation | Association with progression of knee OA 56; Induction by pro-anabolic bone treatment and inhibited by anti-resorptives |
| PINP | Bone formation | The N- and C- terminal pro-peptide are trimeric, globular peptides enzymatically released from newly synthesized pre-pro-collagen prior to incorporation of the collagen molecule into the extracellular bone matrix. A measurement of bone and soft tissue formation | Prognostic and diagnostic for knee OA, especially for progressive osteophytosis 56 |
| RANK-L | Osteclast formation | RANK-L is essential for osteoclast formation | Osteoclast activity is often investigated in osteoporosis studies 53 |
| SOST/DKK-1 | Osteoblast activity | SOST and DKK1 are Wnt signaling inhibitors important for osteoblasts and bone formation | SOST and DKK-1 are often used as serological biomarkers in bone research 57 |
| TRACP | Osteoclast number | A specific enzyme for osteoclasts | Osteoclast activity is often investigated in osteoporosis studies 53, 58 |
| Cartilage | |||
| CTX-II | Cartilage degradation | MMP degraded type II collagen | CTX-II was associated with progression of OA 59, and diagnosis, and responded to therapy 60–62. CTX-II was prognostic for progression in the important FNIH study 47 |
| C1,2C | Connective tissue degradation | Collagenase mediated helical breakdown of Col2 andCcol1 | Increase in serum C1,2C was associated with cartilage thinning (5 year follow-up) 63 |
| C2C-HUSA | Cartilage degradation | MMP-mediated degradation of type II collagen | C2C concentrations were correlated with CTX-II, ARGS, osteocalcin, osteopontin and IL-8, but not structural joint injury by MRI 64. C2C-HUSA was prognostic for progression in the important FNIH study47 |
| C2M | Cartilage degradation | MMP-mediated inter-helical degradation of Col2 quantified by serum/plasma ELISA | C2M was associated with KL-2 score and levels of chronic inflammation 65 |
| Coll2-1 | Cartilage degradation | MMP-mediated inter-helical degradation of Col2 | Curcumin treatment reduced Coll2-1 serum levels, suggesting that the marker may act as a pharmacodynamic marker 66, 67; Coll2-1 is both a biomarker of OA and activates innate immunity as a disease associated molecular pattern31 |
| Coll2-NO2 | Cartilage degradation | MMP-mediated inter-helical degradation of nitrosylated Col2 | Baseline levels were negatively associated with incidence of knee OA 67, 68 |
| PIIANP | Cartilage formation | Type IIA-collagen N-terminal pro-peptide | PIIANP was associated with 2-year radiographic progression in OAI-FNIH and severity of disease 47, 69. PIIANP was prognostic for progression in the important FNIH study 47; a positive balance of collagen formation (by serum PIIANP) exceeded degradation (by urinary CTXII) from 6-24 months following knee joint distraction 70 |
| PIICP/ CPII | Cartilage formation | Type II-collagen C-terminal pro-peptide | Levels in multi-site OA patients were lower than in hip OA only 71 |
| PRO-C2 | Cartilage formation | Type IIB-collagen N-terminal pro-peptide | Serum PRO-C2 is significantly higher in controls (KL0/1) compared to OA groups (KL2/3/4 and low PRO-C2 is associated with 2-year radiographic progression in the oral calcitonin trials 72–74 |
| C10C | Hypertrophic chondrocytes | Collagen type X is expressed by hypertrophic chondrocytes | A urinary Type X collagen epitope was diagnostic for OA, associated with more severe OA and produced by hypertrophic chondrocytes 75 |
| TIINP | Cartilage degradation | Collagenase mediated helical breakdown of Col2 | uTIINE was able to distinguish between OA patients and healthy controls, and between symptomatic and asymptomatic radiographic OA patients 76 |
| COMP | Cartilage turnover | COMP (cartilage oligomeric protein) is important in the process of collagen formation | COMP is associated with incidence and progression of OA 77, 78, serum elevations are phasic and predate radiographic progression and occur with joint replacement 79 |
| ARGS | Cartilage destruction | When aggrecan is destroyed by the protease ADAMTS, this unique fragment is generated | ARGS have demonstrated pharmacodynamic potential 80, 81 and is a well-used biomarker for joint destruction in OA |
| FFGV | Cartilage destruction | When aggrecan is destroyed by MMP activity, this unique fragment is generated | FFGV in particular together with ARGS activity been used in vitro for assessment of drug mechanism of action 82, 83 |
| CS846 | Chondroitin sulfate | A side chondroitin sulfate chain of aggrecan that may reflect pathological increase in turnover of newly formed aggrecan, the most abundant proteoglycan in the cartilage | CS846 has been shown to be associated WOMAC stiffness 84 |
| HA | Hyaluronan | HA is the backbone by which aggrecan binds to in cartilage and contributes to the viscoelastic properties of synovial fluid | HA has been shown to be a predictor of disease progression 85, and prognostic for progression in the important FNIH study 47 |
| Synovium | |||
| MMP-3 | Synovial inflammation | MMP-3 is expressed by synoviocytes | MMP-3 response to inflammatory treatment, is released from synovial explants in culture 86, is elevated in joint fluid after injury 87 and predicts joint space narrowing 88 |
| C3M | Synovial inflammation | Type III collagen degraded by MMP | Respond to anti-inflammatory treatment 89 and predicts response to treatment 90 |
| C1M | Soft tissue inflammation | MMP mediated soft tissue inflammation and destruction | C1M is predictive for progression of joint destruction in RA and respond to treatment for anti-inflammatory diseases 89–91 |
| CRPM | Soft tissue inflammation | A MMP derived fragment of CRP, which is released during tissue remodeling | CRPM respond to anti-inflammatory treatment, predicts response to treatment and is associated with progression of OA 65, 77, 89 |
Information derived from the references cited in the table and from Bay-Jensen et al. 2019 92. The table describes biomarkers used in osteoporosis and osteoarthritis research, with selected examples from rheumatoid arthritis with inflammation driven biomarkers that have proven valuable in different clinical settings