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  • Review Article
  • Published:

Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage–bone crosstalk

Nature Reviews Rheumatology volume 12, pages 632–644 (2016)Cite this article

Subjects

Key Points

  • Osteoarthritis (OA) is a whole-joint disease in which all of the components of the joint are affected

  • The articular cartilage, subchondral bone, and calcified cartilage form an osteochondral biocomposite that is uniquely adapted to transferring loads during weight bearing and joint motion

  • Marked alterations in the composition, functional properties, and structure of the osteochondral tissues occur during the evolution of OA

  • Alteration in the composition or structure of any of the individual components of the osteochondral unit can initiate OA pathology in the joint

  • The differential capacity of bone and cartilage to adapt to the effects of local mechanical and environmental influences has an important role in the development of OA

  • Crosstalk between chondrocytes and bone cells contributes to OA pathogenesis

  • To develop rational therapies for OA, it is essential to have diagnostic tools to define the state of the components of the osteochondral unit

Abstract

In diarthrodial joints, the articular cartilage, calcified cartilage, and subchondral cortical and trabecular bone form a biocomposite — referred to as the osteochondral unit — that is uniquely adapted to the transfer of load. During the evolution of the osteoarthritic process the compositions, functional properties, and structures of these tissues undergo marked alterations. Although pathological processes might selectively target a single joint tissue, ultimately all of the components of the osteochondral unit will be affected because of their intimate association, and thus the biological and physical crosstalk among them is of great importance. The development of targeted therapies against the osteoarthritic processes in cartilage or bone will, therefore, require an understanding of the state of these joint tissues at the time of the intervention. Importantly, these interventions will not be successful unless they are applied at the early stages of disease before considerable structural and functional alterations occur in the osteochondral unit. This Review describes the changes that occur in bone and cartilage during the osteoarthritic process, and highlights strategies for how this knowledge could be applied to develop new therapeutic interventions for osteoarthritis.

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Figure 1: Structure of the normal knee joint and sequential changes in the osteochondral unit during the evolution of osteoarthritis.
Figure 2: Correlation of radiographic and structural changes in osteoarthritis.
Figure 3: Bone marrow lesions in osteoarthritis.

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References

  1. Goldring, S. R. & Goldring, M. B. in Kelley's Textbook of Rheumatology 9th edn Ch. 1 (eds Firestein, G.S., Budd, R.C., Gabriel, S.E., McInnes I.B., & O'Dell J.R.) 1–19 (Saunders, 2013).

    Book  Google Scholar 

  2. Johnson, V. L. & Hunter, D. J. The epidemiology of osteoarthritis. Best Pract. Res. Clin. Rheumatol. 28, 5–15 (2014).

    Article  PubMed  Google Scholar 

  3. Hunter, D. J., Nevitt, M., Losina, E. & Kraus, V. Biomarkers for osteoarthritis: current position and steps towards further validation. Best Pract. Res. Clin. Rheumatol. 28, 61–71 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Loeser, R. F., Goldring, S. R., Scanzello, C. R. & Goldring, M. B. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 64, 1697–1707 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Heinegard, D. & Saxne, T. The role of the cartilage matrix in osteoarthritis. Nat. Rev. Rheumatol. 7, 50–56 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Hunziker, E. B., Lippuner, K. & Shintani, N. How best to preserve and reveal the structural intricacies of cartilaginous tissue. Matrix Biol. 39, 33–43 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Onnerfjord, P., Khabut, A., Reinholt, F. P., Svensson, O. & Heinegard, D. Quantitative proteomic analysis of eight cartilaginous tissues reveals characteristic differences as well as similarities between subgroups. J. Biol. Chem. 287, 18913–18924 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Houard, X., Goldring, M. B. & Berenbaum, F. Homeostatic mechanisms in articular cartilage and role of inflammation in osteoarthritis. Curr. Rheumatol. Rep. 15, 375 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Quinn, T. M., Hauselmann, H. J., Shintani, N. & Hunziker, E. B. Cell and matrix morphology in articular cartilage from adult human knee and ankle joints suggests depth-associated adaptations to biomechanical and anatomical roles. Osteoarthritis Cartilage 21, 1904–1912 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Sandell, L. J. Etiology of osteoarthritis: genetics and synovial joint development. Nat. Rev. Rheumatol. 8, 77–89 (2012).

    Article  CAS  PubMed  Google Scholar 

  11. Andriacchi, T. P. & Favre, J. The nature of in vivo mechanical signals that influence cartilage health and progression to knee osteoarthritis. Curr. Rheumatol. Rep. 16, 463 (2014).

    Article  PubMed  Google Scholar 

  12. Guo, H., Maher, S. A. & Torzilli, P. A. A biphasic finite element study on the role of the articular cartilage superficial zone in confined compression. J. Biomech. 48, 166–170 (2015).

    Article  PubMed  Google Scholar 

  13. Greene, G. W. et al. Adaptive mechanically controlled lubrication mechanism found in articular joints. Proc. Natl. Acad. Sci. USA 108, 5255–5259 (2011).

    Article  PubMed  Google Scholar 

  14. Imhof, H. et al. Subchondral bone and cartilage disease: a rediscovered functional unit. Invest. Radiol. 35, 581–588 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. 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 

  16. 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 

  17. Hunziker, E. B., Kapfinger, E. & Geiss, J. The structural architecture of adult mammalian articular cartilage evolves by a synchronized process of tissue resorption and neoformation during postnatal development. Osteoarthritis Cartilage 15, 403–413 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Wilusz, R. E., Sanchez-Adams, J. & Guilak, F. The structure and function of the pericellular matrix of articular cartilage. Matrix Biol. 39, 25–32 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Pap, T. & Bertrand, J. Syndecans in cartilage breakdown and synovial inflammation. Nat. Rev. Rheumatol. 9, 43–55 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Loeser, R. F. Integrins and chondrocyte-matrix interactions in articular cartilage. Matrix Biol. 39, 11–16 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Xu, L., Golshirazian, I., Asbury, B. J. & Li, Y. Induction of high temperature requirement A1, a serine protease, by TGF-β1 in articular chondrocytes of mouse models of OA. Histol. Histopathol. 29, 609–618 (2014).

    CAS  PubMed  Google Scholar 

  22. Wann, A. K. et al. Primary cilia mediate mechanotransduction through control of ATP-induced Ca2+ signaling in compressed chondrocytes. FASEB J. 26, 1663–1671 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ruhlen, R. & Marberry, K. The chondrocyte primary cilium. Osteoarthritis Cartilage 22, 1071–1076 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Mobasheri, A. et al. Facilitative glucose transporters in articular chondrocytes. Expression, distribution and functional regulation of GLUT isoforms by hypoxia, hypoxia mimetics, growth factors and pro-inflammatory cytokines. Adv. Anat. Embryol. Cell Biol. 200, 1–84 (2008).

    Article  PubMed  Google Scholar 

  25. Pfander, D. & Gelse, K. Hypoxia and osteoarthritis: how chondrocytes survive hypoxic environments. Curr. Opin. Rheumatol. 19, 457–462 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Thoms, B. L., Dudek, K. A., Lafont, J. E. & Murphy, C. L. Hypoxia promotes the production and inhibits the destruction of human articular cartilage. Arthritis Rheum. 65, 1302–1312 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Maes, C. et al. VEGF-independent cell-autonomous functions of HIF-1α regulating oxygen consumption in fetal cartilage are critical for chondrocyte survival. J. Bone Miner. Res. 27, 596–609 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. Simkin, P. A. Consider the tidemark. J. Rheumatol. 39, 890–892 (2012).

    Article  PubMed  Google Scholar 

  29. Burr, D. B. Anatomy and physiology of the mineralized tissues: role in the pathogenesis of osteoarthrosis. Osteoarthritis Cartilage 12 (Suppl A), S20–S30 (2004).

    Article  PubMed  Google Scholar 

  30. Burr, D. B. & Gallant, M. A. Bone remodelling in osteoarthritis. Nat. Rev. Rheumatol. 8, 665–673 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. Goldring, S. R. Role of bone in osteoarthritis pathogenesis. Med. Clin. North Am. 93, 25–35 (2009).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  33. Benjamin, M. & McGonagle, D. The enthesis organ concept and its relevance to the spondyloarthropathies. Adv. Exp. Med. Biol. 649, 57–70 (2009).

    Article  PubMed  Google Scholar 

  34. Frost, H. M. From Wolff's law to the Utah paradigm: insights about bone physiology and its clinical applications. Anat. Rec. 262, 398–419 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Eriksen, E. F. Cellular mechanisms of bone remodeling. Rev. Endocr. Metab. Disord. 11, 219–227 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Xiong, J. et al. Matrix-embedded cells control osteoclast formation. Nat. Med. 17, 1235–1241 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Nakashima, T. et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat. Med. 17, 1231–1234 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Dallas, S. L., Prideaux, M. & Bonewald, L. F. The osteocyte: an endocrine cell... and more. Endocr. Rev. 34, 658–690 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Meunier, P. J. & Boivin, G. Bone mineral density reflects bone mass but also the degree of mineralization of bone: therapeutic implications. Bone 21, 373–377 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Faibish, D., Ott, S. M. & Boskey, A. L. Mineral changes in osteoporosis: a review. Clin. Orthop. Relat. Res. 443, 28–38 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Day, J. S. et al. Adaptation of subchondral bone in osteoarthritis. Biorheology 41, 359–368 (2004).

    CAS  PubMed  Google Scholar 

  42. 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 

  43. Goldring, M. B. & Goldring, S. R. Osteoarthritis. J. Cell. Physiol. 213, 626–634 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Akizuki, S., Mow, V. C., Muller, F., Pita, J. C. & Howell, D. S. Tensile properties of human knee joint cartilage. II. Correlations between weight bearing and tissue pathology and the kinetics of swelling. J. Orthop. Res. 5, 173–186 (1987).

    Article  CAS  PubMed  Google Scholar 

  45. Roberts, S., Weightman, B., Urban, J. & Chappell, D. Mechanical and biochemical properties of human articular cartilage in osteoarthritic femoral heads and in autopsy specimens. J. Bone Joint Surg. Br. 68, 278–288 (1986).

    Article  CAS  PubMed  Google Scholar 

  46. Calvo, E. et al. Histopathological correlation of cartilage swelling detected by magnetic resonance imaging in early experimental osteoarthritis. Osteoarthritis Cartilage 12, 878–886 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Wu, W. et al. Sites of collagenase cleavage and denaturation of type II collagen in aging and osteoarthritic articular cartilage and their relationship to the distribution of matrix metalloproteinase 1 and matrix metalloproteinase 13. Arthritis Rheum. 46, 2087–2094 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Fosang, A. J. & Beier, F. Emerging frontiers in cartilage and chondrocyte biology. Best Pract. Res. Clin. Rheumatol. 25, 751–766 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. Eyre, D. R. Collagens and cartilage matrix homeostasis. Clin. Orthop. Relat. Res. 427 (Suppl.), S118–S122 (2004).

    Article  Google Scholar 

  50. Wang, M. et al. MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Res. Ther. 15, R5 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Scanzello, C. R. & Goldring, S. R. The role of synovitis in osteoarthritis pathogenesis. Bone 51, 249–257 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Loeser, R. F. Aging processes and the development of osteoarthritis. Curr. Opin. Rheumatol. 25, 108–113 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Pritzker, K. P. et al. Osteoarthritis cartilage histopathology: grading and staging. Osteoarthritis Cartilage 14, 13–29 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Zhou, S. et al. Influence of osteoarthritis grade on molecular signature of human cartilage. J. Orthop. Res. 34, 454–462 (2016).

    Article  CAS  PubMed  Google Scholar 

  55. Radin, E. L. et al. Effects of mechanical loading on the tissues of the rabbit knee. J. Orthop. Res. 2, 221–234 (1984).

    Article  CAS  PubMed  Google Scholar 

  56. Lorenzo, P., Bayliss, M. T. & Heinegard, D. Altered patterns and synthesis of extracellular matrix macromolecules in early osteoarthritis. Matrix Biol. 23, 381–391 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Rolauffs, B. et al. Proliferative remodeling of the spatial organization of human superficial chondrocytes distant from focal early osteoarthritis. Arthritis Rheum. 62, 489–498 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. McGlashan, S. R., Cluett, E. C., Jensen, C. G. & Poole, C. A. Primary cilia in osteoarthritic chondrocytes: from chondrons to clusters. Dev. Dyn. 237, 2013–2020 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Hwang, H. S. & Kim, H. A. Chondrocyte apoptosis in the pathogenesis of osteoarthritis. Int. J. Mol. Sci. 16, 26035–26054 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Liu-Bryan, R. & Terkeltaub, R. Emerging regulators of the inflammatory process in osteoarthritis. Nat. Rev. Rheumatol. 11, 35–44 (2015).

    Article  CAS  PubMed  Google Scholar 

  61. 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 

  62. Suri, S. & Walsh, D. A. Osteochondral alterations in osteoarthritis. Bone 51, 204–211 (2012).

    Article  PubMed  Google Scholar 

  63. Saito, T. et al. Transcriptional regulation of endochondral ossification by HIF-2α during skeletal growth and osteoarthritis development. Nat. Med. 16, 678–686 (2010).

    Article  CAS  PubMed  Google Scholar 

  64. Yang, S. et al. Hypoxia-inducible factor-2α is a catabolic regulator of osteoarthritic cartilage destruction. Nat. Med. 16, 687–693 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Hashimoto, K. et al. Regulated transcription of human matrix metalloproteinase 13 (MMP13) and interleukin-1β (IL1B) genes in chondrocytes depends on methylation of specific proximal promoter CpG sites. J. Biol. Chem. 288, 10061–10072 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ruan, M. Z. et al. Proteoglycan 4 expression protects against the development of osteoarthritis. Sci. Transl. Med. 5, 176ra134 (2013).

    Article  CAS  Google Scholar 

  67. Kim, J. H. et al. Regulation of the catabolic cascade in osteoarthritis by the zinc-ZIP8-MTF1 axis. Cell 156, 730–743 (2014).

    Article  CAS  PubMed  Google Scholar 

  68. Lane, L. B., Villacin, A. & Bullough, P. G. The vascularity and remodelling of subchondrial bone and calcified cartilage in adult human femoral and humeral heads. An age- and stress-related phenomenon. J. Bone Joint Surg. Br. 59, 272–278 (1977).

    Article  CAS  PubMed  Google Scholar 

  69. Burr, D. B. & Schaffler, M. B. The involvement of subchondral mineralized tissues in osteoarthrosis: quantitative microscopic evidence. Microsc. Res. Tech. 37, 343–357 (1997).

    Article  CAS  PubMed  Google Scholar 

  70. Bullough, P. G. The role of joint architecture in the etiology of arthritis. Osteoarthritis Cartilage 12 (Suppl. A), S2–S9 (2004).

    Article  PubMed  Google Scholar 

  71. Walsh, D. A. et al. Angiogenesis in the synovium and at the osteochondral junction in osteoarthritis. Osteoarthritis Cartilage 15, 743–751 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Walsh, D. A. Angiogenesis in osteoarthritis and spondylosis: successful repair with undesirable outcomes. Curr. Opin. Rheumatol. 16, 609–615 (2004).

    Article  PubMed  Google Scholar 

  73. Suri, S. et al. Neurovascular invasion at the osteochondral junction and in osteophytes in osteoarthritis. Ann. Rheum. Dis. 66, 1423–1428 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Ashraf, S. et al. Increased vascular penetration and nerve growth in the meniscus: a potential source of pain in osteoarthritis. Ann. Rheum. Dis. 70, 523–529 (2011).

    Article  PubMed  Google Scholar 

  75. Ashraf, S. & Walsh, D. A. Angiogenesis in osteoarthritis. Curr. Opin. Rheumatol. 20, 573–580 (2008).

    Article  PubMed  Google Scholar 

  76. Reichenbach, S. et al. Prevalence of bone attrition on knee radiographs and MRI in a community-based cohort. Osteoarthritis Cartilage 16, 1005–1010 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 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 

  78. Goldring, S. R. The role of bone in osteoarthritis pathogenesis. Rheum. Dis. Clin. North Am. 34, 561–571 (2008).

    Article  PubMed  Google Scholar 

  79. Buckland-Wright, C. Subchondral bone changes in hand and knee osteoarthritis detected by radiography. Osteoarthritis Cartilage 12 (Suppl. A), S10–S19 (2004).

    Article  PubMed  Google Scholar 

  80. Buckland-Wright, J. C., Messent, E. A., Bingham, C. O. 3rd, Ward, R. J. & Tonkin, C. A 2 yr longitudinal radiographic study examining the effect of a bisphosphonate (risedronate) upon subchondral bone loss in osteoarthritic knee patients. Rheumatology (Oxford) 46, 257–264 (2007).

    Article  CAS  Google Scholar 

  81. Dieppe, P., Cushnaghan, J., Young, P. & Kirwan, J. Prediction of the progression of joint space narrowing in osteoarthritis of the knee by bone scintigraphy. Ann. Rheum. Dis. 52, 557–563 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Hutton, C. W., Higgs, E. R., Jackson, P. C., Watt, I. & Dieppe, P. A. 99mTc HMDP bone scanning in generalised nodal osteoarthritis. II. The four hour bone scan image predicts radiographic change. Ann. Rheum. Dis. 45, 622–626 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kim, H. R., So, Y., Moon, S. G., Lee, I. S. & Lee, S. H. Clinical value of 99mTc-methylene diphosphonate (MDP) bone single photon emission computed tomography (SPECT) in patients with knee osteoarthritis. Osteoarthritis Cartilage 16, 212–218 (2008).

    Article  PubMed  Google Scholar 

  84. Addison, S., Coleman, R. E., Feng, S., McDaniel, G. & Kraus, V. B. Whole-body bone scintigraphy provides a measure of the total-body burden of osteoarthritis for the purpose of systemic biomarker validation. Arthritis Rheum. 60, 3366–3373 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Anderson, D. D. et al. Post-traumatic osteoarthritis: improved understanding and opportunities for early intervention. J. Orthop. Res. 29, 802–809 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Kuroki, K., Cook, C. R. & Cook, J. L. Subchondral bone changes in three different canine models of osteoarthritis. Osteoarthritis Cartilage 19, 1142–1149 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. Fahlgren, A., Messner, K. & Aspenberg, P. Meniscectomy leads to an early increase in subchondral bone plate thickness in the rabbit knee. Acta Orthop. Scand. 74, 437–441 (2003).

    Article  PubMed  Google Scholar 

  88. Botter, S. M. et al. Cartilage damage pattern in relation to subchondral plate thickness in a collagenase-induced model of osteoarthritis. Osteoarthritis Cartilage 16, 506–514 (2008).

    Article  CAS  PubMed  Google Scholar 

  89. Pauly, H. M. et al. Assessment of cortical and trabecular bone changes in two models of post-traumatic osteoarthritis. J. Orthop. Res. 33, 1835–1845 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ko, F. C. et al. In vivo cyclic compression causes cartilage degeneration and subchondral bone changes in mouse tibiae. Arthritis Rheum. 65, 1569–1578 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Poulet, B., Hamilton, R. W., Shefelbine, S. & Pitsillides, A. A. Characterizing a novel and adjustable noninvasive murine joint loading model. Arthritis Rheum. 63, 137–147 (2011).

    Article  PubMed  Google Scholar 

  92. 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 

  93. Karvonen, R. L., Miller, P. R., Nelson, D. A., Granda, J. L. & Fernandez-Madrid, F. Periarticular osteoporosis in osteoarthritis of the knee. J. Rheumatol. 25, 2187–2194 (1998).

    CAS  PubMed  Google Scholar 

  94. Wilson, A. J., Murphy, W. A., Hardy, D. C. & Totty, W. G. Transient osteoporosis: transient bone marrow edema? Radiology 167, 757–760 (1988).

    Article  CAS  PubMed  Google Scholar 

  95. Taljanovic, M. S. et al. Bone marrow edema pattern in advanced hip osteoarthritis: quantitative assessment with magnetic resonance imaging and correlation with clinical examination, radiographic findings, and histopathology. Skeletal Radiol. 37, 423–431 (2008).

    Article  PubMed  Google Scholar 

  96. Leydet-Quilici, H. et al. Advanced hip osteoarthritis: magnetic resonance imaging aspects and histopathology correlations. Osteoarthritis Cartilage 18, 1429–1435 (2010).

    Article  CAS  PubMed  Google Scholar 

  97. Zanetti, M., Bruder, E., Romero, J. & Hodler, J. Bone marrow edema pattern in osteoarthritic knees: correlation between MR imaging and histologic findings. Radiology 215, 835–840 (2000).

    Article  CAS  PubMed  Google Scholar 

  98. Kothari, A. et al. Within-subregion relationship between bone marrow lesions and subsequent cartilage loss in knee osteoarthritis. Arthritis Care Res. (Hoboken) 62, 198–203 (2010).

    Google Scholar 

  99. Roemer, F. W., Hunter, D. J. & Guermazi, A. MRI-based semiquantitative assessment of subchondral bone marrow lesions in osteoarthritis research. Osteoarthritis Cartilage 17, 414–415 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Roemer, F. W. et al. Presence of MRI-detected joint effusion and synovitis increases the risk of cartilage loss in knees without osteoarthritis at 30-month follow-up: the MOST study. Ann. Rheum. Dis. 70, 1804–1809 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Roemer, F. W. et al. What comes first? Multitissue involvement leading to radiographic osteoarthritis: magnetic resonance imaging-based trajectory analysis over four years in the osteoarthritis initiative. Arthritis Rheumatol. 67, 2085–2096 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Hunter, D. J. et al. Increase in bone marrow lesions associated with cartilage loss: a longitudinal magnetic resonance imaging study of knee osteoarthritis. Arthritis Rheum. 54, 1529–1535 (2006).

    Article  PubMed  Google Scholar 

  103. Felson, D. T. et al. Bone marrow edema and its relation to progression of knee osteoarthritis. Ann. Intern. Med. 139, 330–336 (2003).

    Article  PubMed  Google Scholar 

  104. Hernandez-Molina, G. et al. The association of bone attrition with knee pain and other MRI features of osteoarthritis. Ann. Rheum. Dis. 67, 43–47 (2008).

    Article  CAS  PubMed  Google Scholar 

  105. Lo, G. H., Hunter, D. J., Nevitt, M., Lynch, J. & McAlindon, T. E. Strong association of MRI meniscal derangement and bone marrow lesions in knee osteoarthritis: data from the osteoarthritis initiative. Osteoarthritis Cartilage 17, 743–747 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Bowes, M. A. et al. Osteoarthritic bone marrow lesions almost exclusively colocate with denuded cartilage: a 3D study using data from the Osteoarthritis Initiative. Ann. Rheum. Dis., http://dx.doi.org/10.1136/annrheumdis-2015-208407 (2015).

  107. Sokoloff, L. Microcracks in the calcified layer of articular cartilage. Arch. Pathol. Lab. Med. 117, 191–195 (1993).

    CAS  PubMed  Google Scholar 

  108. Lacourt, M. et al. Relationship between cartilage and subchondral bone lesions in repetitive impact trauma-induced equine osteoarthritis. Osteoarthritis Cartilage 20, 572–583 (2012).

    Article  CAS  PubMed  Google Scholar 

  109. Norrdin, R. W. & Stover, S. M. Subchondral bone failure in overload arthrosis: a scanning electron microscopic study in horses. J. Musculoskelet. Neuronal Interact. 6, 251–257 (2006).

    CAS  PubMed  Google Scholar 

  110. Boyde, A. & Firth, E. C. High resolution microscopic survey of third metacarpal articular calcified cartilage and subchondral bone in the juvenile horse: possible implications in chondro-osseous disease. Microsc. Res. Tech. 71, 477–488 (2008).

    Article  PubMed  Google Scholar 

  111. Mori, S. & Burr, D. B. Increased intracortical remodeling following fatigue damage. Bone 14, 103–109 (1993).

    Article  CAS  PubMed  Google Scholar 

  112. Mori, S., Harruff, R. & Burr, D. B. Microcracks in articular calcified cartilage of human femoral heads. Arch. Pathol. Lab. Med. 117, 196–198 (1993).

    CAS  PubMed  Google Scholar 

  113. Schaffler, M. B., Cheung, W. Y., Majeska, R. & Kennedy, O. Osteocytes: master orchestrators of bone. Calcif. Tissue Int. 94, 5–24 (2014).

    Article  CAS  PubMed  Google Scholar 

  114. Kennedy, O. D. et al. Activation of resorption in fatigue-loaded bone involves both apoptosis and active pro-osteoclastogenic signaling by distinct osteocyte populations. Bone 50, 1115–1122 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Kennedy, O. D., Laudier, D. M., Majeska, R. J., Sun, H. B. & Schaffler, M. B. Osteocyte apoptosis is required for production of osteoclastogenic signals following bone fatigue in vivo. Bone 64, 132–137 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Schaffler, M. B. & Kennedy, O. D. Osteocyte signaling in bone. Curr. Osteoporos Rep. 10, 118–125 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Bancroft, L. W., Peterson, J. J. & Kransdorf, M. J. Cysts, geodes, and erosions. Radiol. Clin. North Am. 42, 73–87 (2004).

    Article  PubMed  Google Scholar 

  118. Carrino, J. A., Blum, J., Parellada, J. A., Schweitzer, M. E. & Morrison, W. B. MRI of bone marrow edema-like signal in the pathogenesis of subchondral cysts. Osteoarthritis Cartilage 14, 1081–1085 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. Landells, J. W. The bone cysts of osteoarthritis. J. Bone Joint Surg. Br. 35-B, 643–649 (1953).

    Article  CAS  PubMed  Google Scholar 

  120. Rhaney, K. & Lamb, D. W. The cysts of osteoarthritis of the hip; a radiological and pathological study. J. Bone Joint Surg. Br. 37-B, 663–675 (1955).

    Article  CAS  PubMed  Google Scholar 

  121. Crema, M. D. et al. Subchondral cystlike lesions develop longitudinally in areas of bone marrow edema-like lesions in patients with or at risk for knee osteoarthritis: detection with MR imaging—the MOST study. Radiology 256, 855–862 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Crema, M. D. et al. Contrast-enhanced MRI of subchondral cysts in patients with or at risk for knee osteoarthritis: the MOST study. Eur. J. Radiol 75, e92–e96 (2010).

    Article  CAS  PubMed  Google Scholar 

  123. 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 

  124. Tanamas, S. K. et al. The association between subchondral bone cysts and tibial cartilage volume and risk of joint replacement in people with knee osteoarthritis: a longitudinal study. Arthritis Res. Ther. 12, R58 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Wluka, A. E. et al. Bone marrow lesions can be subtyped into groups with different clinical outcomes using two magnetic resonance imaging (MRI) sequences. Arthritis Res. Ther. 17, 270 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Guyton, G. P. & Brand, R. A. Apparent spontaneous joint restoration in hip osteoarthritis. Clin. Orthop. Relat. Res. 404, 302–307 (2002).

    Article  Google Scholar 

  127. Messent, E. A., Ward, R. J., Tonkin, C. J. & Buckland-Wright, C. Osteophytes, juxta-articular radiolucencies and cancellous bone changes in the proximal tibia of patients with knee osteoarthritis. Osteoarthritis Cartilage 15, 179–186 (2007).

    Article  CAS  PubMed  Google Scholar 

  128. van der Kraan, P. M. & van den Berg, W. B. Osteophytes: relevance and biology. Osteoarthritis Cartilage 15, 237–244 (2007).

    Article  PubMed  Google Scholar 

  129. Pottenger, L. A., Phillips, F. M. & Draganich, L. F. The effect of marginal osteophytes on reduction of varus-valgus instability in osteoarthritic knees. Arthritis Rheum. 33, 853–858 (1990).

    Article  CAS  PubMed  Google Scholar 

  130. Felson, D. T. et al. Osteophytes and progression of knee osteoarthritis. Rheumatology (Oxford) 44, 100–104 (2005).

    Article  CAS  Google Scholar 

  131. Scharstuhl, A. et al. Inhibition of endogenous TGF-β during experimental osteoarthritis prevents osteophyte formation and impairs cartilage repair. J. Immunol. 169, 507–514 (2002).

    Article  CAS  PubMed  Google Scholar 

  132. Scharstuhl, A., Vitters, E. L., van der Kraan, P. M. & van den Berg, W. B. Reduction of osteophyte formation and synovial thickening by adenoviral overexpression of transforming growth factor β/bone morphogenetic protein inhibitors during experimental osteoarthritis. Arthritis Rheum. 48, 3442–3451 (2003).

    Article  CAS  PubMed  Google Scholar 

  133. van Beuningen, H. M., Glansbeek, H. L., van der Kraan, P. M. & van den Berg, W. B. Differential effects of local application of BMP-2 or TGF-β 1 on both articular cartilage composition and osteophyte formation. Osteoarthritis Cartilage 6, 306–317 (1998).

    Article  CAS  PubMed  Google Scholar 

  134. van Beuningen, H. M., Glansbeek, H. L., van der Kraan, P. M. & van den Berg, W. B. Osteoarthritis-like changes in the murine knee joint resulting from intra-articular transforming growth factor-β injections. Osteoarthritis Cartilage 8, 25–33 (2000).

    Article  CAS  PubMed  Google Scholar 

  135. Findlay, D. M. & Atkins, G. J. Osteoblast-chondrocyte interactions in osteoarthritis. Curr. Osteoporos. Rep. 12, 127–134 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Brower, t. d., Akahoshi, Y. & Orlic, P. The diffusion of dyes through articular cartilage in vivo. J. Bone Joint Surg. 44, 456–453 (1962).

    Article  Google Scholar 

  137. Maroudas, A., Bullough, P., Swanson, S. A. & Freeman, M. A. The permeability of cartilage. J. Bone Joint Surg. 50, 166–177 (1968).

    Article  CAS  Google Scholar 

  138. Radin, E. L. & Rose, R. M. Role of subchondral bone in the initiation and progression of cartilage damage. Clin. Orthop. Relat. Res. 212, 34–40 (1986).

    Google Scholar 

  139. Huebner, J. L., Hanes, M. A., Beekman, B., TeKoppele, J. M. & Kraus, V. B. A comparative analysis of bone and cartilage metabolism in two strains of guinea-pig with varying degrees of naturally occurring osteoarthritis. Osteoarthritis Cartilage 10, 758–767 (2002).

    Article  CAS  PubMed  Google Scholar 

  140. Amin, A. K., Huntley, J. S., Simpson, A. H. & Hall, A. C. Chondrocyte survival in articular cartilage: the influence of subchondral bone in a bovine model. J. Bone Joint Surg. Br. 91, 691–699 (2009).

    Article  CAS  PubMed  Google Scholar 

  141. Sanchez, C. et al. Subchondral bone osteoblasts induce phenotypic changes in human osteoarthritic chondrocytesfrom the sclerotic zones of osteoarthritic. Osteoarthritis Cartilage 13, 988–997 (2005).

    Article  CAS  PubMed  Google Scholar 

  142. 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 

  143. Zhang, R. et al. Gene expression analysis of subchondral bone in early experimental osteoarthritis by microarray. PLoS ONE 7, e32356 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Chou, C. H. et al. Genome-wide expression profiles of subchondral bone in osteoarthritis. Arthritis Res. Ther. 15, R190 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. 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 

  146. Lotz, M. K. & Kraus, V. B. New developments in osteoarthritis. Posttraumatic osteoarthritis: pathogenesis and pharmacological treatment options. Arthritis Res. Ther. 12, 211 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Martel-Pelletier, J., Wildi, L. M. & Pelletier, J. P. Future therapeutics for osteoarthritis. Bone 51, 297–311 (2012).

    Article  CAS  PubMed  Google Scholar 

  148. Mobasheri, A. The future of osteoarthritis therapeutics: emerging biological therapy. Curr. Rheumatol. Rep. 15, 385 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Mobasheri, A. The future of osteoarthritis therapeutics: targeted pharmacological therapy. Curr. Rheumatol. Rep. 15, 364 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Goldring, M. B. & Berenbaum, F. Emerging targets in osteoarthritis therapy. Curr. Opin. Pharmacol. 22, 51–63 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Goldring, S. R. Needs and opportunities in the assessment and treatment of osteoarthritis of the knee and hip: the view of the rheumatologist. J. Bone Joint Surg. Am. 91 (Suppl. 1), 4–6, (2009).

    Article  PubMed  Google Scholar 

  152. Karsdal, M. A. et al. The coupling of bone and cartilage turnover in osteoarthritis: opportunities for bone antiresorptives and anabolics as potential treatments? Ann. Rheum. Dis. 73, 336–348 (2014).

    Article  CAS  PubMed  Google Scholar 

  153. Roubille, C., Pelletier, J. P. & Martel-Pelletier, J. New and emerging treatments for osteoarthritis management: will the dream come true with personalized medicine? Expert Opin. Pharmacother. 14, 2059–2077 (2013).

    Article  CAS  PubMed  Google Scholar 

  154. Little, C. B. & Hunter, D. J. Post-traumatic osteoarthritis: from mouse models to clinical trials. Nat. Rev. Rheumatol. 9, 485–497 (2013).

    Article  CAS  PubMed  Google Scholar 

  155. Spector, T. D. et al. Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized, controlled trial [ISRCTN01928173]. Arthritis Res. Ther. 7, R625–R633 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Bingham, C. O., 3rd 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. 54, 3494–3507 (2006).

    Article  CAS  PubMed  Google Scholar 

  157. Garnero, P. et al. Relationships between biochemical markers of bone and cartilage degradation with radiological progression in patients with knee osteoarthritis receiving risedronate: the Knee Osteoarthritis Structural Arthritis randomized clinical trial. Osteoarthritis Cartilage 16, 660–666 (2008).

    Article  CAS  PubMed  Google Scholar 

  158. Laslett, L. L. et al. Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: a randomised controlled trial. Ann. Rheum. Dis. 71, 1322–1328 (2012).

    Article  CAS  PubMed  Google Scholar 

  159. Karsdal, M. A. et al. Treatment of symptomatic knee osteoarthritis with oral salmon calcitonin: results from two phase 3 trials. Osteoarthritis Cartilage 23, 532–543 (2015).

    Article  CAS  PubMed  Google Scholar 

  160. Matthews, G. L. & Hunter, D. J. Emerging drugs for osteoarthritis. Expert Opin. Emerg. Drugs 16, 479–491 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Hawker, G. A. & Stanaitis, I. Osteoarthritis year in review 2014: clinical. Osteoarthritis Cartilage 22, 1953–1957 (2014).

    Article  CAS  PubMed  Google Scholar 

  162. Bay-Jensen, A. C. et al. Osteoarthritis year in review 2015: soluble biomarkers and the BIPED criteria. Osteoarthritis Cartilage 24, 9–20 (2016).

    Article  CAS  PubMed  Google Scholar 

  163. Kraus, V. B. et al. OARSI Clinical Trials Recommendations: Soluble biomarker assessments in clinical trials in osteoarthritis. Osteoarthritis Cartilage 23, 686–697 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Eckstein, F., Kwoh, C. K., Link, T. M. & OAI Investigators Imaging research results from the osteoarthritis initiative (OAI): a review and lessons learned 10 years after start of enrolment. Ann. Rheum. Dis. 73, 1289–1300 (2014).

    Article  PubMed  Google Scholar 

  165. Wright, T. Biomechanical factors in osteoarthritis: the effects of joint instability. HSS J. 8, 15–17 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Andriacchi, T. P., Favre, J., Erhart-Hledik, J. C. & Chu, C. R. A systems view of risk factors for knee osteoarthritis reveals insights into the pathogenesis of the disease. Ann. Biomed. Eng. 43, 376–387 (2015).

    Article  PubMed  Google Scholar 

  167. Courties, A., Gualillo, O., Berenbaum, F. & Sellam, J. Metabolic stress-induced joint inflammation and osteoarthritis. Osteoarthritis Cartilage 23, 1955–1965 (2015).

    Article  CAS  PubMed  Google Scholar 

  168. Ko, F. C. et al. Progressive cell-mediated changes in articular cartilage and bone in mice are initiated by a single session of controlled cyclic compressive loading. J. Orthop. Res. http://dx.doi.org/10.1002/jor.23204 (2016).

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Acknowledgements

The authors' work is supported by NIH grants R01-AG022021 (to M.B.G.) and RC4-AR060546 (to M.B.G.).

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    Steven R. Goldring & Mary B. Goldring

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Goldring, S., Goldring, M. Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage–bone crosstalk. Nat Rev Rheumatol 12, 632–644 (2016). https://doi.org/10.1038/nrrheum.2016.148

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