Current Rheumatology Reports

, Volume 3, Issue 6, pp 535–541 | Cite as

Nitric oxide and inflammatory mediators in the perpetuation of osteoarthritis

  • Steven B. Abramson
  • Mukundan Attur
  • Ashok R. Amin
  • Robert Clancy


Articular chondrocyte production of nitric oxide (NO) and other inflammatory mediators, such as eicosanoids and cytokines, are increased in human osteoarthritis. The excessive production of nitric oxide inhibits matrix synthesis and promotes its degradation. Furthermore, by reacting with oxidants such as superoxide anion, nitric oxide promotes cellular injury and renders the chondrocyte susceptible to cytokine-induced apoptosis. PGE2 exerts anabolic and catabolic effects on chondrocytes, depending on the microenvironment and physiologic condition. The increased expression of inducible NOS (iNOS) and cyclo-oxygenase-2 (COX-2) in OA chondrocytes is largely due to the increased expression of pro-inflammatory cytokines, particularly IL-1, which act in an autocrine/paracrine fashion to perpetuate a catabolic state that leads to progressive destruction of articular cartilage. The initiating factors for the production of inflammatory mediators include altered biomechanical forces; their continued production may be augmented by an increase in extracellular matrix proteins acting through ligation of surface integrins.


Nitric Oxide Articular Cartilage Synovial Cell Articular Chondrocytes Proteoglycan Synthesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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References and Recommended Reading

  1. 1.
    Pelletier J-P, Martel-Pelletier J, Abramson SB: Osteoarthritis, an inflammatory disease. Potential implication of new therapeutic targets. Arthritis Rheum 2001, 44:1237–1247. Review of cytokine and inflammatory pathways that are activated in OA synovial cells and chondrocytes. Particular focus on targets for future therapies designed to prevent structural damage, including gene therapy.PubMedCrossRefGoogle Scholar
  2. 2.
    Attur MG, Patel IR, Patel RN, et al.: 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 Physicians 1998, 110:1–8.Google Scholar
  3. 3.
    Nathan C: Perspectives series: Nitric oxide and nitric oxide synthases. Inducible nitric oxide synthase: What difference does it make? J Clin Invest 1997, 100:2417–2423.PubMedGoogle Scholar
  4. 4.
    Christopherson KS, Bredt DS: Perspectives series: Nitric oxide and nitric oxide synthases. Nitric oxide in excitable tissues: Physiological roles and disease. J Clin Invest 1997, 100:2424–2429.PubMedGoogle Scholar
  5. 5.
    Belmont HM, Levartovsky D, Goel A, et al.: Increased nitric oxide production accompanied by the up-regulation of inducible nitric oxide synthase in vascular endothelium from patients with systemic lupus erythematosus. Arthritis Rheum 1997, 40:1810–1816.PubMedCrossRefGoogle Scholar
  6. 6.
    McCartney-Francis NL, Song X, Mizel DE, Wahl SM: Selective inhibition of inducible nitric oxide synthase exacerbates erosive joint disease. J Immunol 2001, 666:2734–2740.Google Scholar
  7. 7.
    Stamler JS, Singel DJ, Loscalzo J: Biochemistry of nitric oxide and its redox-activated forms. Science 1992, 258:1898–1902.PubMedCrossRefGoogle Scholar
  8. 8.
    Clancy RM, Leszczynska-Piziak J, Abramson SB: Nitric oxide, an endothelial cell relaxation factor, inhibits neutrophil superoxide anion production via a direct action on the NADPH oxidase. J Clin Invest 1992, 90:1116–1121.PubMedGoogle Scholar
  9. 9.
    Tomita M, Sato EF, Nishikawa M, et al.: Nitric oxide regulates mitochondrial respiration and functions of articular chondrocytes. Arthritis Rheum 2001, 44:96–104.PubMedCrossRefGoogle Scholar
  10. 10.
    Myers PR, Minor RL Jr, Guerra R Jr, et al.: Vasorelaxant properties of the endothelium-derived relaxing factor more closely resemble S-nitrosocysteine than nitric oxide. Nature 1990, 345:161–163.PubMedCrossRefGoogle Scholar
  11. 11.
    Pryor WA, Squadrito GL: The chemistry of peroxynitrite: A product from the reaction of nitric oxide with superoxide. Am J Physiol 1995, 268:L699–722.PubMedGoogle Scholar
  12. 12.
    Hausladen A, Privalle CT, Keng T, et al.: Nitrosative stress: Activation of the transcription factor OxyR. Cell 1996, 86:719–729.PubMedCrossRefGoogle Scholar
  13. 13.
    Pelletier J-P, Jovanovic V, Lascau-Coman V, 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 2000, 43:1290–1299.PubMedCrossRefGoogle Scholar
  14. 14.
    van den Berg WB, van de Loo F, Joosten LA, Arntz OJ: Animal models of arthritis in NOS2-deficient mice. Osteoarthritis Cartilage 1999, 7:413–415.PubMedCrossRefGoogle Scholar
  15. 15.
    Sakurai H, Kohsaka H, Liu M-F, et al.: Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritides. J Clin Invest 1996, 96:2357.Google Scholar
  16. 16.
    Hayashi T, Abe E, Yamate T, Taguchi Y, Jasin HE: Nitric oxide production by superficial and deep articular chondrocyte. Arthritis Rheum 1997, 40:261–269.PubMedCrossRefGoogle Scholar
  17. 17.
    Amin AR, Di Cesare PE, Vyas P, et al.: The expression and regulation of nitric oxide synthase in human osteoarthritisaffected chondrocytes: Evidence for up-regulated neuronal nitric oxide synthase. J Exp Med 1995, 182:2097.PubMedCrossRefGoogle Scholar
  18. 18.
    Attur M, Dave M, Abramson SB, Amin AR: Functional genomic analysis in arthritis-affected cartilage: Yin-Yang regulation of inflammatory mediators byα5β1 and αvβ3. J Immunol 2000, 164:2684–2691. Example of gene discovery and functional genomic strategy that enhances understanding of disease mechanism. Signaling through β3 and β1 integrins shown to modulate chondrocyte release of inflammatory mediators.PubMedGoogle Scholar
  19. 19.
    Taskiran D, Stefanovic-Racic M, Georgescu H, Evans C:Nitric oxide mediates suppression of cartilage proteoglycan synthesis by interleukin-1. Biochem Biophys Res Comm 1994, 200:142–148.PubMedCrossRefGoogle Scholar
  20. 20.
    Hirai Y, Migita K, Honda S, et al.: Effects of nitric oxide on matrix metalloproteinase-2 production by rheumatoid synovial cells. Life Sci 2001, 68:913–920.PubMedCrossRefGoogle Scholar
  21. 21.
    Clancy R, Abramson SB, Kohne C, Rediske J: Nitric oxide attenuates cellular hexose monophosphate shunt response to oxidants in articular chondrocytes and acts to promote oxidant injury. J Cell Physiol 1997, 172:183–191.PubMedCrossRefGoogle Scholar
  22. 22.
    Lotz M: The role of nitric oxide in articular cartilage damage. Rheum Dis Clin North Am 1999, 25:269–282.PubMedCrossRefGoogle Scholar
  23. 23.
    Van’t Hof RJ, Hocking L, Wright PK, Ralston SH: Nitric oxide is a mediator of apoptosis in the rheumatoid joint. Rheumatology (Oxford) 2000, 39:1004–1008.CrossRefGoogle Scholar
  24. 24.
    Clancy R, Rediske J, Koehne C, et al.: Activation of stress activated protein kinase in ostearthritic cartilage: Evidence for nitric oxide dependence. Osteoarthritis Cartilage 2001, 9:294–299.PubMedCrossRefGoogle Scholar
  25. 25.
    Van’t Hof RJ, Ralston SH: Nitric oxide and bone. Immunology 2001, 103:255–261.CrossRefGoogle Scholar
  26. 26.
    Van’t Hof RJ, Armour KJ, Smith LM, et al.: Requirement of the inducible nitric oxide synthase pathway for IL-1-induced osteoclastic bone resorption. Proc Natl Acad Sci USA 2000, 97:7993–7998.CrossRefGoogle Scholar
  27. 27.
    Nishida K, Doi T, Matsuo M, et al.: Involvement of nitric oxide in chondrocyte cell death in chondro-osteophyte formation. Osteoarthritis Cartilage 2001, 9:232–237.PubMedCrossRefGoogle Scholar
  28. 28.
    Amin AR, Attur M, Patel RJ, et al.: Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. J Clin Invest 1997, 99:1231–1237.PubMedGoogle Scholar
  29. 29.
    Fahmi H, DiBattista JA, Pelletier J-P, et al.: Peroxisome proliferator-activated receptor gamma activators inhibit interleukin-1beta-induced nitric oxide and matrix metalloproteinase 13 production in human chondrocytes. Arthritis Rheum 2001, 44:595–607. Important new area of study that examines the role of PPARγ pathways in the regulation of chondrocyte metabolism. The possible role of eicosanoids other than PGE2, particularly PGJ2, is discussed.PubMedCrossRefGoogle Scholar
  30. 30.
    Boyault S, Simonin MA, Bianchi A, et al.: 15-Deoxy-delta12, 14-PGJ2, but not troglitazone, modulates IL-1beta effects in human chondrocytes by inhibiting NF-kappaB and AP-1 activation pathways. FEBS Lett 2001, 501:24–30.PubMedCrossRefGoogle Scholar
  31. 31.
    Kawahito Y, Kondo M, Tsubouchi Y, et al.: 15-deoxy-′′12, 14-PGJ2 induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats. J Clin Invest 2000, 106:189–197.PubMedCrossRefGoogle Scholar
  32. 32.
    Wittenberg RH, Willburger RE, Kleemeyer KS, Peskar BA:In vitro release of prostaglandins and leukotrienes from synovial tissue, cartilage, and bone in degenerative joint disease. Arthritis Rheum 1993, 36:1444–1450.PubMedCrossRefGoogle Scholar
  33. 33.
    Amat M, Diaz C, Vila L: Leukotriene A4 hydrolase and leukotriene C4 synthase activities in human chondrocytes: Transcellular biosynthesis of leukotrienes during granulocytechondrocyte interaction. Arthritis Rheum 1998, 41:1645–1651.PubMedCrossRefGoogle Scholar
  34. 34.
    Atik SO: Leukotriene B4 and prostaglandin E2 activity in synovial fluid in osteoarthritis. Prostaglandins Leukot Essent Fatty Acids 1990, 39:253–254.CrossRefGoogle Scholar
  35. 35.
    Rainsford KD, Ying C, Smith F: Effects of 5-lipoxygenase inhibitors on interleukin production by human synovial tissues in organ culture: Comparison with interleukin-1-synthesis inhibitors. J Pharm Pharmacol 1996, 48:46–52.PubMedGoogle Scholar
  36. 36.
    Kageyama Y, Koide Y, Miyamoto S, Yoshida TO, Inoue T:Leukotrien B4-induced interleukin 1b in synovial cells from patients with rheumatoid arthritis. Scand J Rheum 1994, 23:148–150.PubMedGoogle Scholar
  37. 37.
    Attur MG, Dave M, Cipoletta C, et al.: Reversal of autocrine and paracrine effects of IL-1 in human arthritis by type II IL-1 receptor: Potential for pharmacological intervention. J Biol Chem 2000, 22:40307–40315.CrossRefGoogle Scholar
  38. 38.
    Stefanovic-Racic M, Stadler J, Evans CH: Nitric oxide and arthritis. Arthritis Rheum 1993, 36:1036–1044.PubMedCrossRefGoogle Scholar
  39. 39.
    Alaaeddine N, Olee T, Hashimoto S, et al.: Production of the chemokine RANTES by articular chondrocytes and role in cartilage degradation. Arthritis Rheum 2001, 44:1633–1643.PubMedCrossRefGoogle Scholar
  40. 40.
    Fermor B, Weinberg JB, Pisetsky DS, et al.: The effects of static and intermittent compression on nitric oxide production in articular cartilage explants. J Orth Res 2001, 19:729–737. The relationship between altered biomechanics and the production of inflammatory mediators by cartilage is an important aspect of the new paradigm of the perpetuation of disease in OA.CrossRefGoogle Scholar
  41. 41.
    Fermor B, Haribabu B, Weinberg JB, et al.: Mechanical stress and nitric oxide influence leukotriene production in cartilage. Biochem Biophys Res Comm 2001, 285:806–810.PubMedCrossRefGoogle Scholar
  42. 42.
    Pelletier J-P, Lascau-Coman V, Jovanovic D, et al.: Selective inhibition of inducible nitric oxide synthase in experimental osteoarthritis is associated with reduction in tissue levels of catabolic factors. J Rheumatol 1999, 26:2002–2014.PubMedGoogle Scholar
  43. 43.
    Homandberg GA, Meyers R, Williams JM: Intra-articular injection of fibronectin fragments causes severe depletion of cartilage proteoglycans in vivo. J Rheumatol 1993, 20:1378–1382.PubMedGoogle Scholar
  44. 44.
    Homandberg GA, Hui F, Wen C, et al.: Fibronectin-fragmentinduced cartilage chondrolysis is associated with release of catabolic cytokines. Biochem J 1997, 321:751–757.PubMedGoogle Scholar
  45. 45.
    Arner EC, Tortorella MD: Signal transduction through chondrocyte integrin receptors induces matrix metalloproteinase synthesis and synergizes with interleukin-1. Arthritis Rheum 1995, 38:1304–1314.PubMedCrossRefGoogle Scholar
  46. 46.
    Attur MG, Dave M, Stuchin S, et al.: Osteopontin: an intrinsic inhibitor of inflammation in cartilage. Arthritis Rheum 2001, 44:578–584.PubMedCrossRefGoogle Scholar
  47. 47.
    PK, Hummel KM, Schedel J, et al.: Expression of osteopontin messenger RNA and protein in rheumatoid arthritis: effects of osteopontin on the release of collagenase 1 from articular chondrocytes and synovial fibroblasts. Arthritis Rheum 2001, 43:15971–1605.Google Scholar
  48. 48.
    Amin AR, Vyas P, Attur M, et al.: The mode of action of aspirin-like drugs: Effect on inducible nitric oxide synthase. Proc Natl Acad Sci USA 1995, 92:7926–7930.PubMedCrossRefGoogle Scholar
  49. 49.
    Amin AR, Attur MG, Thakker GD, et al.: A novel mechanism of action of tetracyclines: Effects on nitric oxide synthases. Proc Natl Acad Sci USA 1996, 93:14014–14019.PubMedCrossRefGoogle Scholar
  50. 50.
    Sadowski T, Steinmeyer J: Minocycline inhibits the production of inducible nitric oxide synthase in articular chondrocytes. J Rheumatol 2001, 28:336–340.PubMedGoogle Scholar
  51. 51.
    Patel R, Attur MG, Dave MN, et al.: Regulation of cytosolic COX-2 and PGE2 in activated murine macrophages. J Immunol 1999, 162:4191–4197.PubMedGoogle Scholar
  52. 52.
    Takahashi K, Hashimoto S, Kubo T, et al.: Hyaluronan suppressed nitric oxide production in the miniscus and synovium of rabbit osteoarthritis model. J Orthop Res 2001, 19:500–503. Interesting paper that may provide insight into the biochemical and anti-inflammatory activities of agents available as "viscosupplements."PubMedCrossRefGoogle Scholar
  53. 53.
    Towheed TE, Anastassiades TP, Shea B, et al.: Glucosamine therapy for treating osteoarthritis (Cochrane Review). Cochrane Database System Rev 2001, 1:CD002946.Google Scholar
  54. 54.
    Reginster JY, Deroisy R, Rovati LC, et al.: Long-term effects of glucosamine sulfate on osteoarthritis progression: a randomized, placebo-controlled clinical trial. Lancet 2001, 357:251–256.PubMedCrossRefGoogle Scholar
  55. 55.
    Meininger CJ, Kelly KA, Li H, et al.: Glucosamine inhibits inducible nitric oxide synthesis. Biochem Biophys Res Commun 2000, 279:234–239.PubMedCrossRefGoogle Scholar
  56. 56.
    Shikhman AR, Kuhn K, Alaaeddine N, Lotz M: N-acetylglucosamine prevents IL-1beta-mediated activation of human chondrocytes. J Immunol 2001, 166:5155–5160.PubMedGoogle Scholar
  57. 57.
    Smith GN Jr, Myers SL, Brandt KD, et al.: Diacerhein treatment reduces the severity of osteoarthritis in the canine cruciate-deficiency model of osteoarthritis. Arthritis Rheum 1999, 42:545–554.PubMedCrossRefGoogle Scholar
  58. 58.
    Hwa SY, Burkhardt D, Little C, Ghosh P: The effects of orally administered diacerein on cartilage and subchondral bone in an ovine model of osteoarthritis. J Rheumatol 2001, 28:825–834.PubMedGoogle Scholar
  59. 59.
    Pelletier J-P, Yaron M, Haraoui B, et al.: Efficacy and safety of diacerein in osteoarthritis of the knee: a double-blind, placebo-controlled trial. The Diacerein Study Group. Arthritis Rheum 2000, 43:2339–2348.PubMedCrossRefGoogle Scholar
  60. 60.
    Lanas A, Bajador E, Serrano P, et al.: Nitrovasodilators, low-dose aspirin, other nonsteroidal antiinflammatory drugs, and the risk of upper gastrointestinal bleeding. N Engl J Med 2000, 21:834–839.CrossRefGoogle Scholar
  61. 61.
    Uchida M, Matsueda K, Shoda R, et al.: Nitric oxide donating compounds inhibit HCl-induced gastric mucosal lesions mainly via prostaglandin. Jpn J Pharmacol 2001, 85:133–138.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2001

Authors and Affiliations

  • Steven B. Abramson
    • 1
  • Mukundan Attur
    • 1
  • Ashok R. Amin
    • 1
  • Robert Clancy
    • 1
  1. 1.Departments of Medicine, Division of Rheumatology and the Department Pathology, NYU School of Medicine; and the Department of Rheumatology and MedicineHospital for Joint DiseasesNew YorkUSA

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