Skip to main content

Advertisement

SpringerLink
Log in

Monitoring cartilage turnover

  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

In arthritic diseases, the stability of the extracellular matrix of articular cartilage is compromised by extensive proteolytic breakdown associated with alterations of synthesis of the proteins of the tissue leading to cartilage loss. This article reviews developments in assays of biochemical markers of cartilage matrix turnover and studies investigating their use. Because type II collagen and aggrecan are the most abundant proteins of the cartilage matrix, current biochemical markers are based mainly on immunologic reagents detecting their synthesis and degradation. Clinical studies indicate that some markers of type II collagen may be useful to predict disease progression in osteoarthritis and rheumatoid arthritis. Conversely, major achievements have been made in the development of immunoassays detecting the various fragments of aggrecan released by matrix metalloproteases or aggrecanases, but their use has been limited mostly to investigating cartilage turnover in ex vivo experiments. Because of the complexity of the mechanisms involved in arthritic joint damage, only a combination of different biochemical markers reflecting the various aspects of synthesis and degradation of matrix molecules will likely provide efficient cartilage turnover monitoring.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Garnero P, Rousseau JC, Delmas PD: Molecular basis and clinical use of biochemical markers of bone, cartilage, and synovium in joint diseases. Arthritis Rheum 2000, 43:953–968.

    Article  PubMed  CAS  Google Scholar 

  2. Gray ML, Eckstein F, Peterfy C, et al.: Toward imaging biomarkers for osteoarthritis. Clin Orthop Relat Res 2004, (427 Suppl):S175–181.

    Article  Google Scholar 

  3. Bauer DC, Hunter DJ, Abramson SB, et al.: Classification of osteoarthritis biomarkers: a proposed approach. Osteoarthritis Cartilage 2006, 14:723–727.

    Article  PubMed  CAS  Google Scholar 

  4. Heinegard D, Saxne T: Molecular markers of processes in cartilage in joint disease. Br J Rheumatol 1991, 30:21–24.

    Article  PubMed  Google Scholar 

  5. Kivirikko KI, Myllyla R: Post-translational processing of procollagens. Ann N Y Acad Sci 1985, 460:187–201.

    Article  PubMed  CAS  Google Scholar 

  6. Hinek A, Reiner A, Poole AR: The calcification of cartilage matrix in chondrocyte culture: studies of the C-propeptide of CII (chondrocalcin). J Cell Biol 1987, 104:1435–1441.

    Article  PubMed  CAS  Google Scholar 

  7. Nelson F, Dahlberg L, Laverty S, et al.: Evidence for altered synthesis of type II collagen in patients with osteoarthritis. J Clin Invest 1998, 102:2115–2125.

    PubMed  CAS  Google Scholar 

  8. Rousseau JC, Sandell LJ, Delmas PD, Garnero P: Development and clinical application in arthritis of a new immunoassay for serum type IIA procollagen NH2 propeptide. Methods Mol Med 2004, 101:25–38.

    PubMed  CAS  Google Scholar 

  9. Sharif M, Kirwan J, Charni N, et al.: A 5-year longitudinal study of type IIA collagen synthesis and total type II collagen degradation in patients with knee osteoarthritis: association with disease progression. Rheumatology 2006, in press.

  10. Meulenbelt I, Kloppenburg M, Kroon HM, et al.: Clusters of biochemical markers are associated with radiographic subtypes of osteoarthritis (OA) in subject with familial OA at multiple sites. The GARP study. Osteoarthritis Cartilage 2006, Epub ahead of print.

  11. Hashimoto J, Garnero P, Miyasaka N, et al.: Early changes in biochemical markers of cartilage turnover and synovial inflammation predict the effects of tocilizumab monotherapy on one-year radiographic progression in patients with early rheumatoid arthritis. Arthritis Rheum 2006, 54(Suppl):P944.

    Google Scholar 

  12. Olsen AK, Sondergaard BC, Byrjalsen I, et al.: Anabolic and catabolic function of chondrocyte exvivo is reflected by the metabolic processing of type II collagen. Osteoarthritis Cartilage 2006, Epub ahead of print.

  13. Billinghurst RC, Dahlberg L, Ionescu M, et al.: Enhanced cleavage of type II collagen by collagenases in osteoarthritis articular cartilage. J Clin Invest 1997, 99:1534–1545.

    PubMed  CAS  Google Scholar 

  14. Mitchell PG, Magna HA, Reeves LM, et al.: Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. J Clin Invest 1996, 97:761–768.

    PubMed  CAS  Google Scholar 

  15. Garnero P, Desmarais S, Charni N, Percival MD. The CII fragments HELIX-II and CTX-II reveal distinct enzymatic pathways of cartilage collagen degradation: Diagnostic and therapeutic implications in rheumatoid arthritis and osteoarthritis. Arthritis Rheum 2005, 52(Suppl):P51.

    Google Scholar 

  16. Charni N, Juillet F, Garnero P: Urinary type II collagen helical peptide (Helix II) as a new biochemical marker of cartilage degradation in patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum 2005, 52:1081–1090.

    Article  PubMed  CAS  Google Scholar 

  17. Briot K, Garnero P, Gossec L, et al.: Etanercept has beneficial effects on bone and cartilage metabolism in patients with spondylarthropathy. Arthritis Rheum 2006, 54(Suppl):P1806.

    Google Scholar 

  18. Garnero P, Charni N, Juillet F, et al.: Urinary type II collagen helical peptide (HELIX-II) levels are increased in patients with a rapidly destructive hip osteoarthritis. Ann Rheum Dis 2006, in press.

  19. Sondergaard BC, Henriksen K, Wulf H, et al.: Relative contribution of matrix metalloprotease and cysteine protease activities to cytokine-stimulated articular cartilage degradation. Osteoarthritis Cartilage 2006, 14:738–748.

    Article  PubMed  CAS  Google Scholar 

  20. Oestergaard S, Chouinard L, Doyle N, et al.: The utility of measuring C-terminal telopeptides of collagen type II (CTX-II) in serum and synovial fluid samples for estimation of articular cartilage status in experimental models of destructive joint diseases. Osteoarthritis Cartilage 2006, 14:670–679.

    Article  PubMed  CAS  Google Scholar 

  21. Garnero P: Use of biochemical markers to study and follow patients with osteoarthritis. Curr Rheumatol Rep 2006, 8:37–44.

    Article  PubMed  Google Scholar 

  22. Garnero P: New biochemical markers of osteoarthritis. Aging Health 2006, 2:639–647.

    Article  CAS  Google Scholar 

  23. Alexandersen P, Karsdal MA, Qvist P, et al.: Strontium ranelate reduces the urinary level of cartilage degradation biomarker CTX-II in postmenopausal women. Bone 2006, in press.

  24. Bingham CO, Buckland-Wright JC, Garnero P, et al.: Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: Results of the two-year multinational knee osteoarthritis structural arthritis study. Arthritis Rheum 2006, 54:3494–3507.

    Article  PubMed  CAS  Google Scholar 

  25. Garnero P, Bingham C, Aronstein W, et al.: Treatment with risedronate reduced urinary CTX-II, a specific biochemical marker of cartilage type II collagen degradation, in a 24 month study of knee OA. Arthritis Rheum 2004, 50(Suppl):P1754.

    Google Scholar 

  26. Manicourt DH, Azria M, Mindeholm L, et al.: Oral salmon calcitonin reduces Lequesne’s algofunctional index scores and decreases urinary and serum levels of biomarkers of joint metabolism in knee osteoarthritis. Arthritis Rheum 2006, 54:3205–3211.

    Article  PubMed  CAS  Google Scholar 

  27. Garnero P, Peterfy C, Zaim S, Schoenharting M: Bone marrow abnormalities on magnetic resonance imaging are associated with type II collagen degradation in knee osteoarthritis: a three-month longitudinal study. Arthritis Rheum 2005, 52:2822–2829.

    Article  PubMed  CAS  Google Scholar 

  28. Bruyère O, Collette J, Kothari M, et al.: Osteoarthritis, magnetic resonance imaging, and biochemical markers: a one year prospective study. Ann Rheum Dis 2006, 65:1050–1054.

    Article  PubMed  Google Scholar 

  29. Cibere J, Zhang H, Thorne A, et al.: Urine CTX-II and urine C2C are differentially associated with radiographic and pre-radiographic knee osteoarthritis (OA): results of a population-based study using MRI. Arthritis Rheum 2006, 54(Suppl):P265.

    Google Scholar 

  30. Otterness IG, Downs JT, Lane C, et al.: Detection of collagenase-induced damage of collagen by 9A4, a monoclonal C-terminal neoepitope antibody. Matrix Biol 1999, 18:331–341.

    Article  PubMed  CAS  Google Scholar 

  31. Downs JT, Lane CL, Nestor NB, et al.: Analysis of collagenase-cleavage of type II collagen using a neoepitope ELISA. J Immunol Methods 2001, 247:25–34.

    Article  PubMed  CAS  Google Scholar 

  32. Saltarelli MJ, Johnson K, Pickering E, et al.: Measurement of urinary type II collagen neoepitope levels in rheumatoid arthritis patients to assess joint status. Arthritis Rheum 1999, 42(Suppl 9):S249.

    Google Scholar 

  33. Woodworth TG, Otterness IG, Johnson K, et al.: Urinary type II collagen neoepitopes in osteoarthritis patients is associated with disease severity. Arthritis Rheum 1999, 42(Suppl 9):S258.

    Google Scholar 

  34. Hellio Le Graverand MP, Brandt KD, et al.: Association between concentrations of urinary type II collagen neoepitope (uTIINE) and joint space narrowing in patients with knee osteoarthritis. Osteoarthritis Cartilage 2006, 14:1189–1195.

    Article  PubMed  Google Scholar 

  35. Deberg M, Labasse A, Christgau S, et al.: New serum biochemical markers (Coll 2-1 and Coll 2-1 NO2) for studying oxidative-related CII network degradation in patients with osteoarthritis and rheumatoid arthritis. Osteoarthritis Cartilage 2005, 13:258–265.

    Article  PubMed  Google Scholar 

  36. Deberg MA, Labasse AH, Collette J, et al.: One year increase of Coll 2-1, a new marker of CII is highly predictive of radiological OA progression. Osteoarthritis Cartilage 2005, 13:258–265.

    Article  PubMed  Google Scholar 

  37. Tortorella MD, Burn TC, Pratta MA, et al.: Purification and Cloning of Aggrecanase-1: A Member of the ADAMTS Family of Proteins. Science 1999, 284:1664–1666.

    Article  PubMed  CAS  Google Scholar 

  38. Kiani C, Chen L, Wu YJ, et al.: Structure and function of aggrecan. Cell Res 2002, 12:19–32.

    Article  PubMed  Google Scholar 

  39. Pratta MA, Su JL, Leesnitzer MA, et al.: Development and characterization of a highly specific and sensitive sandwich ELISA for detection of aggrecanase-generated aggrecan fragments. Osteoarthritis Cartilage 2006, 14:702–713.

    Article  PubMed  CAS  Google Scholar 

  40. Sandy JD, Verscharen C: Analysis of aggrecan in human knee cartilage and synovial fluid indicates that aggrecanase (ADAMTS) activity is responsible for the catabolic turnover and loss of whole aggrecan where as other protease activity is required for C-terminal processing in vivo. Biochem J 2001, 358:615–626.

    Article  PubMed  CAS  Google Scholar 

  41. Zeng W, Collins-Racie LA, Glasson SS, et al.: Utility of aggrecan AGG-C1 Neoepitope (G1-TEGE373) as a biomarker for osteoarthritis. Osteoarthritis Cartilage 2005, 13(Suppl A):P80.

    Google Scholar 

  42. Sumer EU, Sondergaard BC, Rousseau JC, et al.: MMP and non-MMP-mediated release of aggrecan and its fragments from articular cartilage: a comparative study of three different aggrecan and glycosaminoglycan assays. Osteoarthritis Cartilage 2006, Epub ahead of print.

  43. Fosang AJ, Last K, Maciewicz RA: Aggrecan is degraded by matrix metalloproteinases in human arthritis. Evidence that matrix metalloproteinase and aggrecanase activities can be independent. J Clin Invest 1996, 98:2292–2299.

    Article  PubMed  CAS  Google Scholar 

  44. Struglics A, Larsson S, Pratta MA, et al.: Human osteoarthritis synovial fluid and joint cartilage contain both aggrecanase-and matrix metalloproteinase-generated aggrecan fragments. Osteoarthritis Cartilage 2006, 14:101–113.

    Article  PubMed  CAS  Google Scholar 

  45. Yasuda T, Poole AR: A fibronectin fragment induces type II collagen degradation by collagenase through an interleukin-1-mediated pathway. Arthritis Rheum 2002, 46:138–148.

    Article  PubMed  CAS  Google Scholar 

  46. Clemmensen I, Andersen RB: Different molecular forms of fibronectin in rheumatoid synovial fluid. Arthritis Rheum 1982, 25:25–31.

    Article  PubMed  CAS  Google Scholar 

  47. Xie DL, Meyers R, Homandberg GA: Fibronectin fragments in osteoarthritic synovial fluid. J Rheumatol 1992, 19:1448–1452.

    PubMed  CAS  Google Scholar 

  48. Zack MD, Arner EC, Anglin CP, et al.: Identification of fibronectin neoepitopes present in human osteoarthritic cartilage. Arthritis Rheum 2006, 54:2912–2922.

    Article  PubMed  CAS  Google Scholar 

  49. Stanton H, Ung L, Fosang AJ: The 45 kDa collagen-binding fragment of fibronectin induces matrix metalloproteinase-13 synthesis by chondrocytes and aggrecan degradation by aggrecanases. Biochem J 2002, 364:181–190.

    PubMed  CAS  Google Scholar 

  50. Gemba T, Valbracht J, Alsalameh S, Lotz M: Focal adhesion kinase and mitogen-activated protein kinases are involved in chondrocyte activation by the 29-kDa amino-terminal fibronectin fragment. J Biol Chem 2002, 277:907–911.

    Article  PubMed  CAS  Google Scholar 

  51. Yasuda T, Tchetina E, Ohsawa K, et al.: Peptides of type II collagen can induce the cleavage of type II collagen and aggrecan in articular cartilage. Matrix Biol 2006, 25:419–429.

    Article  PubMed  CAS  Google Scholar 

  52. Christgau S, Garnero P, Fledelius C, et al.: Collagen type II C-telopeptide fragments as an index of cartilage degradation. Bone 2001, 29:209–215.

    Article  PubMed  CAS  Google Scholar 

  53. Poole AR, Ionescu M, Fitzcharles MA, Billinghurst RC: The assessment of cartilage degradation in vivo: development of an immunoassay for the measurement in body fluids of type II collagen cleaved by collagenases. J Immunol Methods 2004, 294:145–53.

    Article  PubMed  CAS  Google Scholar 

  54. Otterness IG, Swindell AC, Zimmerer RO, et al.: An analysis of 14 molecular markers for monitoring osteoarthritis. Segregation of the markers into clusters and distinguishing osteoarthritis at baseline. Osteoarthritis Cartilage 2001, 9:224–231.

    Article  PubMed  CAS  Google Scholar 

  55. Harvey S, Weisman M, O’Dell J, et al.: Chondrex: new marker of joint disease. Clin Chem 1998, 44:509–516.

    PubMed  CAS  Google Scholar 

  56. Moser M, Bosserhoff AK, Hunziker EB, et al.: Ultrastructural cartilage abnormalities in MIA/CD-RAP-deficient mice. Mol Cell Biol 2002, 22:1438–1445.

    Article  PubMed  CAS  Google Scholar 

  57. Saxne T, Heinegard D: Cartilage oligomeric matrix protein: a novel marker of cartilage turnover detectable in synovial fluid and blood. Br J Rheumatol 1992, 31:583–591.

    Article  PubMed  CAS  Google Scholar 

  58. Schellekens GA, Visser H, de Jong BA, et al.: The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 2000, 43:155–163.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. SYNARC, Le Buroparc Bâtiment T4, 16, rue Montbrillant, 69003, Lyon, France

    Patrick Garnero PhD, DSc

Authors
  1. Nadine Charni-Ben Tabassi PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patrick Garnero PhD, DSc
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patrick Garnero PhD, DSc.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tabassi, N.CB., Garnero, P. Monitoring cartilage turnover. Curr Rheumatol Rep 9, 16–24 (2007). https://doi.org/10.1007/s11926-007-0017-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11926-007-0017-y

Keywords

Search

Navigation