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  • Review Article
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Biologic agents in osteoarthritis: hopes and disappointments

Nature Reviews Rheumatology volume 9, pages 400–410 (2013)Cite this article

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Abstract

New treatment options are needed for osteoarthritis (OA) to slow down the structural progression of the disease; current therapies mostly target pain and function with minimal effectiveness. OA results from an imbalance between catabolic and anabolic factors, and biologic agents either target specific catabolic proinflammatory mediators, such as cytokines, nitric oxide synthesis, or affect anabolism more generally. Biologic agents have dramatic effects in other rheumatic inflammatory diseases such as rheumatoid arthritis; they were hoped to have similar effects in the treatment of OA. In this Review, we will discuss the three main types of cytokine blockers used in knee and hand OA, which target β-nerve growth factor (β-NGF), IL-1β or TNF. We will also discuss inhibitors of nitrogen oxide production and the use of growth factors to treat OA. Among the targeted agents, anti-β-NGF therapy has shown promising results, although cases of rapid destructive arthropathy caution against its widespread use. The future of therapies targeting cytokines, nitrogen oxide synthesis and growth factors in OA is questionable, as results from clinical trials have been repeatedly negative. Strategies in OA therapy need to be reconsidered. New molecules emerging from preclinical data should focus on treating the early phase of the disease where damage may be reversible, and treatment should be modified to fit each patient.

Key Points

  • Targeted therapy against β-nerve growth factor (β-NGF) in knee osteoarthritis (OA) has resulted in dramatic improvements in symptoms but reports of unexpected, rapid, destructive arthropathies suggest major safety concerns

  • Anti-IL-1β therapy using either intra-articular injection or systemic administration failed to demonstrate any clinical improvement in patients with knee OA

  • Systemic and subcutaneous injections have been used to deliver anti-TNF therapy in patients with polyarticular hand OA and knee OA, respectively; neither strategy has resulted in structural effects or clinical improvement

  • Therapies targeting nitrogen oxide synthesis (administered orally) or local delivery of growth factors in patients with knee OA did not show clinical or structural improvements

  • Future strategies should differentiate between those agents aiming to reduce pain, such as anti-β-NGF treatments, and those targeting structural evolution, which have had disappointing results

  • Emerging therapies should fit the natural progression of OA, focus on early disease where changes might be reversible, and take into account the location and heterogeneity of the disease

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Figure 1: Cytokine production in OA.
Figure 2: Extracellular and intracellular sites of IL-1β blockade.
Figure 3: Effect of a single intra-articular injection of IL-1Ra (anakinra) (50 mg or 150 mg) versus placebo in patients with symptomatic knee OA.51
Figure 4: Effect of adalimumab on new erosions in patients with hand OA.

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References

  1. Felson, D. T. et al. Osteoarthritis: new insight. Part 1: The disease and its risk factors. Ann. Intern. Med. 133, 635–646 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Bijlsma, J. W., Berenbaum, F. & Lafeber, F. P. Osteoarthritis: an update with relevance for clinical practice. Lancet 377, 2115–2126 (2011).

    Article  PubMed  Google Scholar 

  3. Felson, D. Epidemiology of osteoarthritis. In Osteoarthritis (eds Brandt, K. D., Doherty, M. & Lohmander, L. S.) 9–16 (Oxford University Press, 2003).

    Google Scholar 

  4. Pottie, P. et al. Obesity and osteoarthritis: more complex than predicted! Ann. Rheum. Dis. 65, 1403–1405 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhang, W. et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 16, 137–162 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Zhang, W. et al. EULAR evidence based recommendations for the management of hand osteoarthritis: report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann. Rheum. Dis. 66, 377–388 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Hochberg, M. C. et al. American College of Rheumatology 2012 recommendations for the use of non pharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. (Hoboken) 64, 455–474 (2012).

    Article  CAS  Google Scholar 

  8. Cooper, C. et al. Efficacy and safety of oral strontium ranelate for the treatment of knee osteoarthritis: rationale and design of randomised, double-blind, placebo-controlled trial. Curr. Med. Res. Opin. 28, 231–239 (2012).

    Article  CAS  PubMed  Google Scholar 

  9. 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 

  10. Mapp., P. I. & Walsh, D. A. Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis. Nat. Rev. Rheumatol. 8, 390–398 (2012).

    Article  CAS  PubMed  Google Scholar 

  11. Pelletier, J. P., Martel-Pelletier, J. & Abramson, S. E. Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. Arthritis Rheum. 44, 1237–1247 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Chevalier, X. Physiopathogenesis of osteoarthritis. The osteoarthritic cartilage. Presse Med. 27, 81–87 (1998).

    CAS  PubMed  Google Scholar 

  13. Goldring, S. R., and Goldring, M. B. The role of cytokines in cartilage matrix degeneration in osteoarthritis. Clin. Orthop. Rel. Res. 427, S27–S36 (2004).

    Article  Google Scholar 

  14. Chevalier, X. Upregulation of enzymatic activity by interleukin-1 in osteoarthritis. Biomed. Pharmacother. 51, 58–62 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Benito, M. J., Veale, D. J., Fitzgerald, O., Van den Berg, W. B. & Bresnisham, B. Synovial tissue inflammation in early and late osteoarthritis. Ann. Rheum. Dis. 64, 1263–1267 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Blom, A. B. et al. Crucial role of macrophages in matrix metalloproteinases-mediates cartilage destruction during experimental osteoarthritis. Arthritis Rheum. 56, 147–157 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Bondeson, J. Activated synovial macrophages as target for osteoarthritis. Curr. Drug Targets 11, 576–585 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Hill, C. L. et al. Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis. Ann. Rheum. Dis. 66, 1599–1603 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Menashe, L. et al. The diagnostic performance of MRI in osteoarthritis: a systematic review and meta-analysis. Osteoarthritis Cartilage 20, 13–21 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Ayral, X., Pickering, E. H., Woodworth, T. G., Mackillop, N. & Dougados, M. 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 13, 361–367 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Bonnet, C. S. & Walsh, D. A. Osteoarthritis, angiogenesis and inflammation. Rheumatology (Oxford) 44, 7–16 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Pesesse, L., Sanchez, C. & Henrotin, Y. Osteochondral plate angiogenesis: a new treatment target in osteoarthritis. Joint Bone Spine 78, 144–149 (2011).

    Article  PubMed  Google Scholar 

  23. 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, interleukin–1β and oncostatin M pre-treated non-sclerotic osteoblasts. Osteoarthritis Cartilage 13, 979–987 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Mamelud, C. J. Cytokines as therapeutic targets for osteoarthritis. Biodrugs 18, 23–35 (2004).

    Article  Google Scholar 

  25. Sachs, D. et al. Tumour necrosis factor-alpha, interleukin–1β and interleukin-8 induce persistent mechanical nociceptor hypersensitivity. Pain 96, 89–97 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Blom, A. B., van der Kraan, P. M. & van der Berg, W. B. Cytokine targeting in osteoarthritis. Curr. Drug Targets 8, 283–292 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Abramson, S. B. & Yazici, Y. Biologics in the development for rheumatoid arthritis: relevance to osteoarthritis. Adv. Drug Del. Rev. 58, 212–215 (2006).

    Article  CAS  Google Scholar 

  28. Chevalier, X. Intraarticular treatments for osteoarthritis: new perspectives. Curr. Drug Targets 11, 546–560 (2010).

    Article  PubMed  Google Scholar 

  29. Wood, J. N. Nerve growth factor and pain. N. Engl. J. Med. 363, 1572–1573 (2010).

    Article  PubMed  Google Scholar 

  30. Isola, M. et al. Nerve growth factor concentrations in the synovial fluid from healthy dogs and dogs with secondary osteoarthritis. Vet. Comp. Orthop. Traumatol. 24, 279–284 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Barthel, C. et al. Nerve growth factor and receptor expression in rheumatoid arthritis and spondyloarthritis. Arthritis Res. Ther. 11, R82 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Raychaudhuri, S. P., Raychaudhuri, S. K., Atkuri, K. R., Herzenberg, L. A. & Herzenberg, L. A. Nerve growth factor: A key local regulator in the pathogenesis of inflammatory arthritis. Arthritis Rheum. 63, 3243–3252 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Kumar, V., and Mahal, B. A. NGF—the TrkA to successful pain treatment. J. Pain Res. 5, 279–287 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Brown, M. T. et al. Tanezumab reduces osteoarthritic knee pain: results of a randomized, double-blind, placebo-controlled phase III trial. J. Pain 13, 790–798 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Nagashima, H., Suzuki, M., Araki, S., Yamabe, T. & Muto, C. Tanezumab Investigators. Preliminary assessment of the safety and efficacy of tanezumab in Japanese patients with moderate to severe osteoarthritis of the knee: a randomized, double-blind, dose-escalation, placebo-controlled study. Osteoarthritis Cartilage 19, 1405–1412 (2011).

    Article  CAS  PubMed  Google Scholar 

  36. Schnitzer, T. J. et al. Long-term open-label study of tanezumab for moderate to severe osteoarthritic knee pain. Osteoarthritis Cartilage 19, 639–646 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Lane, N. E. et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N. Engl. J. Med. 363, 1521–1531 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Katz, N. et al. Efficacy and safety of tanezumab in the treatment of chronic low back pain. Pain 152, 2248–2258 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Chevalier, X., Mugnier, B. & Bouvenot, G. Targeted anti-cytokine therapies for osteoarthritis. Bull. Acad. Natl Med. 190, 1411–1420 (2006).

    CAS  PubMed  Google Scholar 

  40. Seidel, M. F. & Lane, N. E. Control of arthritis pain with anti-nerve-growth factor: Risk and benefit. Curr. Rheumatol. Rep. 6, 583–588 (2012).

    Article  CAS  Google Scholar 

  41. Chandrasekhar, S., Harvey, A. K. & Hrubey, P. S. Intra-articular administration of interleukin-1 causes prolonged suppression of cartilage proteoglycan synthesis in rats. Matrix 12, 1–10 (1992).

    Article  CAS  PubMed  Google Scholar 

  42. Caron, J. P. et al. Chondroprotective effect of intra-articular injections of interleukin-1 receptor antagonist in experimental osteoarthritis. Suppression of collagenase-1 expression. Arthritis Rheum. 39, 1535–1544 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Pelletier, J. P. et al. In vivo suppression of early experimental osteoarthritis by interleukin-1 receptor antagonist using gene therapy. Arthritis Rheum. 40, 1012–1019 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Fernandes, J. C. et al. In vivo transfer of interleukin-1 receptor antagonist gene in osteoarthritic rabbit knee joints: prevention of osteoarthrosis progression. Am. J. Pathol. 154, 1159–1169 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhang, X, Mao, Z. & Yu, C. Suppression of early experimental osteoarthritis by gene transfer of interleukin-1 antagonist and interleukin-10. J. Orthop. Res. 22, 742–750 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Wang, H.J. et al. Suppression of experimental osteoarthritis by adenovirus-mediated double gene transfer. Chin. Med. J. 119, 1365–1373 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Santangelo, K. S., Nuovo, G. J. & Bertone, A. L. In vivo reduction or blockade of interleukin-1β in primary osteoarthritis influences expression of mediators implicated in pathogenesis. Osteoarthritis Cartilage 20, 1610–1618 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Clements, K. M. et al. Gene deletion of either interleukin-1β, interleukin-1β converting enzyme, inducible nitric oxide synthase, or stromelysin 1 accelerates the development of knee osteoarthritis in mice after surgical transection of the medial collateral ligament and partial medial menisectomy. Arthritis Rheum. 48, 3352–3363 (2003).

    Article  Google Scholar 

  49. Bougault, C. et al. Stress-induced cartilage degradation does not depend on NLRP3 inflammasome in osteoarthritis. Arthritis Rheum. 64, 3972–3981 (2012).

    Article  CAS  PubMed  Google Scholar 

  50. Chevalier, X. et al. Safety study of intraarticular injection of interleukin 1 receptor antagonist in patients with painful knee osteoarthritis: a multicenter study. J. Rheumatol. 32, 1317–1323 (2005).

    CAS  PubMed  Google Scholar 

  51. Chevalier, X. et al. Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 61, 344–352 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Loeuille, D. et al. Macroscopic and microscopic features of synovial membrane inflammation in the osteoarthritic knee: Correlating magnetic resonance imaging findings with disease severity. Arthritis Rheum. 52, 3492–3501 (2005).

    Article  PubMed  Google Scholar 

  53. Cohen, S. et al. A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee. Arthritis Res. Ther. 13, R125 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chevalier, X., Conrozier, T. H. & Richette, P. Desperately looking for the right target in osteoarthritis—The anti IL-1 strategy. Arthritis Res. Ther. 13, 124 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Hanna, F. S. et al. High sensitivity C-reactive protein is associated with lower tibial cartilage volume but not lower patella cartilage volume in healthy women at midlife. Arthritis Res. Ther. 10, R27 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Sharif, M., Shepstone, L., Elson, C. J., Dieppe, P. A. & Kirwan, J. R. Increased serum C reactive protein may reflect events that precede radiographic progression in osteoarthritis of the knee. Ann. Rheum. Dis. 59, 71–4 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Bacconnier, L., Jorgensen, C. & Fabre, S. Erosive osteoarthritis of the hand: clinical experience with anakinra. Ann. Rheum. Dis. 68, 1078–1079 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Bigoni, M. et al. Acute and late changes in intraarticular cytokine levels following anterior cruciate ligament injury. J. Orthop. Res. 31, 315–321 (2013).

    Article  CAS  PubMed  Google Scholar 

  59. Brown, C., Toth, A. & Magnussen, R. Clinical benefits of intra-articular anakinra for persistent knee effusion. J. Knee Surg. 24, 61–65 (2011).

    Article  PubMed  Google Scholar 

  60. Kraus, V. B. et al. Effects of intraarticular IL1-Ra for acute anterior cruciate ligament knee injury: a randomized controlled pilot trial (NCT00332254). Osteoarthritis Cartilage 20, 271–278 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Stannus, O. et al. Circulating levels of IL-6 and TNF-α are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults. Osteoarthritis Cartilage 18, 1441–1447 (2010).

    Article  CAS  PubMed  Google Scholar 

  62. Malfait, A. M. et al. Intra-articular injection of tumor necrosis factor-α in the rat: an acute and reversible in vivo model of cartilage proteoglycan degradation. Osteoarthritis Cartilage 17, 627–635 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Zhang, Q., Lv, H., Chen, A., Liu, F. & Wu, X. Efficacy of infliximab in a rabbit model of osteoarthritis. Connect. Tissue Res. 53, 355–358 (2012).

    Article  CAS  PubMed  Google Scholar 

  64. Punzi, L., Ramonda, R. & Sfriso, P. Erosive osteoarthritis. Best Pract. Res. Clin. Rheumatol. 18, 739–758 (2004).

    Article  PubMed  Google Scholar 

  65. Punzi, L. et al. Value of C reactive protein in the assessment of erosive osteoarthritis of the hand. Ann. Rheum. Dis. 64, 955–957 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Dziedzic, K. S. Osteoarthritis: best evidence for best therapies in hand osteoarthritis. Nat. Rev. Rheumatol. 7, 258–260 (2011).

    Article  PubMed  Google Scholar 

  67. Michon, M, Maheu, E. & Berenbaum, F. Assessing health-related quality of life in hand osteoarthritis: a literature review. Ann. Rheum. Dis. 70, 921–928 (2011).

    Article  CAS  PubMed  Google Scholar 

  68. Hill, S., Dziedzic, K. S. & Nio Ong, B. Patients' perceptions of the treatment and management of hand osteoarthritis: a focus group enquiry. Disabil. Rehabil. 33, 1866–1872 (2011).

    Article  PubMed  Google Scholar 

  69. Avouac, J., Marini-Portugal, A. & Chevalier, X. A propos d'un cas d'arthrose digitale érosive: réponse spectaculaire aux anti-TNF α. Revue Rhum. 71, 158 (2004).

    Google Scholar 

  70. Magnano, M. D., Chakravarty, E. F. & Broudy, C. A pilot study of tumor necrosis factor inhibition in erosive/inflammatory osteoarthritis of the hands. J. Rheumatol. 34, 1323–1327 (2007).

    CAS  PubMed  Google Scholar 

  71. Güler-Yüksel . et al. Treatment with TNF-α inhibitor infliximab might reduce hand osteoarthritis in patients with rheumatoid arthritis. Osteoarthritis Cartilage 18, 1256–1262 (2010).

    Article  PubMed  Google Scholar 

  72. Verbruggen, G., Wittoek, R., Cruyssen, B. V. & Elewaut, D. Tumour necrosis factor blockade for the treatment of erosive osteoarthritis of the interphalangeal finger joints: a double blind, randomised trial on structure modification. Ann. Rheum. Dis. 71, 891–898 (2012).

    Article  CAS  PubMed  Google Scholar 

  73. Chevalier, X. et al. A randomized, multicentre, double blind, placebo-controlled trial of anti TNF α (adalimumab) in refractory hand osteoarthritis: the Dora study. Arthritis Rheum. 64, 10 Suppl 10: 2472 (2012).

    Google Scholar 

  74. Fioravanti, A., Fabbroni, M., Cerase, A. & Galeazzi, M. Treatment of erosive osteoarthritis of the hands by intra-articular infliximab injections: a pilot study. Rheumatol. Int. 29, 961–965 (2009).

    Article  CAS  PubMed  Google Scholar 

  75. Grunke, M. & Schulze-Koops, H. Successful treatment of inflammatory knee osteoarthritis with tumour necrosis factor blockade. Ann. Rheum. Dis. 65, 555–556 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bollet, A. J. Edema of the bone marrow can cause pain in osteoarthritis and other diseases of bone and joints. Ann. Intern. Med. 134, 591–593 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Hayes, C. W. et al. Osteoarthritis of the knee: comparison of MR imaging findings with radiographic severity measurements and pain in middle-aged women. Radiology 237, 998–1007 (2005).

    Article  PubMed  Google Scholar 

  78. Schue, J. R. et al. Treatment of knee osteoarthritis with intraarticular infliximab. Arthritis Rheum. 63 (Suppl 9), S325, 826 (2011).

    Google Scholar 

  79. Maksymowych, W. P. et al. Targeting tumor necrosis factor alleviates signs and symptoms of inflammatory osteoarthritis. Arthritis Res. Ther. 14, R206 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Abramson, S. B. et al. The role of nitric oxide in tissue destruction. Best Pract. Res. Clin. Rheumatol. 15, 831–845 (2001).

    Article  CAS  PubMed  Google Scholar 

  81. Pelletier, J. P. et al. Selective inhibition of inducible nitric oxide synthase reduces progression of experimental osteoarthritis in vivo: possible link with the reduction in chondrocyte apoptosis and caspase 3 level. Arthritis Rheum. 43, 1290–1299 (2000).

    Article  CAS  PubMed  Google Scholar 

  82. Hellio le Graverand, M. P. et al. A 2-year randomised, double-blind, placebo-controlled, multicentre study of oral selective iNOS inhibitor, cindunistat (SD-6010), in patients with symptomatic osteoarthritis of the knee. Ann. Rheum. Dis. 72, 187–195 (2013).

    Article  CAS  PubMed  Google Scholar 

  83. Cook, S. D. & Rueger, D. C. Osteogenic protein-1: biology and applications. Clin. Orthop. Relat. Res. 324, 29–38 (1996).

    Article  Google Scholar 

  84. Sieber, C., Kopf, J., Hiepen, C. & Knaus, P. Recent advances in BMP receptor signaling. Cytokine Growth Factor Rev. 20, 343–355 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Wozney, J. M. Overview of bone morphogenetic proteins. Spine (Phila. Pa. 1976) 27 (16 Suppl. 1), S2–S8 (2002).

    Article  PubMed  Google Scholar 

  86. Hunter, D. J. et al. Phase 1 safety and tolerability study of BMP-7 in symptomatic knee osteoarthritis. BMC Musculoskelet. Disord. 11, 232 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Mc Pherson, R., Flechenshar, K., Hellot, S. & Eckstein, F. A randomized, double–blind, placebo controlled, multicenter study of FGF 18 administered intra articularly using single or multiple ascending doses in patients with primary knee osteoarthritis (0A), not expected to require knee surgery within a year. Osteoarthritis Cartilage 19 (Suppl. 1), S35–S36 (2011).

    Article  Google Scholar 

  88. Stewart, K. et al. The effect of growth factor treatment on meniscal chondrocyte proliferation and differentiation on polyglycolic acid scaffolds. Tissue Eng. 13, 271–280 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Ellsworth, J. L. et al. Fibroblast growth factor-18 is a trophic factor for mature chondrocytes and their progenitors. Osteoarthitis Cartilage 10, 308–320 (2002).

    Article  CAS  Google Scholar 

  90. Ohbayashi, N. et al. FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. Genes Dev. 16, 870–879 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Moore, E. E. et al. Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis. Osteoarthritis Cartilage 13, 623–631 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  93. Richette, P. et al. A high interleukin 1 receptor antagonist/IL-1β ratio occurs naturally in knee osteoarthritis. J. Rheumatol. 35, 1650–1654 (2008).

    CAS  PubMed  Google Scholar 

  94. Hunter, D. J. Pharmacologic therapy for osteoarthritis—the era of disease modification. Nat. Rev. Rheumatol. 7, 13–22 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Scanzello, C. R. et al. Synovial inflammation in patients undergoing arthroscopic meniscectomy: molecular characterization and relationship to symptoms. Arthritis Rheum. 63, 391–400 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Bondeson, J. et al. The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive responses in osteoarthritis. Arthritis Rheum. 62, 647–657 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. Bondeson, J. Are we moving in the right direction with osteoarthritis drug discovery? Expert Opin. Ther. Targets 15, 1355–1368 (2011).

    Article  CAS  PubMed  Google Scholar 

  99. Pelletier, J. P. & Martel-Pelletier, J. DMOAD developments: present and future. Bull. NYU Hosp. Jt Dis. 65, 242–248 (2007).

    PubMed  Google Scholar 

  100. Genovese, M. C. et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum. 50, 1412–1419 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Rose-John, S., Waetzig, G. H., Scheller, J., Grötzinger, J. & Seegert, D. The IL-6/sIL-6R complex as a novel target for therapeutic approaches. Expert Opin. Ther. Targets 11, 613–24 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Desgeorges, A. et al. Concentrations and origins of soluble interleukin-6 receptor-α in serum and synovial fluid. J. Rheumatol. 24, 1510–1516 (1997).

    CAS  PubMed  Google Scholar 

  103. 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 

  104. Tanaka, Y. & Yamaoka, K. JAK inhibitor tofacitinib for treating rheumatoid arthritis: from basic to clinical. Mod. Rheumatol. http://dx.doi.org/10.1007/s10165-012-0799-2.

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Authors and Affiliations

  1. Rheumatology Department, Paris XII University, UPEC, Hopital Henri Mondor, 94010, Créteil, France

    Xavier Chevalier & Florent Eymard

  2. Université Paris 7, UFR médicale, Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Fédération de Rhumatologie, 75475, Paris Cedex 10, France

    Pascal Richette

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X. Chevalier researched data for the article and wrote the article. All authors contributed substantially to discussion of content, and reviewing and editing the manuscript before submission.

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Supplementary information

Supplementary Figure 1

MRI of a knee with OA. (PDF 421 kb)

Supplementary Figure 2

MRI showing a reduction in the extent of bone marrow oedema 6 months after repeated subcutaneous adalimumab injections in a patient with knee OA. (PDF 457 kb)

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Chevalier, X., Eymard, F. & Richette, P. Biologic agents in osteoarthritis: hopes and disappointments. Nat Rev Rheumatol 9, 400–410 (2013). https://doi.org/10.1038/nrrheum.2013.44

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