1. 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 

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

   Article CAS PubMed  Google Scholar 

3. Felson, D. T. et al. Osteoarthritis: new insights. Part 2: treatment approaches.Ann. Intern. Med.133, 726–737 (2000).

   Article CAS PubMed  Google Scholar 

4. Blagojevic, M., Jinks, C., Jeffery, A. & Jordan, K. P. Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis.Osteoarthritis Cartilage18, 24–33 (2010).

   Article CAS PubMed  Google Scholar 

5. Zhuo, Q., Yang, W., Chen, J. & Wang, Y. Metabolic syndrome meets osteoarthritis.Nat. Rev. Rheumatol.8, 729–737 (2012).

   Article CAS PubMed  Google Scholar 

6. 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 

7. 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 

8. 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 

9. 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 

10. 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 

11. Brandt, K. D., Dieppe, P. & Radin, E. L. Commentary: is it useful to subset “primary” osteoarthritis? A critique based on evidence regarding the etiopathogenesis of osteoarthritis.Semin. Arthritis Rheum.39, 81–95 (2009).

    Article PubMed  Google Scholar 

12. Guermazi, A. et al. Assessment of synovitis with contrast-enhanced MRI using a whole-joint semiquantitative scoring system in people with, or at high risk of, knee osteoarthritis: the MOST study.Ann. Rheum. Dis.70, 805–811 (2011).

    Article PubMed  Google Scholar 

13. Ishijima, M. et al. Relationships between biomarkers of cartilage, bone, synovial metabolism and knee pain provide insights into the origins of pain in early knee osteoarthritis.Arthritis Res. Ther.13, R22 (2011).

    Article PubMed PubMed Central  Google Scholar 

14. Pessler, F. et al. The synovitis of “non-inflammatory” orthopaedic arthropathies: a quantitative histological and immunohistochemical analysis.Ann. Rheum. Dis.67, 1184–1187 (2008).

    Article CAS PubMed  Google Scholar 

15. Scanzello, C. R. & Goldring, S. R. The role of synovitis in osteoarthritis pathogenesis.Bone51, 249–257 (2012).

    Article CAS PubMed PubMed Central  Google Scholar 

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

    Article CAS PubMed  Google Scholar 

17. 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 

18. Nettelbladt, E. & Sundblad, L. Protein patterns in synovial fluid and serum in rheumatoid arthritis and osteoarthritis.Arthritis Rheum.2, 144–151 (1959).

    Article CAS PubMed  Google Scholar 

19. Sohn, D. H. et al. Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4.Arthritis Res. Ther.14, R7 (2012).

    Article CAS PubMed PubMed Central  Google Scholar 

20. Gobezie, R. et al. High abundance synovial fluid proteome: distinct profiles in health and osteoarthritis.Arthritis Res. Ther.9, R36 (2007).

    Article CAS PubMed PubMed Central  Google Scholar 

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

    Article CAS PubMed  Google Scholar 

22. 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  Google Scholar 

23. 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 

24. Torres, L. et al. The relationship between specific tissue lesions and pain severity in persons with knee osteoarthritis.Osteoarthritis Cartilage14, 1033–1040 (2006).

    Article CAS PubMed  Google Scholar 

25. Baker, K. et al. Relation of synovitis to knee pain using contrast-enhanced MRIs.Ann. Rheum. Dis.69, 1779–1783 (2010).

    Article CAS PubMed  Google Scholar 

26. 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 

27. Krasnokutsky, S. et al. Quantitative magnetic resonance imaging evidence of synovial proliferation is associated with radiographic severity of knee osteoarthritis.Arthritis Rheum.63, 2983–2991 (2011).

    Article PubMed PubMed Central  Google Scholar 

28. Sowers, M., Karvonen-Gutierrez, C. A., Jacobson, J. A., Jiang, Y. & Yosef, M. Associations of anatomical measures from MRI with radiographically defined knee osteoarthritis score, pain, and physical functioning.J. Bone Joint Surg. Am.93, 241–251 (2011).

    Article PubMed PubMed Central  Google Scholar 

29. 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 Cartilage13, 361–367 (2005).

    Article CAS PubMed  Google Scholar 

30. Sokolove, J. & Lepus, C. M. Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations.Ther. Adv. Musculoskeletal Dis.5, 77–94 (2013).

    Article CAS  Google Scholar 

31. Benito, M. J., Veale, D. J., FitzGerald, O., van den Berg, W. B. & Bresnihan, B. Synovial tissue inflammation in early and late osteoarthritis.Ann. Rheum. Dis.64, 1263–1267 (2005).

    Article CAS PubMed PubMed Central  Google Scholar 

32. Chevalier, X., Eymard, F. & Richette, P. Biologic agents in osteoarthritis: hopes and disappointments.Nat. Rev. Rheumatol.9, 400–410 (2013).

    Article CAS PubMed  Google Scholar 

33. Husa, M., Liu-Bryan, R. & Terkeltaub, R. Shifting HIFs in osteoarthritis.Nat. Med.16, 641–644 (2010).

    Article CAS PubMed PubMed Central  Google Scholar 

34. Glasson, S. S.In vivo osteoarthritis target validation utilizing genetically-modified mice.Curr. Drug Targets8, 367–376 (2007).

    Article CAS PubMed  Google Scholar 

35. van Lent, P. L. et al. Crucial role of synovial lining macrophages in the promotion of transforming growth factor β-mediated osteophyte formation.Arthritis Rheum.50, 103–111 (2004).

    Article CAS PubMed  Google Scholar 

36. Felson, D. T., Anderson, J. J., Naimark, A., Walker, A. M. & Meenan, R. F. Obesity and knee osteoarthritis. The Framingham Study.Ann. Intern. Med.109, 18–24 (1988).

    Article CAS PubMed  Google Scholar 

37. Berenbaum, F., Eymard, F. & Houard, X. Osteoarthritis, inflammation and obesity.Curr. Opin. Rheumatol.25, 114–118 (2013).

    Article CAS PubMed  Google Scholar 

38. You, T. & Nicklas, B. J. Chronic inflammation: role of adipose tissue and modulation by weight loss.Curr. Diabetes Rev.2, 29–37 (2006).

    Article PubMed  Google Scholar 

39. Beavers, K. M. et al. Effects of total and regional fat loss on plasma CRP and IL-6 in overweight and obese, older adults with knee osteoarthritis.Osteoarthritis Cartilage23, 249–256 (2015).

    Article CAS PubMed  Google Scholar 

40. Vincent, H. K., Heywood, K., Connelly, J. & Hurley, R. W. Obesity and weight loss in the treatment and prevention of osteoarthritis.PM R.4 (5 Suppl.), S59–S67 (2012).

    Article PubMed PubMed Central  Google Scholar 

41. Haseeb, A. & Haqqi, T. M. Immunopathogenesis of osteoarthritis.Clin. Immunol.146, 185–196 (2013).

    Article CAS PubMed PubMed Central  Google Scholar 

42. Scanzello, C. R., Plaas, A. & Crow, M. K. Innate immune system activation in osteoarthritis: is osteoarthritis a chronic wound?Current opinion in rheumatology20, 565–572 (2008).

    Article CAS PubMed  Google Scholar 

43. Krenn, V. et al. Grading of chronic synovitis — a histopathological grading system for molecular and diagnostic pathology.Pathol. Res. Pract.198, 317–325 (2002).

    Article CAS PubMed  Google Scholar 

44. Slansky, E. et al. Quantitative determination of the diagnostic accuracy of the synovitis score and its components.Histopathology57, 436–443 (2010).

    Article PubMed  Google Scholar 

45. de Lange-Brokaar, B. J. et al. Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review.Osteoarthritis Cartilage20, 1484–1499 (2012).

    Article CAS PubMed  Google Scholar 

46. Cohen, S. B. 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 

47. Magnano, M. D. et al. 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 

48. Verbruggen, G., Wittoek, R., Vander Cruyssen, B. & 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 

49. 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 

50. Orlowsky, E. W. & Kraus, V. B. The role of innate immunity in osteoarthritis: when our first line of defense goes on the offensive.J. Rheumatol.42, 363–371 (2015).

    Article CAS PubMed PubMed Central  Google Scholar 

51. Fearon, D. T. & Locksley, R. M. The instructive role of innate immunity in the acquired immune response.Science272, 50–53 (1996).

    Article CAS PubMed  Google Scholar 

52. Holers, V. M. & Thurman, J. M. The alternative pathway of complement in disease: opportunities for therapeutic targeting.Mol. Immunol.41, 147–152 (2004).

    Article CAS PubMed  Google Scholar 

53. Wang, Q. et al. Identification of a central role for complement in osteoarthritis.Nat. Med.17, 1674–1679 (2011).

    Article CAS PubMed PubMed Central  Google Scholar 

54. Rus, H., Cudrici, C. & Niculescu, F. The role of the complement system in innate immunity.Immunol. Res.33, 103–112 (2005).

    Article CAS PubMed  Google Scholar 

55. Song, W. C., Sarrias, M. R. & Lambris, J. D. Complement and innate immunity.Immunopharmacology49, 187–198 (2000).

    Article CAS PubMed  Google Scholar 

56. Happonen, K. E. et al. Regulation of complement by COMP allows for a novel molecular diagnostic principle in rheumatoid arthritis.Arthritis Rheum.62, 3574–3783 (2010).

    Article CAS PubMed PubMed Central  Google Scholar 

57. Sjoberg, A. P. et al. Short leucine-rich glycoproteins of the extracellular matrix display diverse patterns of complement interaction and activation.Mol. Immunol.46, 830–839 (2009).

    Article CAS PubMed  Google Scholar 

58. Sjoberg, A., Onnerfjord, P., Morgelin, M., Heinegard, D. & Blom, A. M. The extracellular matrix and inflammation: fibromodulin activates the classical pathway of complement by directly binding C1q.J. Biol. Chem.280, 32301–32308 (2005).

    Article CAS PubMed  Google Scholar 

59. Moreth, K., Iozzo, R. V. & Schaefer, L. Small leucine-rich proteoglycans orchestrate receptor crosstalk during inflammation.Cell Cycle11, 2084–2091 (2012).

    Article CAS PubMed PubMed Central  Google Scholar 

60. Rosenthal, A. K. Crystals, inflammation, and osteoarthritis.Curr. Opin. Rheumatol.23, 170–173 (2011).

    Article CAS PubMed PubMed Central  Google Scholar 

61. Sofat, N. Analysing the role of endogenous matrix molecules in the development of osteoarthritis.Int. J. Exp. Pathol.90, 463–479 (2009).

    Article CAS PubMed PubMed Central  Google Scholar 

62. Nasi, S. et al. Dispensable role of myeloid differentiation primary response gene 88 (MyD88) and MyD88-dependent Toll-like receptors (TLRs) in a murine model of osteoarthritis.Joint Bone Spine81, 320–324 (2014).

    Article CAS PubMed  Google Scholar 

63. Liu-Bryan, R. Synovium and the innate inflammatory network in osteoarthritis progression.Curr. Rheumatol. Rep.15, 323 (2013).

    Article CAS PubMed PubMed Central  Google Scholar 

64. Rosado, C. J. et al. A common fold mediates vertebrate defense and bacterial attack.Science317, 1548–1551 (2007).

    Article CAS PubMed  Google Scholar 

65. Tschopp, J., Masson, D. & Stanley, K. K. Structural/functional similarity between proteins involved in complement- and cytotoxic T-lymphocyte-mediated cytolysis.Nature322, 831–834 (1986).

    Article CAS PubMed  Google Scholar 

66. Bohana-Kashtan, O., Ziporen, L., Donin, N., Kraus, S. & Fishelson, Z. Cell signals transduced by complement.Mol. Immunol.41, 583–597 (2004).

    Article CAS PubMed  Google Scholar 

67. Cooke, T. D., Bennett, E. L. & Ohno, O. The deposition of immunoglobulins and complement in osteoarthritic cartilage.Int. Orthop.4, 211–217 (1980).

    Article CAS PubMed  Google Scholar 

68. Corvetta, A. et al. Terminal complement complex in synovial tissue from patients affected by rheumatoid arthritis, osteoarthritis and acute joint trauma.Clin. Exp. Rheumatol.10, 433–438 (1992).

    CAS PubMed  Google Scholar 

69. Bradley, K. et al. Synthesis of classical pathway complement components by chondrocytes.Immunology88, 648–656 (1996).

    CAS PubMed PubMed Central  Google Scholar 

70. Kemper, C. & Atkinson, J. P. T-Cell regulation: with complements from innate immunity.Nat. Rev. Immunol.7, 9–18 (2007).

    Article CAS PubMed  Google Scholar 

71. Lepus, C. M. et al. Brief report: carboxypeptidase B serves as a protective mediator in osteoarthritis.Arthritis Rheumatol.66, 101–106 (2014).

    Article CAS PubMed PubMed Central  Google Scholar 

72. Boffa, M. C., Burke, B. & Haudenschild, C. C. Preservation of thrombomodulin antigen on vascular and extravascular surfaces.J. Histochem. Cytochem.35, 1267–1276 (1987).

    Article CAS PubMed  Google Scholar 

73. McCachren, S. S., Diggs, J., Weinberg, J. B. & Dittman, W. A. Thrombomodulin expression by human blood monocytes and by human synovial tissue lining macrophages.Blood78, 3128–3132 (1991).

    CAS PubMed  Google Scholar 

74. Conway, E. M., Nowakowski, B. & Steiner-Mosonyi, M. Human neutrophils synthesize thrombomodulin that does not promote thrombin-dependent protein C activation.Blood80, 1254–1263 (1992).

    CAS PubMed  Google Scholar 

75. Leung, L. L., Myles, T., Nishimura, T., Song, J. J. & Robinson, W. H. Regulation of tissue inflammation by thrombin-activatable carboxypeptidase B (or TAFI).Mol. Immunol.45, 4080–4083 (2008).

    Article CAS PubMed PubMed Central  Google Scholar 

76. Sharif, S. A. et al. Thrombin-activatable carboxypeptidase B cleavage of osteopontin regulates neutrophil survival and synoviocyte binding in rheumatoid arthritis.Arthritis Rheum.60, 2902–2912 (2009).

    Article CAS PubMed PubMed Central  Google Scholar 

77. Benoit, M. E., Clarke, E. V., Morgado, P., Fraser, D. A. & Tenner, A. J. Complement protein C1q directs macrophage polarization and limits inflammasome activity during the uptake of apoptotic cells.J. Immunol.188, 5682–5693 (2012).

    Article CAS PubMed  Google Scholar 

78. Foell, D., Wittkowski, H. & Roth, J. Mechanisms of disease: a 'DAMP' view of inflammatory arthritis.Nat. Clin. Pract. Rheumatol.3, 382–390 (2007).

    Article CAS PubMed  Google Scholar 

79. Blom, A. B. et al. Crucial role of macrophages in matrix metalloproteinase-mediated cartilage destruction during experimental osteoarthritis: involvement of matrix metalloproteinase 3.Arthritis Rheum.56, 147–157 (2007).

    Article CAS PubMed  Google Scholar 

80. Bondeson, J. Activated synovial macrophages as targets for osteoarthritis drug therapy.Curr. Drug Targets11, 576–585 (2010).

    Article CAS PubMed  Google Scholar 

81. Irani, A. A., Schechter, N. M., Craig, S. S., DeBlois, G. & Schwartz, L. B. Two types of human mast cells that have distinct neutral protease compositions.Proc. Natl Acad. Sci. USA83, 4464–4468 (1986).

    Article CAS PubMed PubMed Central  Google Scholar 

82. Buckley, M. G., Gallagher, P. J. & Walls, A. F. Mast cell subpopulations in the synovial tissue of patients with osteoarthritis: selective increase in numbers of tryptase-positive, chymase-negative mast cells.J. Pathol.186, 67–74 (1998).

    Article CAS PubMed  Google Scholar 

83. Gotis-Graham, I. & McNeil, H. P. Mast cell responses in rheumatoid synovium. Association of the MCTC subset with matrix turnover and clinical progression.Arthritis Rheum.40, 479–489 (1997).

    Article CAS PubMed  Google Scholar 

84. Nakano, S. et al. Distinct expression of mast cell tryptase and protease activated receptor-2 in synovia of rheumatoid arthritis and osteoarthritis.Clin. Rheumatol.26, 1284–1292 (2007).

    Article PubMed  Google Scholar 

85. Bridges, A. J. et al. Human synovial mast cell involvement in rheumatoid arthritis and osteoarthritis. Relationship to disease type, clinical activity, and antirheumatic therapy.Arthritis Rheum.34, 1116–1124 (1991).

    Article CAS PubMed  Google Scholar 

86. Gruber, B. et al. Characterization and functional studies of rheumatoid synovial mast cells. Activation by secretagogues, anti-IgE, and a histamine-releasing lymphokine.Arthritis Rheum.29, 944–955 (1986).

    Article CAS PubMed  Google Scholar 

87. Kopicky-Burd, J. A. et al. Characterization of human synovial mast cells.J. Rheumatol.15, 1326–1333 (1988).

    CAS PubMed  Google Scholar 

88. Cooke, T. D. Significance of immune complex deposits in osteoarthritic cartilage.J. Rheumatol.14, 77–79 (1987).

    PubMed  Google Scholar 

89. Vargas, M. E., Watanabe, J., Singh, S. J., Robinson, W. H. & Barres, B. A. Endogenous antibodies promote rapid myelin clearance and effective axon regeneration after nerve injury.Proc. Natl Acad. Sci. USA107, 11993–11998 (2010).

    Article PubMed PubMed Central  Google Scholar 

90. Kapoor, M., Martel-Pelletier, J., Lajeunesse, D., Pelletier, J. P. & Fahmi, H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis.Nat. Rev. Rheumatol.7, 33–42 (2011).

    Article CAS PubMed  Google Scholar 

91. Goldring, M. B., Fukuo, K., Birkhead, J. R., Dudek, E. & Sandell, L. J. Transcriptional suppression by interleukin-1 and interferon-γ of type II collagen gene expression in human chondrocytes.J. Cell Biochem.54, 85–99 (1994).

    Article CAS PubMed  Google Scholar 

92. Saklatvala, J. Tumour necrosis factor α stimulates resorption and inhibits synthesis of proteoglycan in cartilage.Nature322, 547–549 (1986).

    Article CAS PubMed PubMed Central  Google Scholar 

93. Attur, M. G., Patel, I. R., Patel, R. N., Abramson, S. B. & Amin, A. R. Autocrine production of IL-1β by human osteoarthritis-affected cartilage and differential regulation of endogenous nitric oxide, IL-6, prostaglandin E2, and IL-8.Proc. Assoc. Am. Physicians110, 65–72 (1998).

    CAS PubMed  Google Scholar 

94. Krzeski, P. et al. Development of musculoskeletal toxicity without clear benefit after administration of PG-116800, a matrix metalloproteinase inhibitor, to patients with knee osteoarthritis: a randomized, 12-month, double-blind, placebo-controlled study.Arthritis Res. Ther.9, R109 (2007).

    Article CAS PubMed PubMed Central  Google Scholar 

95. Catterall, J. B. & Cawston, T. E. Drugs in development: bisphosphonates and metalloproteinase inhibitors.Arthritis Res. Ther.5, 12–24 (2003).

    Article CAS PubMed  Google Scholar 

96. Clutterbuck, A. L., Asplin, K. E., Harris, P., Allaway, D. & Mobasheri, A. Targeting matrix metalloproteinases in inflammatory conditions.Curr. Drug Targets10, 1245–1254 (2009).

    Article CAS PubMed  Google Scholar 

97. Endres, M. et al. Chemokine profile of synovial fluid from normal, osteoarthritis and rheumatoid arthritis patients: CCL25, CXCL10 and XCL1 recruit human subchondral mesenchymal progenitor cells.Osteoarthritis Cartilage18, 1458–1466 (2010).

    Article CAS PubMed  Google Scholar 

98. Haringman, J. J., Smeets, T. J., Reinders-Blankert, P. & Tak, P. P. Chemokine and chemokine receptor expression in paired peripheral blood mononuclear cells and synovial tissue of patients with rheumatoid arthritis, osteoarthritis, and reactive arthritis.Ann. Rheum. Dis.65, 294–300 (2006).

    Article CAS PubMed  Google Scholar 

99. Borzi, R. M. et al. Human chondrocytes express functional chemokine receptors and release matrix-degrading enzymes in response to C-X-C and C-C chemokines.Arthritis Rheum.43, 1734–1741 (2000).

    Article CAS PubMed  Google Scholar 

100. Miller, R. J., Banisadr, G. & Bhattacharyya, B. J. CXCR4 signaling in the regulation of stem cell migration and development.J. Neuroimmunol.198, 31–38 (2008).

     Article CAS PubMed PubMed Central  Google Scholar 

101. Haringman, J. J., Ludikhuize, J. & Tak, P. P. Chemokines in joint disease: the key to inflammation?Ann. Rheum. Dis.63, 1186–1194 (2004).

     Article CAS PubMed PubMed Central  Google Scholar 

102. Shen, J., Li, S. & Chen, D. TGF-β signaling and the development of osteoarthritis.Bone Res.2, 14002 (2014).

     Article CAS PubMed PubMed Central  Google Scholar 

103. Blaney Davidson, E. N., van der Kraan, P. M. & van den Berg, W. B. TGF-β and osteoarthritis.Osteoarthritis Cartilage15, 597–604 (2007).

     Article CAS PubMed  Google Scholar 

104. Ellman, M. B. et al. Fibroblast growth factor control of cartilage homeostasis.J. Cell Biochem.114, 735–742 (2013).

     Article CAS PubMed PubMed Central  Google Scholar 

105. Haywood, L. et al. Inflammation and angiogenesis in osteoarthritis.Arthritis Rheum.48, 2173–2177 (2003).

     Article CAS PubMed  Google Scholar 

106. Prencipe, G. et al. Nerve growth factor downregulates inflammatory response in human monocytes through TrkA.J. Immunol.192, 3345–3354 (2014).

     Article CAS PubMed  Google Scholar 

107. 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 

108. Thysen, S., Luyten, F. P. & Lories, R. J. Targets, models and challenges in osteoarthritis research.Dis. Model. Mech.8, 17–30 (2015).

     Article CAS PubMed PubMed Central  Google Scholar 

109. Henrotin, Y., Pesesse, L. & Lambert, C. Targeting the synovial angiogenesis as a novel treatment approach to osteoarthritis.Ther. Adv. Musculoskeletal Dis.6, 20–34 (2014).

     Article CAS  Google Scholar 

110. de Boer, T. N. et al. Serum adipokines in osteoarthritis; comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage.Osteoarthritis Cartilage20, 846–853 (2012).

     Article CAS PubMed  Google Scholar 

111. Kluzek, S., Newton, J. L. & Arden, N. K. Is osteoarthritis a metabolic disorder?Br. Med. Bull.115, 111–121 (2015).

     Article CAS PubMed  Google Scholar 

112. Malemud, C. J. Biologic basis of osteoarthritis: state of the evidence.Curr. Opin. Rheumatol.27, 289–294 (2015).

     Article CAS PubMed PubMed Central  Google Scholar 

113. Yusuf, E. et al. Association between weight or body mass index and hand osteoarthritis: a systematic review.Ann. Rheum. Dis.69, 761–765 (2010).

     Article PubMed  Google Scholar 

114. Le Clanche, S., Bonnefont-Rousselot, D., Sari-Ali, E., Rannou, F. & Borderie, D. Inter-relations between osteoarthritis and metabolic syndrome: a common link?Biochimie121, 238–252 (2016).

     Article CAS PubMed  Google Scholar 

115. Conde, J. et al. Adipokines and osteoarthritis: novel molecules involved in the pathogenesis and progression of disease.Arthritis2011, 203901 (2011).

     Article PubMed PubMed Central  Google Scholar 

116. Gomez, R. et al. What's new in our understanding of the role of adipokines in rheumatic diseases?Nat. Rev. Rheumatol.7, 528–536 (2011).

     Article CAS PubMed  Google Scholar 

117. Dumond, H. et al. Evidence for a key role of leptin in osteoarthritis.Arthritis Rheum.48, 3118–3129 (2003).

     Article CAS PubMed  Google Scholar 

118. Filkova, M. et al. Increased serum adiponectin levels in female patients with erosive compared with non-erosive osteoarthritis.Ann. Rheum. Dis.68, 295–296 (2009).

     Article CAS PubMed  Google Scholar 

119. Francin, P. J. et al. Association between adiponectin and cartilage degradation in human osteoarthritis.Osteoarthritis Cartilage22, 519–526 (2014).

     Article PubMed  Google Scholar 

120. Liao, L., Chen, Y. & Wang, W. The current progress in understanding the molecular functions and mechanisms of visfatin in osteoarthritis.J. Bone Miner. Metab.http://dx.doi.org/10.1007/s00774-016-0743-1 (2016).

121. Koskinen, A., Vuolteenaho, K., Moilanen, T. & Moilanen, E. Resistin as a factor in osteoarthritis: synovial fluid resistin concentrations correlate positively with interleukin 6 and matrix metalloproteinases MMP-1 and MMP-3.Scand. J. Rheumatol.43, 249–253 (2014).

     Article CAS PubMed  Google Scholar 

122. Goldring, M. B. & Otero, M. Inflammation in osteoarthritis.Curr. Opin. Rheumatol.23, 471–478 (2011).

     Article CAS PubMed PubMed Central  Google Scholar 

123. Jiang, L., Bao, J., Zhou, X., Xiong, Y. & Wu, L. Increased serum levels and chondrocyte expression of nesfatin-1 in patients with osteoarthritis and its relation with BMI, hsCRP, and IL-18.Mediators Inflamm.2013, 631251 (2013).

     PubMed PubMed Central  Google Scholar 

124. Yang, S. et al. NAMPT (visfatin), a direct target of hypoxia-inducible factor-2α, is an essential catabolic regulator of osteoarthritis.Ann. Rheum. Dis.74, 595–602 (2015).

     Article CAS PubMed  Google Scholar 

125. Gegout, P. P., Francin, P. J., Mainard, D. & Presle, N. Adipokines in osteoarthritis: friends or foes of cartilage homeostasis?Joint Bone Spine75, 669–671 (2008).

     Article PubMed  Google Scholar 

126. Presle, N. et al. Differential distribution of adipokines between serum and synovial fluid in patients with osteoarthritis. Contribution of joint tissues to their articular production.Osteoarthritis Cartilage14, 690–695 (2006).

     Article CAS PubMed  Google Scholar 

127. Martel-Pelletier, J., Pelletier, J. P. & Fahmi, H. Cyclooxygenase-2 and prostaglandins in articular tissues.Semin. Arthritis Rheum.33, 155–167 (2003).

     Article CAS PubMed  Google Scholar 

128. Wittenberg, R. H., Willburger, R. E., Kleemeyer, K. S. & Peskar, B. A.In vitro release of prostaglandins and leukotrienes from synovial tissue, cartilage, and bone in degenerative joint diseases.Arthritis Rheum.36, 1444–1450 (1993).

     Article CAS PubMed  Google Scholar 

129. Casale, T. B., Abbas, M. K. & Carolan, E. J. Degree of neutrophil chemotaxis is dependent upon the chemoattractant and barrier.Am. J. Respir. Cell. Mol. Biol.7, 112–117 (1992).

     Article CAS PubMed  Google Scholar 

130. He, W., Pelletier, J. P., Martel-Pelletier, J., Laufer, S. & Di Battista, J. A. Synthesis of interleukin 1β, tumor necrosis factor-α, and interstitial collagenase (MMP-1) is eicosanoid dependent in human osteoarthritis synovial membrane explants: interactions with antiinflammatory cytokines.J. Rheumatol.29, 546–553 (2002).

     CAS PubMed  Google Scholar 

131. Peters-Golden, M. & Henderson, W. R. Jr. Leukotrienes.N. Engl. J. Med.357, 1841–1854 (2007).

     Article CAS PubMed  Google Scholar 

132. Geng, Y., Blanco, F. J., Cornelisson, M. & Lotz, M. Regulation of cyclooxygenase-2 expression in normal human articular chondrocytes.J. Immunol.155, 796–801 (1995).

     CAS PubMed  Google Scholar 

133. Li, X. et al. Expression and regulation of microsomal prostaglandin E synthase-1 in human osteoarthritic cartilage and chondrocytes.J. Rheumatol.32, 887–895 (2005).

     CAS PubMed  Google Scholar 

134. Masuko-Hongo, K. et al. Up-regulation of microsomal prostaglandin E synthase 1 in osteoarthritic human cartilage: critical roles of the ERK-1/2 and p38 signaling pathways.Arthritis Rheum.50, 2829–2838 (2004).

     Article CAS PubMed  Google Scholar 

135. Kojima, F. et al. Membrane-associated prostaglandin E synthase-1 is upregulated by proinflammatory cytokines in chondrocytes from patients with osteoarthritis.Arthritis Res. Ther.6, R355–R365 (2004).

     Article CAS PubMed PubMed Central  Google Scholar 

136. Paredes, Y. et al. Study of the role of leukotriene B4 in abnormal function of human subchondral osteoarthritis osteoblasts: effects of cyclooxygenase and/or 5-lipoxygenase inhibition.Arthritis Rheum.46, 1804–1812 (2002).

     Article CAS PubMed  Google Scholar 

137. Scarpignato, C. et al. Safe prescribing of non-steroidal anti-inflammatory drugs in patients with osteoarthritis — an expert consensus addressing benefits as well as gastrointestinal and cardiovascular risks.BMC Med.13, 55 (2015).

     Article PubMed PubMed Central  Google Scholar 

138. Steinhilber, D. & Hofmann, B. Recent advances in the search for novel 5-lipoxygenase inhibitors.Bas. Clin. Pharmacol. Toxicol.114, 70–77 (2014).

     Article CAS  Google Scholar 

139. Tonge, D. P., Pearson, M. J. & Jones, S. W. The hallmarks of osteoarthritis and the potential to develop personalised disease-modifying pharmacological therapeutics.Osteoarthritis Cartilage22, 609–621 (2014).

     Article CAS PubMed  Google Scholar 

140. Abramson, S. B. Osteoarthritis and nitric oxide.Osteoarthritis Cartilage16 (Suppl. 2), S15–S20 (2008).

     Article PubMed  Google Scholar 

141. Palmer, R. M., Hickery, M. S., Charles, I. G., Moncada, S. & Bayliss, M. T. Induction of nitric oxide synthase in human chondrocytes.Biochem. Biophys. Res. Commun.193, 398–405 (1993).

     Article CAS PubMed  Google Scholar 

142. McInnes, I. B. et al. Production of nitric oxide in the synovial membrane of rheumatoid and osteoarthritis patients.J. Exp. Med.184, 1519–1524 (1996).

     Article CAS PubMed  Google Scholar 

143. Farrell, A. J., Blake, D. R., Palmer, R. M. & Moncada, S. Increased concentrations of nitrite in synovial fluid and serum samples suggest increased nitric oxide synthesis in rheumatic diseases.Ann. Rheum. Dis.51, 1219–1222 (1992).

     Article CAS PubMed PubMed Central  Google Scholar 

144. Hashimoto, S., Takahashi, K., Amiel, D., Coutts, R. D. & Lotz, M. Chondrocyte apoptosis and nitric oxide production during experimentally induced osteoarthritis.Arthritis Rheum.41, 1266–1274,http://dx.doi.org/10.1002/1529-0131(199807)41:7<1266::AID-ART18>3.0.CO;2-Y (1998).

     Article CAS PubMed  Google Scholar 

145. Notoya, K. et al. The induction of cell death in human osteoarthritis chondrocytes by nitric oxide is related to the production of prostaglandin E2 via the induction of cyclooxygenase-2.J. Immunol.165, 3402–3410 (2000).

     Article CAS PubMed  Google Scholar 

146. Scher, J. U., Pillinger, M. H. & Abramson, S. B. Nitric oxide synthases and osteoarthritis.Curr. Rheumatol. Rep.9, 9–15 (2007).

     Article CAS PubMed  Google Scholar 

147. 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 

148. Sutton, S. et al. The contribution of the synovium, synovial derived inflammatory cytokines and neuropeptides to the pathogenesis of osteoarthritis.Vet. J.179, 10–24 (2009).

     Article CAS PubMed  Google Scholar 

149. Meini, S. & Maggi, C. A. Knee osteoarthritis: a role for bradykinin?Inflamm. Res.57, 351–361 (2008).

     Article CAS PubMed  Google Scholar 

150. Song, I. H. et al. Contrast-enhanced ultrasound in monitoring the efficacy of a bradykinin receptor 2 antagonist in painful knee osteoarthritis compared with MRI.Ann. Rheum. Dis.68, 75–83 (2009).

     Article CAS PubMed  Google Scholar 

151. Dudek, M. et al. The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity.J. Clin. Invest.126, 365–376 (2016).

     Article PubMed  Google Scholar 

152. Kc, R. et al. Environmental disruption of circadian rhythm predisposes mice to osteoarthritis-like changes in knee joint.J. Cell. Physiol.230, 2174–2183 (2015).

     Article CAS PubMed PubMed Central  Google Scholar 

153. Gossan, N. et al. The circadian clock in murine chondrocytes regulates genes controlling key aspects of cartilage homeostasis.Arthritis Rheum.65, 2334–2345 (2013).

     Article CAS PubMed PubMed Central  Google Scholar 

154. Guo, B. et al. Catabolic cytokines disrupt the circadian clock and the expression of clock-controlled genes in cartilage via an NFκB-dependent pathway.Osteoarthritis Cartilage23, 1981–1988 (2015).

     Article CAS PubMed PubMed Central  Google Scholar 

155. Honda, K. K. et al. Different circadian expression of major matrix-related genes in various types of cartilage: modulation by light-dark conditions.J. Biochem.154, 373–381 (2013).

     Article CAS PubMed  Google Scholar 

156. Takarada, T. et al. Clock genes influence gene expression in growth plate and endochondral ossification in mice.J. Biol. Chem.287, 36081–36095 (2012).

     Article CAS PubMed PubMed Central  Google Scholar 

157. Gibbs, J. et al. An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action.Nat. Med.20, 919–926 (2014).

     Article CAS PubMed PubMed Central  Google Scholar 

158. Nguyen, K. D. et al. Circadian gene Bmal1 regulates diurnal oscillations of Ly6C^hi inflammatory monocytes.Science341, 1483–1488 (2013).

     Article CAS PubMed  Google Scholar 

159. Gibbs, J. E. et al. The nuclear receptor REV-ERBα mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines.Proc. Natl Acad. Sci. USA109, 582–587 (2012).

     Article PubMed  Google Scholar 

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

     Article CAS PubMed PubMed Central  Google Scholar 

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

     Article CAS PubMed PubMed Central  Google Scholar 

162. Hunter, D. J. Are there promising biologic therapies for osteoarthritis?Curr. Rheumatol. Rep.10, 19–25 (2008).

     Article PubMed  Google Scholar 

163. Pelletier, J. P. et al. Disease-modifying effect of strontium ranelate in a subset of patients from the Phase III knee osteoarthritis study SEKOIA using quantitative MRI: reduction in bone marrow lesions protects against cartilage loss.Ann. Rheum. Dis.74, 422–429 (2015).

     Article CAS PubMed  Google Scholar 

164. Reginster, J. Y. et al. Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial.Ann. Rheum. Dis.72, 179–186 (2013).

     Article CAS PubMed  Google Scholar 

165. Pelletier, J. P. et al. Strontium ranelate reduces the progression of experimental dog osteoarthritis by inhibiting the expression of key proteases in cartilage and of IL-1β in the synovium.Ann. Rheum. Dis.72, 250–257 (2013).

     Article CAS PubMed  Google Scholar 

166. Tat, S. K., Pelletier, J. P., Mineau, F., Caron, J. & Martel-Pelletier, J. Strontium ranelate inhibits key factors affecting bone remodeling in human osteoarthritic subchondral bone osteoblasts.Bone49, 559–567 (2011).

     Article CAS PubMed  Google Scholar 

167. Lafeber, F. P. & van Laar, J. M. Strontium ranelate: ready for clinical use as disease-modifying osteoarthritis drug?Ann. Rheum. Dis.72, 157–161 (2013).

     Article PubMed  Google Scholar 

168. Felson, D. T. Developments in the clinical understanding of osteoarthritis.Arthritis Res. Ther.11, 203 (2009).

     Article PubMed PubMed Central  Google Scholar 

169. Midwood, K. et al. Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease.Nat. Med.15, 774–780 (2009).

     Article CAS PubMed  Google Scholar 

170. van Lent, P. L. et al. Active involvement of alarmins S100A8 and S100A9 in the regulation of synovial activation and joint destruction during mouse and human osteoarthritis.Arthritis Rheum.64, 1466–1476 (2012).

     Article CAS PubMed  Google Scholar 

171. Schelbergen, R. F. et al. Alarmins S100A8/S100A9 aggravate osteophyte formation in experimental osteoarthritis and predict osteophyte progression in early human symptomatic osteoarthritis.Ann. Rheum. Dis.75, 218–225 (2016).

     Article CAS PubMed  Google Scholar 

172. Joosten, L. A., Helsen, M. M., van de Loo, F. A. & van den Berg, W. B. Anticytokine treatment of established type II collagen-induced arthritis in DBA/1 mice: a comparative study using anti-TNFα, anti-IL-1α/β and IL-1Ra.Arthritis Rheum.58, S110–122 (2008).

     Article CAS PubMed  Google Scholar 

173. Rudolphi, K., Gerwin, N., Verzijl, N., van der Kraan, P. & van den Berg, W. Pralnacasan, an inhibitor of interleukin-1β converting enzyme, reduces joint damage in two murine models of osteoarthritis.Osteoarthritis Cartilage11, 738–746 (2003).

     Article CAS PubMed  Google Scholar 

174. 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 

175. Urech, D. M. et al. Anti-inflammatory and cartilage-protecting effects of an intra-articularly injected anti-TNFα single-chain Fv antibody (ESBA105) designed for local therapeutic use.Ann. Rheum. Dis.69, 443–449 (2010).

     Article CAS PubMed  Google Scholar 

176. Koewler, N. J. et al. Effects of a monoclonal antibody raised against nerve growth factor on skeletal pain and bone healing after fracture of the C57BL/6J mouse femur.J. Bone Miner. Res.22, 1732–1742 (2007).

     Article CAS PubMed  Google Scholar 

177. Moore, E. E. et al. Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis.Osteoarthritis Cartilage13, 623–631 (2005).

     Article CAS PubMed  Google Scholar 

178. Evans, C. H., Kraus, V. B. & Setton, L. A. Progress in intra-articular therapy.Nat. Rev. Rheumatol.10, 11–22 (2014).

     Article CAS PubMed  Google Scholar 

179. Ou, Y. et al. Selective COX-2 inhibitor ameliorates osteoarthritis by repressing apoptosis of chondrocyte.Med. Sci. Monit.18, 247–252 (2012).

     Article  Google Scholar 

180. Bresalier, R. S. et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.N. Engl. J. Med.352, 1092–1102 (2005).

     Article CAS PubMed  Google Scholar 

181. Drazen, J. M. COX-2 inhibitors — a lesson in unexpected problems.N. Engl. J. Med.352, 1131–1132 (2005).

     Article CAS PubMed  Google Scholar 

182. Nussmeier, N. A. et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery.N. Engl. J. Med.352, 1081–1091 (2005).

     Article CAS PubMed  Google Scholar 

183. Solomon, S. D. et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention.N. Engl. J. Med.352, 1071–1080 (2005).

     Article CAS PubMed  Google Scholar 

184. Riendeau, D. et al. Etoricoxib (MK-0663): preclinical profile and comparison with other agents that selectively inhibit cyclooxygenase-2.J. Pharmacol. Exp. Ther.296, 558–566 (2001).

     CAS PubMed  Google Scholar 

185. Song, G. G. et al. Relative efficacy and tolerability of etoricoxib, celecoxib, and naproxen in the treatment of osteoarthritis: a Bayesian network meta-analysis of randomized controlled trials based on patient withdrawal.Z. Rheumatol.75, 508–516 (2016).

     Article CAS PubMed  Google Scholar 

186. Croom, K. F. & Siddiqui, M. A. Etoricoxib: a review of its use in the symptomatic treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and acute gouty arthritis.Drugs69, 1513–1532 (2009).

     Article CAS PubMed  Google Scholar 

187. Ratcliffe, A. et al. Thein vivo effects of naproxen on canine experimental osteoarthritic articular cartilage: composition, metalloproteinase activities and metabolism.Agents Actions Suppl.39, 207–211 (1993).

     Article CAS PubMed  Google Scholar 

188. Svensson, O., Malmenas, M., Fajutrao, L., Roos, E. M. & Lohmander, L. S. Greater reduction of knee than hip pain in osteoarthritis treated with naproxen, as evaluated by WOMAC and SF-36.Ann. Rheum. Dis.65, 781–784 (2006).

     Article CAS PubMed  Google Scholar 

189. Coxib and traditional NSAID Trialists' (CNT) Collaboration et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.Lancet382, 769–779 (2013).

190. Masferrer, J. L. et al. Pharmacology of PF-4191834, a novel, selective non-redox 5-lipoxygenase inhibitor effective in inflammation and pain.J. Pharmacol. Exp. Ther.334, 294–301 (2010).

     Article CAS PubMed  Google Scholar 

191. Jovanovic, D. V. et al.In vivo dual inhibition of cyclooxygenase and lipoxygenase by ML-3000 reduces the progression of experimental osteoarthritis: suppression of collagenase 1 and interleukin-1β synthesis.Arthritis Rheum.44, 2320–2330 (2001).

     Article CAS PubMed  Google Scholar 

192. Raynauld, J. P. et al. Protective effects of licofelone, a 5-lipoxygenase and cyclo-oxygenase inhibitor, versus naproxen on cartilage loss in knee osteoarthritis: a first multicentre clinical trial using quantitative MRI.Ann. Rheum. Dis.68, 938–947 (2009).

     Article CAS PubMed  Google Scholar 

193. Bitto, A. et al. Flavocoxid, a nutraceutical approach to blunt inflammatory conditions.Mediators Inflamm.2014, 790851 (2014).

     Article CAS PubMed PubMed Central  Google Scholar 

194. Levy, R. M. et al. Efficacy and safety of flavocoxid, a novel therapeutic, compared with naproxen: a randomized multicenter controlled trial in subjects with osteoarthritis of the knee.Adv. Ther.27, 731–742 (2010).

     Article CAS PubMed  Google Scholar 

195. Chalasani, N. et al. Acute liver injury due to flavocoxid (Limbrel), a medical food for osteoarthritis: a case series.Ann. Intern. Med.156, 857–860 (2012).

     Article PubMed  Google Scholar 

196. Stefanovic-Racic, M. et al.N-Monomethyl arginine, an inhibitor of nitric oxide synthase, suppresses the development of adjuvant arthritis in rats.Arthritis Rheum.37, 1062–1069 (1994).

     Article CAS PubMed  Google Scholar 

197. McCartney-Francis, N. et al. Suppression of arthritis by an inhibitor of nitric oxide synthase.J. Exp. Med.178, 749–754 (1993).

     Article CAS PubMed  Google Scholar 

198. Miyasaka, N. & Hirata, Y. Nitric oxide and inflammatory arthritides.Life Sci.61, 2073–2081 (1997).

     Article CAS PubMed  Google Scholar 

199. More, A. S. et al. Effect of iNOS inhibitorS-methylisothiourea in monosodium iodoacetate-induced osteoathritic pain: implication for osteoarthritis therapy.Pharmacol. Biochem. Behav.103, 764–772 (2013).

     Article CAS PubMed  Google Scholar 

200. Brewster, M., Lewis, E. J., Wilson, K. L., Greenham, A. K. & Bottomley, K. M. Ro 32–3555, an orally active collagenase selective inhibitor, prevents structural damage in the STR/ORT mouse model of osteoarthritis.Arthritis Rheum.41, 1639–1644 (1998).

     Article CAS PubMed  Google Scholar 

201. Close, D. R. Matrix metalloproteinase inhibitors in rheumatic diseases.Ann. Rheum. Dis.60 (Suppl. 3), 62–67 (2001).

     Google Scholar 

202. Fujisawa, T. et al. Highly water-soluble matrix metalloproteinases inhibitors and their effects in a rat adjuvant-induced arthritis model.Bioorg. Med. Chem.10, 2569–2581 (2002).

     Article CAS PubMed  Google Scholar 

203. Janusz, M. J. et al. Moderation of iodoacetate-induced experimental osteoarthritis in rats by matrix metalloproteinase inhibitors.Osteoarthritis Cartilage9, 751–760 (2001).

     Article CAS PubMed  Google Scholar 

204. Lewis, E. J. et al. Ro 32–3555, an orally active collagenase inhibitor, prevents cartilage breakdownin vitro andin vivo.Br. J. Pharmacol.121, 540–546 (1997).

     Article CAS PubMed PubMed Central  Google Scholar 

Download references