Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The bone–cartilage unit in osteoarthritis

Nature Reviews Rheumatology volume 7, pages 43–49 (2011)Cite this article

Subjects

Abstract

Osteoarthritis (OA) refers to a group of mechanically-induced joint disorders to which both genetic and acquired factors contribute. Current pathophysiological concepts focus on OA as a disease of the whole joint. Within these models, the functional unit formed by the articular cartilage and the subchondral bone seems to be of particular interest. Cartilage and bone receive and dissipate the stress associated with movement and loading, and are therefore continuously challenged biomechanically. Recent data support the view that cartilage and bone can communicate over the calcified tissue barrier; vessels reach out from bone into the cartilage zone, patches of uncalcified cartilage are in contact with bone, and microcracks and fissures further facilitate transfer of molecules. Several molecular signaling pathways such as bone morphogenetic proteins and Wnts are hypothesized to have a role in OA and can activate cellular and molecular processes in both cartilage and bone cells. In addition, intracellular activation of different kinase cascades seems to be involved in the molecular crosstalk between cartilage and bone cells. Further research is required to integrate these different elements into a comprehensive approach that will increase our understanding of the disease processes in OA, and that could lead to the development of specific therapeutics or treatment strategies.

Key Points

  • Osteoarthritis (OA) is a disease of the whole joint, to which changes in cartilage, bone, bone marrow, synovium, menisci, ligaments and neural tissue contribute

  • Subchondral bone changes, with increased metabolism and sclerosis, are often the first detectable alterations in the OA process

  • Increased subchondral remodeling might lead to decreased local mineralization

  • Molecular crosstalk between the cartilage and bone is possible, and it increases with progression of OA

  • Identifying risk factors for disease and halting disease progression are the main clinical challenges in OA

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Osteoarthritis is determined by a complex interplay between genetic and environmental or acquired risk factors.
Figure 2: The bone–cartilage unit is at the center of joint function and disease.
Figure 3: Complex changes in the bone–cartilage unit increase the flow of fluid and solutes in osteoarthritic joints.

Similar content being viewed by others

References

  1. Hunter, D. J. & Felson, D. T. Osteoarthritis. BMJ 332, 639–642 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Lane, N. E. Clinical practice. Osteoarthritis of the hip. N. Engl. J. Med. 357, 1413–1421 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Felson, D. T. Clinical practice. Osteoarthritis of the knee. N. Engl. J. Med. 354, 841–848 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Lawrence, R. C. et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 58, 26–35 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Berenbaum, F. New horizons and perspectives in the treatment of osteoarthritis. Arthritis Res. Ther. 10 (Suppl. 2), 1 (2008).

    Article  Google Scholar 

  6. Felson, D. T., Anderson, J. J. & Meenan, R. F. The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses. Arthritis Rheum. 33, 1449–1461 (1990).

    Article  CAS  PubMed  Google Scholar 

  7. Li, Y., Xu, L. & Olsen, B. R. Lessons from genetic forms of osteoarthritis for the pathogenesis of the disease. Osteoarthritis Cartilage 15, 1101–1105 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Miyamoto, Y. et al. A functional polymorphism in the 5′ UTR of GDF5 is associated with susceptibility to osteoarthritis. Nat. Genet. 39, 529–533 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Valdes, A. M. & Spector, T. D. The contribution of genes to osteoarthritis. Rheum. Dis. Clin. North Am. 34, 581–603 (2008).

    Article  PubMed  Google Scholar 

  10. Valdes, A. M. & Spector, T. D. The clinical relevance of genetic susceptibility to osteoarthritis. Best Pract. Res. Clin. Rheumatol. 24, 3–14 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Southam, L. et al. An SNP in the 5′-UTR of GDF5 is associated with osteoarthritis susceptibility in Europeans and with in vivo differences in allelic expression in articular cartilage. Hum. Mol. Genet. 16, 2226–2232 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Evangelou, E. et al. Large-scale analysis of association between GDF5 and FRZB variants and osteoarthritis of the hip, knee, and hand. Arthritis Rheum. 60, 1710–1721 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Baker-LePain, J. C. & Lane, N. E. Relationship between joint shape and the development of osteoarthritis. Curr. Opin. Rheumatol. 22, 538–543 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Brandt, K. D., Radin, E. L., Dieppe, P. A. & van de Putte, L. Yet more evidence that osteoarthritis is not a cartilage disease. Ann. Rheum. Dis. 65, 1261–1264 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sellam, J. & Berenbaum, F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat. Rev. Rheumatol. 6, 625–635 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Luyten, F. P., Lories, R. J., Verschueren, P., de Vlam, K. & Westhovens, R. Contemporary concepts of inflammation, damage and repair in rheumatic diseases. Best Pract. Res. Clin. Rheumatol. 20, 829–848 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Goldring, M. B. & Goldring, S. R. Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann. NY Acad. Sci. 1192, 230–237 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Thambyah, A. & Broom, N. On new bone formation in the pre-osteoarthritic joint. Osteoarthritis Cartilage 17, 456–463 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Radin, E. L. & Rose, R. M. Role of subchondral bone in the initiation and progression of cartilage damage. Clin. Orthop. Relat. Res. 213, 34–40 (1986).

    Google Scholar 

  20. Day, J. S. et al. A decreased subchondral trabecular bone tissue elastic modulus is associated with pre-arthritic cartilage damage. J. Orthop. Res. 19, 914–918 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Brown, T. D., Radin, E. L., Martin, R. B. & Burr, D. B. Finite element studies of some juxtarticular stress changes due to localized subchondral stiffening. J. Biomech. 17, 11–24 (1984).

    Article  CAS  PubMed  Google Scholar 

  22. Blair-Levy, J. M. et al. A type I collagen defect leads to rapidly progressive osteoarthritis in a mouse model. Arthritis Rheum. 58, 1096–1106 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Muraoka, T., Hagino, H., Okano, T., Enokida, M. & Teshima, R. Role of subchondral bone in osteoarthritis development: a comparative study of two strains of guinea pigs with and without spontaneously occurring osteoarthritis. Arthritis Rheum. 56, 3366–3374 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Daans, M., Luyten, F. P. & Lories, R. J. GDF5 deficiency in mice is associated with instability-driven joint damage, gait and subchondral bone changes. Ann. Rheum. Dis. doi:10.1136/ard.2010.134619

  25. Roemer, F. W. et al. Change in MRI-detected subchondral bone marrow lesions is associated with cartilage loss: the MOST Study. A longitudinal multicentre study of knee osteoarthritis. Ann. Rheum. Dis. 68, 1461–1465 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Javaid, M. K. et al. Pre-radiographic MRI findings are associated with onset of knee symptoms: the MOST study. Osteoarthritis Cartilage 18, 323–328 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Raynauld, J. P. et al. Correlation between bone lesion changes and cartilage volume loss in patients with osteoarthritis of the knee as assessed by quantitative magnetic resonance imaging over a 24-month period. Ann. Rheum. Dis. 67, 683–688 (2008).

    Article  PubMed  Google Scholar 

  28. Neogi, T. et al. Cartilage loss occurs in the same subregions as subchondral bone attrition: a within-knee subregion-matched approach from the Multicenter Osteoarthritis Study. Arthritis Rheum. 61, 1539–1544 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Roemer, F. W. et al. Subchondral bone marrow lesions are highly associated with, and predict subchondral bone attrition longitudinally: the MOST study. Osteoarthritis Cartilage 18, 47–53 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Neogi, T. et al. Subchondral bone attrition may be a reflection of compartment-specific mechanical load: the MOST Study. Ann. Rheum. Dis. 69, 841–844 (2010).

    Article  PubMed  Google Scholar 

  31. Berry, J. L., Thaeler-Oberdoerster, D. A. & Greenwald, A. S. Subchondral pathways to the superior surface of the human talus. Foot Ankle 7, 2–9 (1986).

    Article  CAS  PubMed  Google Scholar 

  32. Imhof, H., Breitenseher, M., Kainberger, F., Rand, T. & Trattnig, S. Importance of subchondral bone to articular cartilage in health and disease. Top. Magn. Reson. Imaging 10, 180–192 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Lyons, T. J., McClure, S. F., Stoddart, R. W. & McClure, J. The normal human chondro-osseous junctional region: evidence for contact of uncalcified cartilage with subchondral bone and marrow spaces. BMC Musculoskelet. Disord. 7, 52 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Walsh, D. A. et al. Angiogenesis and nerve growth factor at the osteochondral junction in rheumatoid arthritis and osteoarthritis. Rheumatology (Oxford) 49, 1852–1861 (2010).

    Article  CAS  Google Scholar 

  35. Madry, H., van Dijk, C. N. & Mueller-Gerbl, M. The basic science of the subchondral bone. Knee Surg. Sports Traumatol. Arthrosc. 18, 419–433 (2010).

    Article  PubMed  Google Scholar 

  36. Bashir, A., Gray, M. L., Boutin, R. D. & Burstein, D. Glycosaminoglycan in articular cartilage: in vivo assessment with delayed Gd(DTPA)(2-)-enhanced MR imaging. Radiology 205, 551–558 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Pan, J. et al. In situ measurement of transport between subchondral bone and articular cartilage. J. Orthop. Res. 27, 1347–1352 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Hwang, J. et al. Increased hydraulic conductance of human articular cartilage and subchondral bone plate with progression of osteoarthritis. Arthritis Rheum. 58, 3831–3842 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Luyten, F. P., Tylzanowski, P. & Lories, R. J. Wnt signaling and osteoarthritis. Bone 44, 522–527 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. van der Kraan, P. M., Davidson, E. N. & van den Berg, W. B. Bone morphogenetic proteins and articular cartilage: to serve and protect or a wolf in sheep's clothing? Osteoarthritis Cartilage 18, 735–741 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Blom, A. B., van Lent, P. L., van der Kraan, P. M. & van den Berg, W. B. To seek shelter from the WNT in osteoarthritis? WNT-signaling as a target for osteoarthritis therapy. Curr. Drug Targets 11, 620–629 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Zhu, M. et al. Activation of β-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult β-catenin conditional activation mice. J. Bone Miner. Res. 24, 12–21 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Zhu, M. et al. Inhibition of β-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum. 58, 2053–2064 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lories, R. J. et al. Articular cartilage and biomechanical properties of the long bones in Frzb-knockout mice. Arthritis Rheum. 56, 4095–4103 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Bodine, P. V. et al. The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice. Mol. Endocrinol. 18, 1222–1237 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Weng, L. H., Wang, C. J., Ko, J. Y., Sun, Y. C. & Wang, F. S. Control of Dkk-1 ameliorates chondrocyte apoptosis, cartilage destruction, and subchondral bone deterioration in osteoarthritic knees. Arthritis Rheum. 62, 1393–1402 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Lories, R. J. & Luyten, F. P. Bone morphogenetic protein signaling and arthritis. Cytokine Growth Factor Rev. 20, 467–473 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Westacott, C. I., Webb, G. R., Warnock, M. G., Sims, J. V. & Elson, C. J. Alteration of cartilage metabolism by cells from osteoarthritic bone. Arthritis Rheum. 40, 1282–1291 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. Hilal, G., Martel-Pelletier, J., Pelletier, J. P., Ranger, P. & Lajeunesse, D. Osteoblast-like cells from human subchondral osteoarthritic bone demonstrate an altered phenotype in vitro: possible role in subchondral bone sclerosis. Arthritis Rheum. 41, 891–899 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Massicotte, F. et al. Can altered production of interleukin-1β, interleukin-6, transforming growth factor-β and prostaglandin E2 by isolated human subchondral osteoblasts identify two subgroups of osteoarthritic patients? Osteoarthritis Cartilage 10, 491–500 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Sanchez, C. et al. Phenotypic characterization of osteoblasts from the sclerotic zones of osteoarthritic subchondral bone. Arthritis Rheum. 58, 442–455 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Mutabaruka, M. S., Aoulad Aissa, M., Delalandre, A., Lavigne, M. & Lajeunesse, D. Local leptin production in osteoarthritis subchondral osteoblasts may be responsible for their abnormal phenotypic expression. Arthritis Res. Ther. 12, R20 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Sanchez, C. et al. Osteoblasts from the sclerotic subchondral bone downregulate aggrecan but upregulate metalloproteinases expression by chondrocytes. This effect is mimicked by interleukin-6, -1β and oncostatin M pre-treated non-sclerotic osteoblasts. Osteoarthritis Cartilage 13, 979–987 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Sanchez, C. et al. Subchondral bone osteoblasts induce phenotypic changes in human osteoarthritic chondrocytes. Osteoarthritis Cartilage 13, 988–997 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Lin, Y. Y. et al. Applying an excessive mechanical stress alters the effect of subchondral osteoblasts on chondrocytes in a co-culture system. Eur. J. Oral Sci. 118, 151–158 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Prasadam, I. et al. ERK-1/2 and p38 in the regulation of hypertrophic changes of normal articular cartilage chondrocytes induced by osteoarthritic subchondral osteoblasts. Arthritis Rheum. 62, 1349–1360 (2010).

    Article  CAS  PubMed  Google Scholar 

  57. Prasadam, I. et al. Osteoarthritic cartilage chondrocytes alter subchondral bone osteoblast differentiation via MAPK signalling pathway involving ERK1/2. Bone 46, 226–235 (2010).

    Article  CAS  PubMed  Google Scholar 

  58. Amiable, N. et al. Proteinase-activated receptor (PAR)-2 activation impacts bone resorptive properties of human osteoarthritic subchondral bone osteoblasts. Bone 44, 1143–1150 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ferrell, W. R., Kelso, E. B., Lockhart, J. C., Plevin, R. & McInnes, I. B. Protease-activated receptor 2: a novel pathogenic pathway in a murine model of osteoarthritis. Ann. Rheum. Dis. 69, 2051–2054 (2010).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

R. J. Lories is the recipient of a post-doctoral fellowship from the Flanders Research Foundation (FWO Vlaanderen). Research on osteoarthritis in the authors' laboratory is supported by FWO Vlaanderen, a GOA grant from KU Leuven, and Translational Research in Europe—Applied Technologies for Osteoarthritis (TREAT-OA), a large collaborative FP7 project supported by the European Union.

Author information

Authors and Affiliations

  1. Department of Musculoskeletal Sciences, Division of Rheumatology, Laboratory for Skeletal Development and Joint Disorders, University Hospitals Leuven, Herestraat 49, B-3000, Leuven, Belgium

    Rik J. Lories & Frank P. Luyten

Authors
  1. Rik J. Lories
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Frank P. Luyten
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R. J. Lories and F. P. Luyten contributed equally to all aspects of preparation of this manuscript.

Corresponding author

Correspondence to Rik J. Lories.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lories, R., Luyten, F. The bone–cartilage unit in osteoarthritis. Nat Rev Rheumatol 7, 43–49 (2011). https://doi.org/10.1038/nrrheum.2010.197

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2010.197

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing