Skip to main content
Top

01-01-2015 | Osteoarthritis | Book Chapter | Article

9. Osteoarthritis Biomarkers

Authors: Ying-Hua Li, PhD, Christopher Kim, MD, MSc, Rajiv Gandhi, MD, MSc

Publisher: Springer International Publishing

Abstract

  • Biomarkers in OA can be categorized using the BIPEDS classification: burden of disease, investigative, prognostic, efficacy of intervention, diagnostic, and safety.
  • Urine CTX-II and serum COMP seemed to have the best performance and promise of all commercially available OA biomarkers.
  • Identification and validation of panels of biomarkers correlated with imaging modalities may provide improved diagnosis, prediction, and understanding of the pathogenesis of OA.
  • Catabolic factors reflecting the degradation of cartilage joint tissue remain the most promising OA biomarkers and are awaiting validation in clinical trials.
  • Omics-based technology platforms, including DNA microarray, transcriptomics, proteomics, and metabolomics, are being increasingly applied in OA research and have identified significant amount of new potential OA biomarkers.
  • Aberrantly expressed miRNAs contribute to the pathogenesis of OA and could serve as potential therapeutic targets to treat OA, as well as diagnostic biomarkers.
  • Circulating miRNAs have emerged as a new class of minimally or noninvasive OA biomarkers due to their highly stability and ease of detection.
Literature
1.
Bijlsma JW, Berenbaum F, Lafeber FP. Osteoarthritis: an update with relevance for clinical practice. Lancet. 2011;377:2115–26.CrossRefPubMed
2.
Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, et al. Development of criteria for the classification and reporting of knee osteoarthritis. Arthritis Rheum. 1986;29(8):1039–49.CrossRefPubMed
3.
Bauer DC, Hunter DJ, Abramson SB, et al. Classification of osteoarthritis biomarkers: a proposed approach. Osteoarthritis Cartilage. 2006;14:723–7.CrossRefPubMed
4.
Atkinson AJ, Colburn WA, DeGruttola VG, Biomarkers Definitions Working Group, et al. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69:89–95.CrossRef
5.
De Gruttola VG, Clax P, DeMets DL, Downing GJ, Ellenberg SS, Friedman L, et al. Considerations in the evaluation of surrogate endpoints in clinical trials. Summary of a National Institutes of Health workshop. Control Clin Trials. 2001;22(5):485–502.CrossRefPubMed
6.
van Spil WE, Degroot J, Lems WF, et al. Serum and urinary biochemical markers for knee and hip-osteoarthritis: a systematic review applying the consensus BIPED criteria. Osteoarthritis Cartilage. 2010;18:605–12.CrossRefPubMed
7.
Kraus VB, Nevitt M, Sandell LJ. Summary of the OA biomarkers workshop 2009–biochemical biomarkers: biology, validation, and clinical studies. Osteoarthritis Cartilage. 2010;18(6):742–5.CrossRefPubMed
8.
Kraus VB, Burnett B, Coindreau J, Cottrell S, Eyre D, Gendreau M, et al. Application of biomarkers in the development of drugs intended for the treatment of osteoarthritis. OARSI FDA Osteoarthritis Biomarkers Working Group. Osteoarthritis Cartilage. 2011;19(5):515–42.PubMedCentralCrossRefPubMed
9.
Perruccio AV, Mahomed NN, Chandran V, Gandhi R. Plasma adipokine levels and their association with overall burden of painful joints among individuals with hip and knee osteoarthritis. J Rheumatol. 2014;41(2):334–7.CrossRefPubMed
10.
Laurberg TB, Frystyk J, Ellingsen T, Hansen IT, Jorgensen A, Tarp U, et al. Plasma adiponectin in patients with active, early, and chronic rheumatoid arthritis who are steroid- and disease-modifying antirheumatic drug-naive compared with patients with osteoarthritis and controls. J Rheumatol. 2009;36:1885–91.CrossRefPubMed
11.
Staikos C, Ververidis A, Drosos G, Manolopoulos VG, Verettas DA, Tavridou A. The association of adipokine levels in plasma and synovial fluid with the severity of knee osteoarthritis. Rheumatology. 2013;52:1077–83.CrossRefPubMed
12.
Ding C, Parameswaran V, Cicuttini F, Burgess J, Zhai G, Quinn S, et al. Association between leptin, body composition, sex and knee cartilage morphology in older adults: the Tasmanian older adult cohort (TASOAC) study. Ann Rheum Dis. 2008;67:1256–61.CrossRefPubMed
13.
Stannus OP, Jones G, Quinn SJ, Cicuttini FM, Dore D, Ding C. The association between leptin, interleukin-6, and hip radiographic osteoarthritis in older people: a cross-sectional study. Arthritis Res Ther. 2010;12:R95.PubMedCentralCrossRefPubMed
14.
Pearle AD, Scanzello CR, George S, Mandl LA, DiCarlo EF, Peterson M, et al. Elevated high-sensitivity C-reactive protein levels are associated with local inflammatory findings in patients with osteoarthritis. Osteoarthritis Cartilage. 2007;15:516–23.CrossRefPubMed
15.
Spector TD, Hart DJ, Nandra D, et al. Low-level increases in serum C-reactive protein are present in early osteoarthritis of the knee and predict progressive disease. Arthritis Rheum. 1997;40:723–7.CrossRefPubMed
16.
Sharif M, Shepstone L, Elson CJ, et al. Increased serum C reactive protein may reflect events that precede radiographic progression in osteoarthritis of the knee. Ann Rheum Dis. 2000;59:71–4.PubMedCentralCrossRefPubMed
17.
Smith JW, Martins TB, Gopez E, et al. Significance of C-reactive protein in osteoarthritis and total knee arthroplasty outcomes. Ther Adv Musculoskelet Dis. 2012;4:315–25.PubMedCentralCrossRefPubMed
18.
Stannus O, Jones G, Cicuttini F, et al. Circulating levels of IL-6 and TNF-alpha are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults. Osteoarthritis Cartilage. 2010;18:1441–7.CrossRefPubMed
19.
Livshits G, Zhai G, Hart DJ, Kato BS, Wang H, Williams FMK, et al. Interleukin-6 is a significant predictor of radiographic knee osteoarthritis: the Chingford Study. Arthritis Rheum. 2009;60:2037–45.PubMedCentralCrossRefPubMed
20.
Pelletier JP, Raynauld JP, Caron J, Mineau F, Abram F, Dorais M, 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. Ann Rheum Dis. 2010;69(12):2095–101.CrossRefPubMed
21.
Ayral X, Pickering EH, Woodworth TG, et al. Synovitis: a potential predictive factor of structural progression of medial tibiofemoral knee osteoarthritis – results of a 1 year longitudinal arthroscopic study in 422 patients. Osteoarthritis Cartilage. 2005;13:361–7.CrossRefPubMed
22.
Goldring SR, Goldring MB. Clinical aspects, pathology and pathophysiology of osteoarthritis. J Musculoskelet Neuronal Interact. 2006;6(4):376–8.PubMed
23.
Garvican ER, et al. Biomarkers of cartilage turnover. Part 1: Markers of collagen degradation and synthesis. Vet J. 2010;185(1):36–42.CrossRefPubMed
24.
Jayabalan P, Sowa GA. The development of biomarkers for degenerative musculoskeletal conditions. Discov Med. 2014;17(92):59–66.PubMed
25.
Christgau S, et al. Collagen type II C-telopeptide fragments as an index of cartilage degradation. Bone. 2001;29(3):209–15.CrossRefPubMed
26.
Reijman M, et al. A new marker for osteoarthritis: cross-sectional and longitudinal approach. Arthritis Rheum. 2004;50(8):2471–8.CrossRefPubMed
27.
Gineyts E, et al. Effects of ibuprofen on molecular markers of cartilage and synovium turnover in patients with knee osteoarthritis. Ann Rheum Dis. 2004;63(7):857–61.PubMedCentralCrossRefPubMed
28.
Ameye LG, et al. The chemical biomarkers C2C, Coll2-1, and Coll2-1NO2 provide complementary information on type II collagen catabolism in healthy and osteoarthritic mice. Arthritis Rheum. 2007;56(10):3336–46.CrossRefPubMed
29.
Henrotin Y, et al. Collagen catabolism through Coll2-1 and Coll2-`O and myeloperoxidase activity in marathon runners. Springerplus. 2013;2(1):92.PubMedCentralCrossRefPubMed
30.
Deberg M, et al. New serum biochemical markers (Coll 2–1 and Coll 2–1 NO2) for studying oxidative-related type II collagen network degradation in patients with osteoarthritis and rheumatoid arthritis. Osteoarthritis Cartilage. 2005;13(3):258–65.CrossRefPubMed
31.
Tseng S, Reddi AH, Di Cesare PE. Cartilage oligomeric matrix protein (COMP): a biomarker of arthritis. Biomark Insights. 2009;4:33–44.PubMedCentralPubMed
32.
Clark AG, et al. Serum cartilage oligomeric matrix protein reflects osteoarthritis presence and severity: the Johnston County Osteoarthritis Project. Arthritis Rheum. 1999;42(11):2356–64.CrossRefPubMed
33.
Sharif M, et al. Suggestion of nonlinear or phasic progression of knee osteoarthritis based on measurements of serum cartilage oligomeric matrix protein levels over five years. Arthritis Rheum. 2004;50(8):2479–88.CrossRefPubMed
34.
Ahrman E, et al. Novel cartilage oligomeric matrix protein (COMP) neoepitopes identified in synovial fluids from patients with joint diseases using affinity chromatography and mass spectrometry. J Biol Chem. 2014;289(30):20908–16.PubMedCentralCrossRefPubMed
35.
Sharif M, et al. Serum hyaluronic acid level as a predictor of disease progression in osteoarthritis of the knee. Arthritis Rheum. 1995;38(6):760–7.CrossRefPubMed
36.
Bierma-Zeinstra SM, Koes BW. Risk factors and prognostic factors of hip and knee osteoarthritis. Nat Clin Pract Rheumatol. 2007;3(2):78–85.CrossRefPubMed
37.
Pavelka K, et al. Hyaluronic acid levels may have predictive value for the progression of knee osteoarthritis. Osteoarthritis Cartilage. 2004;12(4):277–83.CrossRefPubMed
38.
Kaneko H, et al. Reference intervals of serum hyaluronic acid corresponding to the radiographic severity of knee osteoarthritis in women. BMC Musculoskelet Disord. 2013;14:34.PubMedCentralCrossRefPubMed
39.
Elliott AL, et al. Serum hyaluronan levels and radiographic knee and hip osteoarthritis in African Americans and Caucasians in the Johnston County Osteoarthritis Project. Arthritis Rheum. 2005;52(1):105–11.CrossRefPubMed
40.
Chua Jr SD, et al. Effect of an exercise and dietary intervention on serum biomarkers in overweight and obese adults with osteoarthritis of the knee. Osteoarthritis Cartilage. 2008;16(9):1047–53.PubMedCentralCrossRefPubMed
41.
Peltonen L, McKusick VA. Genomics and medicine. Dissecting human disease in the postgenomic era. Science. 2001;291(5507):1224–9.CrossRefPubMed
42.
Gharbi M, Deberg M, Henrotin Y. Application for proteomic techniques in studying osteoarthritis: a review. Front Physiol. 2011;2:90.PubMedCentralCrossRefPubMed
43.
Pedrotty DM, Morley MP, Cappola TP. Transcriptomic biomarkers of cardiovascular disease. Prog Cardiovasc Dis. 2012;55(1):64–9.PubMedCentralCrossRefPubMed
44.
Geyer M, et al. Differential transcriptome analysis of intraarticular lesional vs intact cartilage reveals new candidate genes in osteoarthritis pathophysiology. Osteoarthritis Cartilage. 2009;17(3):328–35.CrossRefPubMed
45.
Ramos YF, et al. Genes involved in the osteoarthritis process identified through genome wide expression analysis in articular cartilage; the RAAK study. PLoS One. 2014;9(7):e103056.PubMedCentralCrossRefPubMed
46.
Xu Y, et al. Identification of the pathogenic pathways in osteoarthritic hip cartilage: commonality and discord between hip and knee OA. Osteoarthritis Cartilage. 2012;20(9):1029–38.CrossRefPubMed
47.
Peffers M, Liu X, Clegg P. Transcriptomic signatures in cartilage ageing. Arthritis Res Ther. 2013;15(4):R98.PubMedCentralCrossRefPubMed
48.
Marshall KW, et al. Blood-based biomarkers for detecting mild osteoarthritis in the human knee. Osteoarthritis Cartilage. 2005;13(10):861–71.CrossRefPubMed
49.
Attur M, et al. Increased interleukin-1beta gene expression in peripheral blood leukocytes is associated with increased pain and predicts risk for progression of symptomatic knee osteoarthritis. Arthritis Rheum. 2011;63(7):1908–17.PubMedCentralCrossRefPubMed
50.
Williams A, et al. Applications of proteomics in cartilage biology and osteoarthritis research. Front Biosci (Landmark Ed). 2011;16:2622–44.CrossRef
51.
Hsueh MF, Onnerfjord P, Kraus VB. Biomarkers and proteomic analysis of osteoarthritis. Matrix Biol. 2014;39C:56–66.CrossRef
52.
Wu J, et al. Comparative proteomic characterization of articular cartilage tissue from normal donors and patients with osteoarthritis. Arthritis Rheum. 2007;56(11):3675–84.CrossRefPubMed
53.
Guo D, et al. Proteomic analysis of human articular cartilage: identification of differentially expressed proteins in knee osteoarthritis. Joint Bone Spine. 2008;75(4):439–44.CrossRefPubMed
54.
Ruiz-Romero C, et al. Proteomic analysis of human osteoarthritic chondrocytes reveals protein changes in stress and glycolysis. Proteomics. 2008;8(3):495–507.CrossRefPubMed
55.
Kubo T, et al. Stress-induced proteins in chondrocytes from patients with osteoarthritis. Arthritis Rheum. 1985;28(10):1140–5.CrossRefPubMed
56.
Tillmann K. Pathological aspects of osteoarthritis related to surgery. Inflammation. 1984;8(Suppl):S57–74.CrossRefPubMed
57.
Fernandez-Puente P, et al. Identification of a panel of novel serum osteoarthritis biomarkers. J Proteome Res. 2011;10(11):5095–101.CrossRefPubMed
58.
Han MY, et al. Identification of osteoarthritis biomarkers by proteomic analysis of synovial fluid. J Int Med Res. 2012;40(6):2243–50.CrossRefPubMed
59.
Ritter SY, et al. Proteomic analysis of synovial fluid from the osteoarthritic knee: comparison with transcriptome analyses of joint tissues. Arthritis Rheum. 2013;65(4):981–92.PubMedCentralCrossRefPubMed
60.
Wang Q, et al. Identification of a central role for complement in osteoarthritis. Nat Med. 2011;17(12):1674–9.PubMedCentralCrossRefPubMed
61.
Kamphorst JJ, et al. Profiling of endogenous peptides in human synovial fluid by NanoLC-MS: method validation and peptide identification. J Proteome Res. 2007;6(11):4388–96.CrossRefPubMed
62.
Blanco FJ, Ruiz-Romero C. Osteoarthritis: metabolomic characterization of metabolic phenotypes in OA. Nat Rev Rheumatol. 2012;8(3):130–2.CrossRefPubMed
63.
Zhai G, et al. Serum branched-chain amino acid to histidine ratio: a novel metabolomic biomarker of knee osteoarthritis. Ann Rheum Dis. 2010;69(6):1227–31.CrossRefPubMed
64.
Jiang M, et al. Serum metabolic signatures of four types of human arthritis. J Proteome Res. 2013;12(8):3769–79.CrossRefPubMed
65.
Adams Jr SB, et al. Global metabolic profiling of human osteoarthritic synovium. Osteoarthritis Cartilage. 2012;20(1):64–7.PubMedCentralCrossRefPubMed
66.
Adams Jr SB, Setton LA, Nettles DL. The role of metabolomics in osteoarthritis research. J Am Acad Orthop Surg. 2013;21(1):63–4.PubMedCentralCrossRefPubMed
67.
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.CrossRefPubMed
68.
Li Y, et al. Mirsynergy: detecting synergistic miRNA regulatory modules by overlapping neighbourhood expansion. Bioinformatics. 2014;30(18):2627–35.CrossRefPubMed
69.
Kozomara A, Griffiths-Jones S. MiRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 2014;42(Database issue):D68–73.PubMedCentralCrossRefPubMed
70.
Wu C, et al. MicroRNAs play a role in chondrogenesis and osteoarthritis. Int J Mol Med. 2014;34(1):13–23.PubMed
71.
Nair VS, et al. Design and analysis for studying microRNAs in human disease: a primer on -Omic Technologies. Am J Epidemiol. 2014;180(2):140–52.PubMedCentralCrossRefPubMed
72.
Kobayashi T, et al. Dicer-dependent pathways regulate chondrocyte proliferation and differentiation. Proc Natl Acad Sci U S A. 2008;105(6):1949–54.PubMedCentralCrossRefPubMed
73.
Tuddenham L, et al. The cartilage specific microRNA-140 targets histone deacetylase 4 in mouse cells. FEBS Lett. 2006;580(17):4214–7.CrossRefPubMed
74.
Miyaki S, et al. MicroRNA-140 is expressed in differentiated human articular chondrocytes and modulates interleukin-1 responses. Arthritis Rheum. 2009;60(9):2723–30.PubMedCentralCrossRefPubMed
75.
Miyaki S, et al. MicroRNA-140 plays dual roles in both cartilage development and homeostasis. Genes Dev. 2010;24(11):1173–85.PubMedCentralCrossRefPubMed
76.
Tardif G, et al. Regulation of the IGFBP-5 and MMP-13 genes by the microRNAs miR-140 and miR-27a in human osteoarthritic chondrocytes. BMC Musculoskelet Disord. 2009;10:148.PubMedCentralCrossRefPubMed
77.
Tardif G, et al. NFAT3 and TGF-beta/SMAD3 regulate the expression of miR-140 in osteoarthritis. Arthritis Res Ther. 2013;15(6):R197.PubMedCentralCrossRefPubMed
78.
Akhtar N, et al. MicroRNA-27b regulates the expression of matrix metalloproteinase 13 in human osteoarthritis chondrocytes. Arthritis Rheum. 2010;62(5):1361–71.PubMedCentralCrossRefPubMed
79.
Yamasaki K, et al. Expression of MicroRNA-146a in osteoarthritis cartilage. Arthritis Rheum. 2009;60(4):1035–41.PubMedCentralCrossRefPubMed
80.
Nakasa T, et al. Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum. 2008;58(5):1284–92.PubMedCentralCrossRefPubMed
81.
Jones SW, et al. The identification of differentially expressed microRNA in osteoarthritic tissue that modulate the production of TNF-alpha and MMP13. Osteoarthritis Cartilage. 2009;17(4):464–72.CrossRefPubMed
82.
Jin L, et al. Role of miR-146a in human chondrocyte apoptosis in response to mechanical pressure injury in vitro. Int J Mol Med. 2014;34(2):451–63.PubMedCentralPubMed
83.
Li X, et al. MicroRNA-146a is linked to pain-related pathophysiology of osteoarthritis. Gene. 2011;480(1–2):34–41.PubMedCentralCrossRefPubMed
84.
Li X, et al. Altered spinal microRNA-146a and the microRNA-183 cluster contribute to osteoarthritic pain in knee joints. J Bone Miner Res. 2013;28(12):2512–22.PubMedCentralCrossRefPubMed
85.
Iliopoulos D, et al. Integrative microRNA and proteomic approaches identify novel osteoarthritis genes and their collaborative metabolic and inflammatory networks. PLoS One. 2008;3(11):e3740.PubMedCentralCrossRefPubMed
86.
Diaz-Prado S, et al. Characterization of microRNA expression profiles in normal and osteoarthritic human chondrocytes. BMC Musculoskelet Disord. 2012;13:144.PubMedCentralCrossRefPubMed
87.
Weber JA, et al. The microRNA spectrum in 12 body fluids. Clin Chem. 2010;56(11):1733–41.CrossRefPubMed
88.
Mitchell PS, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A. 2008;105(30):10513–8.PubMedCentralCrossRefPubMed
89.
Kumar P, et al. Circulating miRNA biomarkers for Alzheimer’s disease. PLoS One. 2013;8(7):e69807.PubMedCentralCrossRefPubMed
90.
Ward J, et al. Circulating microRNA profiles in human patients with acetaminophen hepatotoxicity or ischemic hepatitis. Proc Natl Acad Sci U S A. 2014;111(33):12169–74.PubMedCentralCrossRefPubMed
91.
Murata K, et al. Plasma and synovial fluid microRNAs as potential biomarkers of rheumatoid arthritis and osteoarthritis. Arthritis Res Ther. 2010;12(3):R86.PubMedCentralCrossRefPubMed
92.
Beyer C, et al. Signature of circulating microRNAs in osteoarthritis. Ann Rheum Dis. 2015;74(3):e18.
93.
Borgonio Cuadra VM, et al. Altered expression of circulating microRNA in plasma of patients with primary osteoarthritis and in silico analysis of their pathways. PLoS One. 2014;9(6):e97690.PubMedCentralCrossRefPubMed
94.
Redova M, Sana J, Slaby O. Circulating miRNAs as new blood-based biomarkers for solid cancers. Future Oncol. 2013;9(3):387–402.CrossRefPubMed
95.
Lotz M, Martel-Pelletier J, Christiansen C, Brandi ML, Bruyère O, Chapurlat R, Collette J, Cooper C, Giacovelli G, Kanis JA, Karsdal MA, Kraus V, Lems WF, Meulenbelt I, Pelletier JP, Raynauld JP, Reiter-Niesert S, Rizzoli R, Sandell LJ, Van Spil WE, Reginster JY. Republished: Value of biomarkers in osteoarthritis: current status and perspectives. Postgrad Med J. 2014;90(1061):171–8.PubMedCentralCrossRefPubMed
96.
Kraus VB. Biomarkers in osteoarthritis. Curr Opin Rheumatol. 2005;17(5):641–6.CrossRefPubMed
97.
Mobasheri A, Henrotin Y. Biomarkers of osteoarthritis: a review of recent research progress on soluble biochemical markers, published patents and areas for future development. Recent Pat Biomarkers. 2011;1:25–43.