BioDrugs

, Volume 18, Issue 1, pp 23–35 | Cite as

Cytokines as Therapeutic Targets for Osteoarthritis

Novel Therapeutic Strategies

Abstract

Osteoarthritis (OA) is a debilitating, progressive disease of diarthrodial joints associated with the aging process. With the exception of anti-inflammatory corticosteroids and nonsteroidal anti-inflammatory drugs which inhibit cyclo-oxygenase-2, the enzyme responsible for prostaglandin biosynthesis in inflammation, no specific therapy based on fundamental intracellular pathways of chondrocytes and synoviocytes exists for the medical management of OA. At the molecular level, OA is characterized by an imbalance between chondrocyte anabolism and catabolism. Disruption of chondrocyte homeostasis primarily affects the cartilage extracellular matrix (ECM), which is responsible for the biomechanical properties of the tissue. Recent evidence has implicated cytokines, among which interleukin (IL)-1, tumor necrosis factor-α, IL-6, and IL-17 seem most involved in the OA process of cartilage destruction. The primary role of these cytokines is to modulate the expression of matrix metalloproteinases and cartilage ECM proteins. Cartilage repair that could restore the functional integrity of the joint is also impaired because chondrocytes in OA cartilage appear unable to respond to insulin-like growth factor-1 or respond abnormally to transforming growth factor-β. As these growth factors also modulate cytokine expression, they may prove useful in designing strategies for suppressing ‘chondrocyte activation’. Although cytokines and growth factors provide a potential therapeutic target for OA, it will be necessary to elucidate the fundamental mechanisms that cytokines employ to cause chondrocyte and synoviocyte dysfunction before ‘anti-cytokine’ therapy can be employed in the medical management of the disease.

References

  1. 1.
    Malemud CJ. Fundamental pathways in osteoarthritis: an overview. Front Biosci 1999; 4: D659–61PubMedCrossRefGoogle Scholar
  2. 2.
    Malemud CJ, Islam N, Haqqi TM. Pathophysiological mechanisms in osteoarthritis lead to novel therapeutic strategies. Cells Tissues Organs 2003; 174(1-2): 34–48PubMedCrossRefGoogle Scholar
  3. 3.
    Dieppe P. The classification and diagnosis of osteoarthritis. In: Kuettner KE, Goldberg VM, editors. Osteoarthritic disorders. Rosemont (IL): American Association of Orthopaedic Surgeons}, 1995: 5–12Google Scholar
  4. 4.
    Nuki G. Role of mechanical factors in the aetiology, pathogenesis and progression of osteoarthritis. In: Reginster J-Y, Pelletier JP, Martel-Pelletier J, et al., editors. Osteoarthritis: clinical and experimental aspects. Heidelberg: Springer-Verlag, 1999: 101–14Google Scholar
  5. 5.
    Hamerman D, Klagsbrun M. Osteoarthritis: emerging evidence for cell interactions in the breakdown and remodeling of cartilage. Am J Med 1985; 78: 495–9PubMedCrossRefGoogle Scholar
  6. 6.
    Pelletier JP, Martel-Pelletier J, Abramson SB. Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic agents. Arthritis Rheum 2001; 44: 1237–47PubMedCrossRefGoogle Scholar
  7. 7.
    Haqqi TM, Anthony DD, Malemud CJ. Chondrocytes. In: Tsokos G, editor. Current molecular medicine: principles of molecular rheumatology. Totowa (NJ): Humana Press, 2000: 267–77CrossRefGoogle Scholar
  8. 8.
    Malemud CJ, Goldberg VM. Future directions for research and treatment of osteoarthritis. Front Biosci 1999; 4: D762–71PubMedCrossRefGoogle Scholar
  9. 9.
    Chikanza I, Fernandes L. Novel strategies for the treatment of osteoarthritis. Expert Opin Investig Drugs 2000; 9: 1499–510PubMedCrossRefGoogle Scholar
  10. 10.
    Attur MG, Dave M, Akamatsu M, et al. Osteoarthritis or osteoarthrosis: the definition of inflammation becomes a semantic issue in the genomic era of molecular medicine. Osteoarthritis Cartilage 2002; 10: 1–4PubMedCrossRefGoogle Scholar
  11. 11.
    Martel-Pelletier J, Di Battista J, Lajeunesse D. Biochemical factors in joint articular tissue degradation in osteoarthritis. In: Reginster J-Y, Pelletier JP, Martel-Pelletier J, et al., editors}. Osteoarthritis: clinical and experimental aspects}. Heidelberg: Springer-Verlag}, 1999}: 156–87Google Scholar
  12. 12.
    Hedbom E, Hauselmann HJ. Molecular aspects of pathogenesis in osteoarthritis: the role of inflammation. Cell Mol Life Sci 2002; 59: 45–53PubMedCrossRefGoogle Scholar
  13. 13.
    Malemud CJ, Shuckett R. Impact loading and lower extremity disease. In: Hadler NM, editor. Clinical concepts in regional musculoskeletal illness. Orlando (FL): Grune and Stratton}, 1987}: 109–58Google Scholar
  14. 14.
    Martel-Pelletier J, Alaaeddine N, Pelletier JP. Cytokines and their role in the pathophysiology of osteoarthritis. Front Biosci 1999; 4: D694–703PubMedCrossRefGoogle Scholar
  15. 15.
    Pelletier JP, Di Battista JA, Roughley P, et al. Cytokines and inflammation in cartilage degradation. Rheum Dis Clin North Am 1993; 19: 545–68PubMedGoogle Scholar
  16. 16.
    van den Berg WB. The role of cytokines and growth factors in cartilage destruction in osteoarthritis and rheumatoid arthritis. Z Rheumatol 1999; 58: 136–41PubMedCrossRefGoogle Scholar
  17. 17.
    Jiang Y, Genant HK, Watt I, et al. A multicenter, double-blind, dose-ranging, randomized placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: radiologic progression and correlation of Genant and Larsen scores. Arthritis Rheum 2000; 43(5): 1001–9PubMedCrossRefGoogle Scholar
  18. 18.
    Cvetkovic RS, Keating G. Anakinra. BioDrugs 2002; 16: 303–11PubMedCrossRefGoogle Scholar
  19. 19.
    Fleischmann RM, Schechtman J, Bennett R, et al. Anakinra, a recombinant human interleukin-1 receptor anatagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: a large, international, multicenter, placebo-controlled trial. Arthritis Rheum 2003; 48: 927–34PubMedCrossRefGoogle Scholar
  20. 20.
    Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis: Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 2000; 343(22): 1594–602PubMedCrossRefGoogle Scholar
  21. 21.
    Genovese MC, Bathon JM, Martin RW, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two year radiographic and clinical outcomes. Arthritis Rheum 2002; 46: 1443–50PubMedCrossRefGoogle Scholar
  22. 22.
    Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human antitumor necrosis factor a monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003; 48: 35–45PubMedCrossRefGoogle Scholar
  23. 23.
    Brandt S, Sieper J, Braun J. Infliximab in the treatment of active and severe ankylosing spondylitis. Clin Exp Rheumatol 2002; 20Suppl. 28: S106–10PubMedGoogle Scholar
  24. 24.
    Davis Jr JC. The role of etanercept in ankylosing spondylitis. Clin Exp Rheumatol 2002; 20Suppl. 28: S111–5PubMedGoogle Scholar
  25. 25.
    Gorman JD, Sack KE, Davis Jr JC. Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor α. N Engl J Med 2002; 346: 1349–56PubMedCrossRefGoogle Scholar
  26. 26.
    Fernandes JC, Martel-Pelletier J, Pelletier JP. The role of cytokines in osteoarthritis pathophysiology. Biorheology 2002; 39: 237–46PubMedGoogle Scholar
  27. 27.
    Goldring MB. The role of cytokines as inflammatory mediators in osteoarthritis: lessons from animal models. Connect Tissue Res 1999; 40: 1–11PubMedCrossRefGoogle Scholar
  28. 28.
    Lotz M. Cytokines in cartilage injury and trauma. Clin Orthop 2001; 3915: S108–15Google Scholar
  29. 29.
    Towle CA, Hung HH, Bonassar LJ, et al. Detection of interleukin-1 in the cartilage of patients with osteoarthritis: a possible autocrine/paracrine role in pathogenesis. Osteoarthritis Cartilage 1997; 5: 293–300PubMedCrossRefGoogle Scholar
  30. 30.
    Pelletier JP, Martel-Pelletier J. Evidence for the involvement of interleukin 1 in human osteoarthritic degeneration: protective effect of NSAID. J Rheumatol Suppl 1989; 18: 19–27PubMedCrossRefGoogle Scholar
  31. 31.
    Tetlow LC, Adlam DJ, Woolley DE. Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: associations with degenerative changes. Arthritis Rheum 2001; 44: 585–94PubMedCrossRefGoogle Scholar
  32. 32.
    Schlaak JF, Pfers I, Meyer Zum Buschenfeld KH, et al. Different cytokine profiles in synovial fluid of patients with osteoarthritis, rheumatoid arthritis and seronegative spondylarthopathies. Clin Exp Rheumatol 1996; 14: 155–62PubMedGoogle Scholar
  33. 33.
    Westacott CI, Sharif M. Cytokines in osteoarthritis: mediators or markers of joint destruction. Semin Arthritis Rheum 1996; 25: 254–72PubMedCrossRefGoogle Scholar
  34. 34.
    Holt I, Cooper RG, Denton J, et al. Cytokine inter-relationships and their association with disease activity in arthritis. Br J Rheumatol 1992; 31: 725–33PubMedCrossRefGoogle Scholar
  35. 35.
    Chandrasekhar S, Harvey AK, Higginbotham JD, et al. Interleukin-1 induced suppression of type II collagen gene transcription involves DNA regulatory elements. Exp Cell Res 1990; 191: 105–14PubMedCrossRefGoogle Scholar
  36. 36.
    Moos V, Rudwaleit M, Herzog V, et al. Association of genotypes affecting the expression of interleukin-1β or IL-1 receptor antagonist with osteoarthritis. Arthritis Rheum 2000; 43: 2417–22PubMedCrossRefGoogle Scholar
  37. 37.
    Maier M, Ganu V, Lotz M. Interleukin-11, an inducible cytokine in human articular chondrocytes and synoviocytes, stimulates the production of tissue inhibitor of metalloproteinases. J Biol Chem 1993; 268: 1527–32Google Scholar
  38. 38.
    Alaaeddine N, Di Battista JA, Pelletier JP, et al. Differential effects of IL-8, LIF (pro-inflammatory) and IL-11 (anti-inflammatory) on TNF-α-induced PGE2 release and on signaling pathways in human OA synovial fibroblasts. Cytokine 1999; 11: 1020–30PubMedCrossRefGoogle Scholar
  39. 39.
    Leistad L, Ostensen M, Faxvaag A. Detection of cytokine mRNA in human, articular cartilage from patients with rheumatoid arthritis and osteoarthritis by reverse transcriptase-polymerase chain reaction. Scand J Rheumatol 1998; 27: 61–7PubMedCrossRefGoogle Scholar
  40. 40.
    Remick DG, De Forge LE, Sullivan JF, et al. Profile of cytokines in synovial fluid from patients with arthritis: interleukin-8 (IL-8) and IL-6 correlate with inflammatory arthritides. Immunol Invest 1992; 21: 321–7PubMedCrossRefGoogle Scholar
  41. 41.
    Kaneko S, Satoh T, Chiba J, et al. Interleukin-6 and interleukin-8 levels in serum and synovial fluid of patients with osteoarthritis. Cytokines Cell Mol Ther 2000; 6: 71–9PubMedCrossRefGoogle Scholar
  42. 42.
    Nietfeld JJ, Wilbrink B, Helle M, et al. Interleukin-1-induced interleukin-6 is required for the inhibition of proteoglycan synthesis by interleukin-1 in human articular cartilage. Arthritis Rheum 1990; 33: 1695–701PubMedCrossRefGoogle Scholar
  43. 43.
    Jikko A, Wakisaka T, Iwamoto M, et al. Effects of interleukin-6 on proliferation and proteoglycan metabolism in articular chondrocyte cultures. Cell Biol Int 1998; 22: 615–21PubMedCrossRefGoogle Scholar
  44. 44.
    Lotz M, Guerne PA. Interleukin-6 induces the synthesis of tissue inhibitor of metalloproteinase-1/erythroid potentiating activity. J Biol Chem 1991; 266: 2017–20PubMedGoogle Scholar
  45. 45.
    Silacci P, Dayer JM, Desgeorges A, et al. Interleukin (IL)-6 and its soluble receptor induce TIMP-1 expression in synoviocytes and chondrocytes, and block IL-1-induced collagenolytic activity. J Biol Chem 1998; 273: 13625–9PubMedCrossRefGoogle Scholar
  46. 46.
    Yu CL, Sun KH, Sun SC, et al. Interleukin-8 modulates interleukin-1β, interleukin-6 and tumor necrosis factor-α release from normal mononuclear cells. Immunopharmacology 1994; 27: 207–14PubMedCrossRefGoogle Scholar
  47. 47.
    Pulsatelli L, Dolzani P, Piacentini A, et al. Chemokine production by human chondrocytes. J Rheumatol 1999; 26: 1992–2001PubMedGoogle Scholar
  48. 48.
    Deleuran B, Lemche P, Kristensen MS, et al. Localisation of interleukin 8 in the synovial membrane, cartilage pannus junction, and chondrocytes in rheumatoid arthritis. Scand J Rheumatol 1994; 23: 2–7PubMedCrossRefGoogle Scholar
  49. 49.
    Lubberts E, van den Berg WB. Potential of modulatory cytokines in the rheumatoid arthritis process. Drug News Perspect 2001; 14: 517–22PubMedCrossRefGoogle Scholar
  50. 50.
    Honorati MC, Bovara M, Cattini L, et al. Contribution of interleukin 17 to human cartilage degradation and synovial inflammation in osteoarthritis. Osteoarthritis Cartilage 2002; 10: 799–807PubMedCrossRefGoogle Scholar
  51. 51.
    Attur MT, Patel RN, Abramson SB. Interleukin-17 up-regulation of nitric oxide production in human osteoarthritic cartilage. Arthritis Rheum 1997; 40: 1050–3PubMedCrossRefGoogle Scholar
  52. 52.
    Koshy PJ, Henderson N, Logan C, et al. Interleukin 17 induces cartilage collagen breakdown: novel synergistic effects in combination with proinflammatory cytokines. Ann Rheum Dis 2002; 61: 704–13PubMedCrossRefGoogle Scholar
  53. 53.
    Benderdour M, Tardif G, Pelletier JP, et al. Interleukin-17 (IL-17) induces collagenase-3 production in human osteoarthritic chondrocytes via AP-1 dependent activation: differential activation of AP-1 members by IL-17 and IL-1β. J Rheumatol 2002; 29: 1262–72PubMedGoogle Scholar
  54. 54.
    Saha N, Moldovan F, Tardif G, et al. Interleukin-1 β-converting enzyme/caspase-1 in human osteoarthritic tissues: localization and role in the maturation of interleukin-Iβ and interleukin-18. Arthritis Rheum 1999; 42: 1577–87PubMedCrossRefGoogle Scholar
  55. 55.
    Alaaeddine N, Olee T, Hashimoto S, et al. Production of the chemokine RANTES by articular chondrocytes and role in cartilage degradation. Arthritis Rheum 2001; 44: 1633–44PubMedCrossRefGoogle Scholar
  56. 56.
    Futani H, Okayama A, Matsui K, et al. Relation between interleukin-18 and PGE2 in synovial fluid of osteoarthritis: a potential therapeutic target for cartilage degradation. J Immunother 2002; 25Suppl. 1: S61–4PubMedCrossRefGoogle Scholar
  57. 57.
    Alaaeddine N, Di Battista JA, Pelletier JP, et al. Inhibition of tumor necrosis factor-α-induced prostaglandin E2 production by anti-inflammatory cytokines inter-leukin-4, interleukin-10 and interleukin-13 in osteoarthritic synovial fibroblasts: distinct targeting in the signal pathways. Arthritis Rheum 1999; 42: 710–8PubMedCrossRefGoogle Scholar
  58. 58.
    Relic B, Guicheux J, Mezin F, et al. IL-4 and IL-13, but not IL-10, protect human synoviocytes from apoptosis. J Immunol 2001; 166: 2775–82PubMedGoogle Scholar
  59. 59.
    Jovanovic D, Pelletier JP, Alaaeddine N, et al. Effect of IL-13 on cytokine receptors and inhibitors on human osteoarthritis synovium and synovial fibroblasts. Osteoarthritis Cartilage 1998; 6: 40–9PubMedCrossRefGoogle Scholar
  60. 60.
    Metcalf D. The leukemia inhibitory factor (LIF). Int J Cell Cloning 1991; 9: 95–118PubMedCrossRefGoogle Scholar
  61. 61.
    Reid LR, Lowe C, Cornish J, et al. Leukemia inhibitory factor: a novel bone-active cytokine. Endocrinology 1990; 126: 1416–20PubMedCrossRefGoogle Scholar
  62. 62.
    Carroll GJ, Bell MC. Leukaemia inhibitory factor stimulates proteoglycan resorption in porcine articular cartilage. Rheumatol Int 1993; 13: 5–8PubMedCrossRefGoogle Scholar
  63. 63.
    Lotz M, Moats T, Villiger PM. Leukemia inhibitory factor is expressed in cartilage and synovium and can contribute to the pathogenesis of arthritis. J Clin Invest 1992; 90: 888–96PubMedCrossRefGoogle Scholar
  64. 64.
    Dechanet J, Taupin JL, Chomarat P, et al. Interleukin-4, but not interleukin 10 inhibits production of leukemia inhibitory factor by rheumatoid synovium and synoviocytes. Eur J Immunol 1994; 24: 3222–8PubMedCrossRefGoogle Scholar
  65. 65.
    Tracey KJ, Cerami A. Tumor necrosis factor, other cytokines and disease. Annu Rev Cell Biol 1993; 9: 317–43PubMedCrossRefGoogle Scholar
  66. 66.
    Gearing AJ, Beckett M, Christodoulous M, et al. Processing of tumor necrosis factor-α by metalloproteinases. Nature 1994; 370: 555–7PubMedCrossRefGoogle Scholar
  67. 67.
    Patel IR, Attur MG, Patel RN, et al. TNF-α convertase enzyme from human arthritis-affected cartilage: isolation of cDNA by differential display, expression of the active enzyme, and regulation of TNF-α. J Immunol 1998; 160: 4570–9PubMedGoogle Scholar
  68. 68.
    Fisher BA, Mundle S, Cole AA. Tumor necrosis factor-α induced DNA cleavage in human articular chondrocytes may involve multiple endonucleotytic activities during apoptosis. Microsc Res Tech 2000; 50: 303–9Google Scholar
  69. 69.
    Aizawa T, Kon T, Einhorn TA, et al. Induction of apoptosis in chondrocytes by tumor necrosis factor-α. J Orthop Res 2001; 19: 785–96PubMedCrossRefGoogle Scholar
  70. 70.
    Petterson I, Figenshau E, Olsen W, et al. Tumor necrosis factor-related apoptosisinducing ligand induces apoptosis in human articular chondrocytes. Biochem Biophys Res Commun 2002; 296: 671–6CrossRefGoogle Scholar
  71. 71.
    Islam N, Haqqi TM, Jepsen KJ, et al. Hydrostatic pressure induces apoptosis in human chondrocytes from osteoarthritic cartilage through up-regulation of tumor necrosis factor-α, inducible nitric oxide synthase, p53, c-myc and bax-α and suppression of bcl-2. J Cell Biochem 2002; 87: 266–78PubMedCrossRefGoogle Scholar
  72. 72.
    Vuolteenaho K, Moilanen T, Hämäläinen M, et al. Effects of TNF-α antagonists on nitric oxide production in human cartilage. Osteoarthritis Cartilage 2002; 10: 327–32PubMedCrossRefGoogle Scholar
  73. 73.
    Greenwel P, Tanaka S, Penkov D, et al. Tumor necrosis factor α inhibits type I collagen synthesis through repressive CCAAT/enhancer-binding proteins. Mol Cell Biol 2000; 20: 912–8PubMedCrossRefGoogle Scholar
  74. 74.
    Takahashi K, Kubo T, Arai Y, et al. Hydrostatic pressure induces expression of interleukin 6 and tumor necrosis factor α mRNAs in a chondrocyte-like cell line. Ann Rheum Dis 1998; 57: 231–6PubMedCrossRefGoogle Scholar
  75. 75.
    Patwari P, Cook MN, Di Micco MA, et al. Proteoglycan degradation after injurious compression of bovine and human cartilage in vitro: interaction with exogenous cytokines. Arthritis Rheum 2003; 48: 1292–301PubMedCrossRefGoogle Scholar
  76. 76.
    Webb GR, Westacott CI, Elson CJ. Cartilage tumor necrosis factor receptors and focal loss of cartilage in osteoarthritis. Osteoarthritis Cartilage 1997; 5: 427–37PubMedCrossRefGoogle Scholar
  77. 77.
    Westacott CI, Barakat AF, Wood L, et al. Tumor necrosis factor-α can contribute to focal of cartilage in osteoarthritis. Osteoarthritis Cartilage 2000; 8: 213–21PubMedCrossRefGoogle Scholar
  78. 78.
    Shlopov BV, Lie WR, Mainardi CL, et al. Osteoarthritic lesions: involvement of three different collagenases. Arthritis Rheum 1997; 40: 2065–74PubMedCrossRefGoogle Scholar
  79. 79.
    Freemont AJ, Hampson V, Tillman R, et al. Gene expression of matrix metalloproteinases 1,3, and 9 by chondrocytes in osteoarthritic human knee cartilage is zone and grade specific. Ann Rheum Dis 1997; 56: 542–9PubMedCrossRefGoogle Scholar
  80. 80.
    He W, Pelletier JP, Martel-Pelletier J, et al. Synthesis of interleukin-Iβ, tumor necrosis factor-α and interstitial collagenase (MMP-1) is eicosanoid dependent in human osteoarthritis synovial membrane expiants: interactions with antiinflammatory cytokines. J Rheumatol 2002; 29: 546–53PubMedGoogle Scholar
  81. 81.
    Barakat AF, Elson CJ, Westacott CI. Susceptibility to physiological concentrations of IL-Iβ varies in cartilage at different anatomical locations on human osteoarthritic knee joints. Osteoarthritis Cartilage 2002; 10: 264–9PubMedCrossRefGoogle Scholar
  82. 82.
    Pratta MA, Scherle PA, Yang G, et al. Induction of aggrecanase 1 (ADAM-TS4) by interleukin-1 occurs through activation of constitutively produced protein. Arthritis Rheum 2003; 48: 119–33PubMedCrossRefGoogle Scholar
  83. 83.
    Ganu VS, Hu S-I, Melton R, et al. Biochemical and molecular characterization of stromelysin synthesized by human osteoarthritic chondrocytes stimulated with recombinant interleukin-1. Clin Exp Rheumatol 1994; 12: 489–96PubMedGoogle Scholar
  84. 84.
    Bord S, Horner A, Hembry RM, et al. Stromelysin-1 (MMP-3) and stromelysin-2 (MMP-10) expression in developing human bone: potential roles in skeletal development. Bone 1998; 23: 7–12PubMedCrossRefGoogle Scholar
  85. 85.
    Rechardt O, Elomaa O, Vaalamo M, et al. Stromelysin-2 is upregulated during normal wound repair and is induced by cytokines. J Invest Dermatol 2000; 115: 778–87PubMedCrossRefGoogle Scholar
  86. 86.
    Kerkela E, Ala-aho R, Lohi J, et al. Differential patterns of stromelysin-2 (MMP-10) and MT1-MMP (MMP-14) expression in epithelial skin cancers. Br J Cancer 2001; 84: 659–69PubMedCrossRefGoogle Scholar
  87. 87.
    Malemud CJ, Holderbaum D, Goldberg VM, et al. Aggrecan mRNA in human non-arthritic and osteoarthritis cartilage [abstract]. Osteoarthritis Cartilage 1994; 2Suppl. 1: 45Google Scholar
  88. 88.
    Shlopov BV, Gumanovskaya ML, Hasty KA. Autocrine regulation of collagenase 3 (matrix metalloproteinase 13) during osteoarthritis. Arthritis Rheum 2000; 43: 195–205PubMedCrossRefGoogle Scholar
  89. 89.
    Doege KJ, Sasaki M, Kimura T, et al. Complete coding sequence and deduced primary structure of the human large aggregating proteoglycan, aggrecan: human specific repeats, and additional alternatively spliced forms. J Biol Chem 1991; 266: 894–902PubMedGoogle Scholar
  90. 90.
    Saus J, Quinones S, Otani Y, et al. The complete primary structure of human matrix metalloproteinase-3: identity with stromelysin. J Biol Chem 1988; 263: 6742–5PubMedGoogle Scholar
  91. 91.
    Milner JM, Elliott SF, Cawston TE. Activation of procollagenases is a key control point in cartilage collagen degradation: interaction of serine and metalloproteinase pathways. Arthritis Rheum 2001; 44: 2084–96PubMedCrossRefGoogle Scholar
  92. 92.
    Oleksyszyn J, Augustine AJ. Plasminogen modulation of IL-1 stimulated degradation in bovine and human articular cartilage expiants: the role of the endogenous inhibitors PAI-1, α-2 antiplasmin, α-1-PI, α2-macroglobulin and TIMP. Inflamm Res 1996; 45: 464–72PubMedCrossRefGoogle Scholar
  93. 93.
    Smith RL. Degradative enzymes in osteoarthritis. Front Biosci 1999; 4: D704–12PubMedGoogle Scholar
  94. 94.
    Pap G, Eberhardt R, Rocken C, et al. Expression of stromelysin and urokinase plasminogen activator protein in resection specimens and biopsies at different stages of osteoarthritis of the knee. Pathol Res Pract 2000; 196: 219–26PubMedCrossRefGoogle Scholar
  95. 95.
    Mankin HJ, Dorfman H, Lippiello L, et al. Biochemical and metabolic abnormalities in articular cartilage from osteo-arthritic human hips: II. Correlation of morphology with biochemical and metabolic data. J Bone Joint Surg Am 1971; 53(3): 523–37PubMedGoogle Scholar
  96. 96.
    Pelletier JP, Mineau F, Fernandes F, et al. Two NSAIDs, nimesulide and naproxen, can reduce the synthesis of urokinase and IL-6 while increasing PAI-1, in human OA synovial fibroblasts. Clin Exp Rheumatol 1997; 4: 393–8Google Scholar
  97. 97.
    Apte SS, Mattei M, Olsen BR. Cloning of the cDNA encoding tissue inhibitor of metalloproteinases-3 (TIMP-3) and mapping of the TIMP-3 gene to chromosome 22. Genomics 1994; 19: 86–90PubMedCrossRefGoogle Scholar
  98. 98.
    Martel-Pelletier J, McCollum R, Fujimoto N, et al. Excess of metalloproteinases over tissue inhibitor of metalloproteinase may contribute to cartilage degradation in osteoarthritis and rheumatoid arthritis. Lab Invest 1994; 70: 807–15PubMedGoogle Scholar
  99. 99.
    Bigg HF, Shi YE, Lui YE, et al. Specific, high affinity binding of tissue inhibitor of metalloproteinases-4 (TIMP-4) to the COOH-terminal hemopexin-like domain of human gelatinase A: TIMP-4 binds to progelatinase-A and the COOH-terminal domain in a similar manner to TIMP-2. J Biol Chem 1997; 272: 15496–500PubMedCrossRefGoogle Scholar
  100. 100.
    Huang W, Li WQ, Dehnade F, et al. Tissue inhibitor of metalloproteinase-4 (TIMP-4) gene expression is increased in human osteoarthritic femoral head cartilage. J Cell Biochem 2002; 85: 295–303PubMedCrossRefGoogle Scholar
  101. 101.
    Grabowski PS, Wright PK, Van’t Hof RJ, et al. Immunolocalization of inducible nitric oxide synthase in synovium and cartilage in rheumatoid and osteoarthritis. Br J Rheumatol 1997; 36: 651–5PubMedCrossRefGoogle Scholar
  102. 102.
    Murrell GAC, Jang D, Williams RD. Nitric oxide activated metalloprotease enzymes in articular cartilage. Biochem Biophys Res Commun 1995; 206: 15–21PubMedCrossRefGoogle Scholar
  103. 103.
    Singh R, Ahmed S, Islam N, et al. Epigallocatechin-3-gallate inhibits IL-lβ-induced expression of nitric oxide synthase and production of nitric oxide in human chondrocytes: suppression of nuclear factor κB activation by degradation of the inhibitor of nuclear factor KB. Arthritis Rheum 2002; 46: 2079–86PubMedCrossRefGoogle Scholar
  104. 104.
    Ahmadzadeh N, Shingu M, Nobunaga M. The effect of recombinant tumor necrosis factor-α on Superoxide and metalloproteinase production by synovial cells and chondrocytes. Clin Exp Rheumatol 1990; 8: 387–91PubMedGoogle Scholar
  105. 105.
    Maier R, Bilbe G, Rediske J, et al. Inducible nitric oxide synthase from human articular chondrocytes: cDNA cloning and analysis of mRNA expression. Biochim Biophys Acta 1994; 1208: 145–50PubMedCrossRefGoogle Scholar
  106. 106.
    Blanco FJ, Ochs RL, Schwarz H, et al. Chondrocyte apoptosis induced by nitric oxide. Am J Pathol 1995; 146: 75–85PubMedGoogle Scholar
  107. 107.
    Notoya K, Jovanovic DV, Reboul P, et al. The induction of cell death in human chondrocytes by nitric oxide is related to the production of prostaglandin E2 via the induction of cyclooxygenase-2. J Immunol 2000; 165: 3402–10PubMedGoogle Scholar
  108. 108.
    Relic B, Bentires-Alj M, Ribbens C, et al. TNF-α protects human primary chondrocytes from nitric oxide-induced apoptosis via nuclear factor-κB. Lab Invest 2002; 82: 1661–72PubMedGoogle Scholar
  109. 109.
    Vuolteenaho K, Moilanen T, Hamalainen M, et al. Regulation of nitric oxide production in osteoarthritic and rheumatoid cartilage: role of endogenous IL-1 inhibitors. Scand J Rheumatol 2003; 32: 19–24PubMedCrossRefGoogle Scholar
  110. 110.
    Maneiro E, Lopez-Armada MJ, Fernandez-Sueiro JL, et al. Aceclofenac increases synthesis of interleukin 1 receptor antagonist and decreases the production of nitric oxide in human articular chondrocytes. J Rheumatol 2001; 28: 2692–9PubMedGoogle Scholar
  111. 111.
    Guerne PA, Desgeorges A, Jaspar JM, et al. Effects of IL-6 and its soluble receptor on proteoglycan synthesis and NO release by human articular chondrocytes: comparison with IL-1. Modulation by dexamethasone. Matrix Biol 1999; 18: 253–60PubMedCrossRefGoogle Scholar
  112. 112.
    Martel-Pelletier J, Di Battista J, Lajeunesse D, et al. IGF/IGFBP axis in cartilage and bone in osteoarthritis pathogenesis. Inflamm Res 1998; 47: 90–100PubMedCrossRefGoogle Scholar
  113. 113.
    vanden Berg W, vander Kraan PM, van Beuningen HM. Role of growth factors in cartilage repair. In: Reginster J-Y, Pelletier JP, Martel-Pelletier J, et al., editors. Osteoarthritis: clinical and experimental aspects. Heidelberg: Springer-Verlag, 1999: 188–209Google Scholar
  114. 114.
    Blumenfeld I, Livne E. The role of transforming growth factor (TGF)-β, insulinlike growth factor (IGF)-1 and interleukin (IL)-1 in osteoarthritis and aging of joints. Exp Gerontol 1999; 34: 821–9PubMedCrossRefGoogle Scholar
  115. 115.
    Middleton JF, Tyler JA. Up-regulation of insulin-like growth factor I gene expression in the lesions of osteoarthritic human articular cartilage. Ann Rheum Dis 1992; 51: 440–7PubMedCrossRefGoogle Scholar
  116. 116.
    Denko CW, Malemud CJ. Metabolic disturbances and synovial fluid responses in osteoarthritis. Front Biosci 1999; 4: D686–93PubMedGoogle Scholar
  117. 117.
    Hilal G, Martel-Pelletier J, Pelletier JP, et al. Abnormal regulation of urokinase plasminogen activator by insulin-like growth factor 1 in human osteoarthritic subchondral osteoblasts. Arthritis Rheum 1999; 42: 2112–22PubMedCrossRefGoogle Scholar
  118. 118.
    Sunic D, McNeil JD, Rayner TE, et al. Regulation of insulin-like growth factorbinding protein-5 by insulin-like growth factor and interleukin-lα in ovine articular chondrocytes. Endocrinology 1998; 139: 2356–62PubMedCrossRefGoogle Scholar
  119. 119.
    Morales TI. The insulin-like growth factor binding proteins in uncultured human cartilage: increases in insulin-like growth factor binding protein 3 during osteoarthritis. Arthritis Rheum 2002; 46: 2358–67PubMedCrossRefGoogle Scholar
  120. 120.
    Im HJ, Pacione C, Chubinskaya S, et al. Inhibitory effects of insulin-like growth factor-1 and osteogenic protein-1 on fibronectin fragment and interleukin-1β-stimulated matrix metalloproteinase-13 expression in human chondrocytes. J Biol Chem 2003; 278: 25386–94PubMedCrossRefGoogle Scholar
  121. 121.
    Chandrasekhar S, Harvey AK. Transforming growth factor-β is a potent inhibitor of IL-1 induced protease activity and cartilage proteoglycan degradation. Biochem Biophys Res Commun 1988; 157: 1352–9PubMedCrossRefGoogle Scholar
  122. 122.
    Dubois CM, Ruscetti FW, Palaszynski EW, et al. Transforming growth factor β is a potent inhibitor of interleukin-1 (IL-1) receptor expression: proposed mechanism of inhibition of IL-1 action. J Exp Med 1990; 172: 737–44PubMedCrossRefGoogle Scholar
  123. 123.
    Harvey AK, Hrubey PS, Chandrasekhar S. Transforming growth factor-β inhibition of interleukin-1 involves down-regulation of interleukin-1 receptors on chondrocytes. Exp Cell Res 1991; 195: 376–85PubMedCrossRefGoogle Scholar
  124. 124.
    Hui W, Rowan AD, Cawston T. Modulation of the expression of matrix metalloproteinase and tissue inhibitors of metalloproteinases by TGF-β1 and IGF-1 in primary human and bovine nasal chondrocytes stimulated with TNF-α. Cytokine 2001; 16: 31–5PubMedCrossRefGoogle Scholar
  125. 125.
    Moldovan F, Pelletier JP, Mineau F, et al. Modulation of collagenase 3 in human osteoarthritic cartilage by activation of extracellular transforming growth factor-β: role of furin convertase. Arthritis Rheum 2000; 43: 2100–9PubMedCrossRefGoogle Scholar
  126. 126.
    Yamanishi Y, Boyle DL, Clark M, et al. Expression and regulation of aggrecanase in arthritis: the role of TGF-β. J Immunol 2002; 168: 1405–12PubMedGoogle Scholar
  127. 127.
    Villiger PM, Kusari AB, ten Dijke P, et al. IL-1β and IL-6 selectively induce transforming growth factor-β isoforms in human articular chondrocytes. J Immunol 1993; 151: 3337–44PubMedGoogle Scholar
  128. 128.
    Brandt KD. Animal models of osteoarthritis. In: Reginster J-Y, Pelletier JP, Martel-Pelletier J, et al., editors. Osteoarthritis: clinical and experimental aspects. Heidelberg: Springer-Verlag, 1999: 81–100Google Scholar
  129. 129.
    van den Berg WB. Lessons from animal models of osteoarthritis. Curr Opin Rheumatol 2001; 13: 452–6PubMedCrossRefGoogle Scholar
  130. 130.
    Venn G, Nietfeld JJ, Duits AJ, et al. Elevated synovial fluid levels of interleukin- 6 and tumor necrosis factor associated with early experimental osteoarthritis. Arthritis Rheum 1993; 36: 819–26PubMedCrossRefGoogle Scholar
  131. 131.
    Kammermann JR, Kincaid SA, Rumph PF, et al. Tumor necrosis factor-α (TNF-α) in canine osteoarthritis: immunolocalization of TNF-α, stromelysin and TNF receptors in canine osteoarthritic cartilage. Osteoarthritis Cartilage 1996; 4: 23–34PubMedCrossRefGoogle Scholar
  132. 132.
    Chambers MG, Bayliss MT, Mason RM. Chondrocyte cytokine and growth factor expression in murine osteoarthritis. Osteoarthritis Cartilage 1997; 5: 301–8PubMedCrossRefGoogle Scholar
  133. 133.
    Pelletier JP, Martel-Pelletier J, Malemud CJ. Canine osteoarthritis: effect of endogenous neutral metalloproteoglycanases on articular cartilage proteoglycans. J Orthop Res 1988; 6: 379–88PubMedCrossRefGoogle Scholar
  134. 134.
    Fernandes JC, Martel-Pelletier J, Lascau-Coman V, et al. Collagenase-1 and collagenase-3 synthesis in normal and early experimental osteoarthritic canine cartilage: an immunohistochemical study. J Rheumatol 1998; 25: 1585–94PubMedGoogle Scholar
  135. 135.
    Neuhold LA, Killar L, Zhao W, et al. Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. J Clin Invest 2001; 107: 35–44PubMedCrossRefGoogle Scholar
  136. 136.
    Mehraban F, Lark MW, Ahmed FN, et al. Increased secretion and activity of metalloproteinase-3 in synovial tissues and chondrocytes from experimental osteoarthritis. Osteoarthritis Cartilage 1998; 6: 286–94PubMedCrossRefGoogle Scholar
  137. 137.
    Bluteau G, Conrozier T, Mathieu P, et al. Matrix metalloproteinase-1, −3, −13 and aggrecanase-1 and −2 are differentially expressed in experimental osteoarthritis. Biochim Biophys Acta 2001; 1526: 147–58PubMedCrossRefGoogle Scholar
  138. 138.
    Jovanovic DV, Fernandes JC, Martel-Pelletier J, et al. In vivo inhibition of cyclooxygenase and lipoxygenase by ML-3000 reduces the progression of experimental osteoarthritis: suppression of collagenase 1 and interleukin-1β synthesis. Arthritis Rheum 2001; 44: 2320–30PubMedCrossRefGoogle Scholar
  139. 139.
    Pelletier JP, Jovanovic D, Fernandes JC, et al. Reduced progression of experimental osteoarthritis in vivo by selective inhibition of inducible nitric oxide synthase. Arthritis Rheum 1998; 41: 1275–86PubMedCrossRefGoogle Scholar
  140. 140.
    Boileau G, Martel-Pelletier J, Moldovan F, et al. The in situ up-regulation of chondrocyte interleukin-1-converting enzyme and interleukin-18 levels in experimental osteoarthritis is mediated by nitric oxide. Arthritis Rheum 2002; 46: 2637–47PubMedCrossRefGoogle Scholar
  141. 141.
    van den Berg WB, van de Loo PA, Joosten LA, et al. Animal models of arthritis in NOS2-deficient mice. Osteoarthritis Cartilage 1999; 7: 413–5PubMedCrossRefGoogle Scholar
  142. 142.
    Wojtowicz-Praga SM, Dickson RB, Hawkins MJ. Matrix metalloproteinase inhibitors. Invest New Drugs 1997; 15: 61–75PubMedCrossRefGoogle Scholar
  143. 143.
    Kim S-J, Ju J-W, Oh C-D, et al. ERK-1/2 and p38 oppositely regulate nitric oxideinduced apoptosis of chondrocytes in association with p53, caspase-3 and differentiation state. J Biol Chem 2002; 277: 1332–9PubMedCrossRefGoogle Scholar
  144. 144.
    Ridley SH, Sarsfield SJ, Lee JC, et al. Actions of IL-1 are selectively controlled by p38 mitogen-activated protein kinase: regulation of prostaglandin H synthase-2, metalloproteinases and IL-6 at different levels. J Immunol 1997; 158: 3165–73PubMedGoogle Scholar
  145. 145.
    Geng V, Valbrecht J, Lotz M. Selective activation of the mitogen-activated protein kinase subgroups c-Jun NH2 terminal kinase and p38 by IL-1 and TNF in human articular chondrocytes. J Clin Invest 1996; 98: 2425–30PubMedCrossRefGoogle Scholar
  146. 146.
    Scherle PA, Pratta MA, Feeser WS, et al. The effects of IL-1 on mitogen-activated protein kinases in rabbit articular chondrocytes. Biochem Biophys Res Commun 1997; 230: 573–7PubMedCrossRefGoogle Scholar
  147. 147.
    Han Z, Boyle DL, Chang L, et al. c-Jun-N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest 2001; 108: 73–81PubMedGoogle Scholar
  148. 148.
    Vincenti MP, Brinckerhoff CE. The potential of signal transduction inhibitors for the treatment of arthritis: is it all just JNK? J Clin Invest 2001; 108: 181–3PubMedGoogle Scholar
  149. 149.
    Liacini A, Sylvester J, Qing Li W, et al. Inhibition of interleukin-1-stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor KB (NF-κB) transcription factors down-regulates matrix metalloproteinase gene expression in articular chondrocytes. Matrix Biol 2002; 21: 251–62PubMedCrossRefGoogle Scholar
  150. 150.
    Mengshol JA, Vincenti MP, Brinckerhoff CE. IL-1 induces collagenase-3 (MMP-13) promoter activity in stably transfected chondrocytic cells: requirement for Runx-2 and activation of p38 and JNK pathways. Nucleic Acids Res 2001; 29: 4361–72PubMedCrossRefGoogle Scholar
  151. 151.
    Ahmed S, Rahman A, Hasnain A, et al. Phenyl N-tert-butylnitrone down-regulates interleukin-1 β stimulated matrix metalloproteinase-13 gene expression in human chondrocytes: suppression of c-Jun-NH2-terminal kinase, p38-mitogenactivated protein kinase and activating protein-1. J Pharmacol Exp Ther 2003; 305: 981–8PubMedCrossRefGoogle Scholar
  152. 152.
    Liacini A, Sylvester J, Qing Li W, et al. Induction of matrix metalloproteinase 13 gene expression by TNF-α is mediated by MAP kinases, AP-1 and NF-κB transcription factors in articular chondrocytes. Exp Cell Res 2003; 288: 208–17PubMedCrossRefGoogle Scholar
  153. 153.
    Martel-Pelletier J, Mineau F, Jovanovic D, et al. Mitogen-activated protein kinase and nuclear factor κB together regulate IL-17 induced nitric oxide production in human osteoarthritic chondrocytes: possible role of transactivating factor mitogen-activated protein kinase-activated protein kinase (MAPKAPK). Arthritis Rheum 1999; 42: 2399–409PubMedCrossRefGoogle Scholar
  154. 154.
    Shakibaei M, Schulze-Tanzil G, de Souza P, et al. Inhibition of mitogen-activated protein kinase induces apoptosis of human chondrocytes. J Biol Chem 2001; 276: 13289–94PubMedCrossRefGoogle Scholar
  155. 155.
    Wang CY, Mayo MW, Korneluk RG, et al. NF-κB anti-apoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and C-IAP2 to suppress caspase-8 activation. Science 1998; 281: 1680–2PubMedCrossRefGoogle Scholar
  156. 156.
    Andreakos E, Smith C, Kiriakidis S, et al. Heterogenous requirement of IκB kinase 2 for inflammatory cytokine and matrix metalloproteinase production in rheumatoid arthritis: implications for therapy. Arthritis Rheum 2003; 48: 1901–12PubMedCrossRefGoogle Scholar
  157. 157.
    Elliott SF, Coon CI, Hays E, et al. Bcl-3 is an interleukin-1-responsive gene in chondrocytes and synovial fibroblasts that activates transcription of the matrix metalloproteinase 1 gene. Arthritis Rheum 2002; 46: 3230–9PubMedCrossRefGoogle Scholar
  158. 158.
    Zhang R, He X, Liu W, et al. A1P1 mediates TNF-α-induced ASK1 activation by facilitating dissociation of ASK1 from its inhibitor 14-3-3. J Clin Invest 2003; 111: 1933–43PubMedGoogle Scholar
  159. 159.
    Guicciardi ME, Gores GJ. A1P1: a new player in TNF signaling. J Clin Invest 2003; 111: 1813–5PubMedGoogle Scholar
  160. 160.
    Wrana J, Pawson T. Mad about SMADs. Nature 1997; 388: 28–9PubMedCrossRefGoogle Scholar
  161. 161.
    Bau B, Haag J, Schmid E, et al. Bone morphogenetic protein-mediating receptorassociated Smads as well as common Smad are expressed in human articular chondrocytes but not up-regulated or down-regulated in osteoarthritic cartilage. J Bone Miner Res 2002; 17: 2141–50PubMedCrossRefGoogle Scholar
  162. 162.
    Tardif G, Reboul P, Dupuis M, et al. Transforming growth factor-α induced collagenase-3 production in human osteoarthritic chondrocytes is triggered by Smad proteins: cooperation between activator protein-1 and PEA-3 binding sites. J Rheumatol 2001; 28: 1631–9PubMedGoogle Scholar
  163. 163.
    Andriamanaalijaona R, Felisaz N, Kim SJ, et al. Mediation of interleukin-lβ-induced transforming growth factor-β1 expression by activator protein 4 transcription factor in primary cultures of bovine articular chondrocytes: possible cooperation with activator protein 1. Arthritis Rheum 2003; 48: 1569–81CrossRefGoogle Scholar
  164. 164.
    Hidaka K, Kanematsu T, Takeuichi H, et al. Involvement of the phosphoinositide 3-kinase/protein kinase B signaling pathway in insulin/IGF-I-induced chondrogenesis of the mouse embryonal carcinoma-derived cell line ATDC5. Int J Biochem Cell Biol 2001; 33: 1094–103PubMedCrossRefGoogle Scholar
  165. 165.
    Di Battista JA, Doré S, Morin T, et al. Prostaglandin E2 up-regulates insulin-like growth factor binding protein-3 expression and synthesis in human articular chondrocytes by a c-AMP-independent pathway: role of calcium and protein kinase A and C. J Cell Biochem 1996; 63: 320–33CrossRefGoogle Scholar
  166. 166.
    Dupont J, Dunn SE, Barrett JC, et al. Microarray analysis and identification of novel molecules involved in insulin-like-growth factor-1 receptor signaling and gene expression. Recent Prog Horm Res 2003; 58: 325–42PubMedCrossRefGoogle Scholar
  167. 167.
    Doré S, Pelletier JP, Di Battista JA, et al. Human osteoarthritic chondrocytes possess an increased number of insulin-like growth factor-1 binding sites but are unresponsive to its stimulation. Arthritis Rheum 1994; 37: 253–63PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  1. 1.Departments of Medicine and AnatomyCase Western Reserve University School of MedicineClevelandUSA
  2. 2.Department of Medicine, Division of Rheumatic DiseasesUniversity Hospitals of ClevelandClevelandUSA

Personalised recommendations