Abstract
The production of nitric oxide (NO) and prostaglandin E2 (PGE2) is increased in human osteoarthritis-affected cartilage. These and other inflammatory mediators are spontaneously released by OA cartilage explants ex vivo. 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 both anabolic and catabolic effects on chondrocytes, depending on the microenvironment and physiological condition. Thus, NO and PGE2, produced by activated chondrocytes in diseased cartilage, may modulate disease rogression in osteoarthritis, and should therefore be considered potential targets for therapeutic intervention.
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References and Recommended Reading
Amin AR, Attur MG, Abramson SB: Regulation of nitric oxide and inflammatory mediators in human osteoarthritisaffected cartilage: implication for pharmacological intervention. In The Pathophysiology and Clinical Applications of Nitric Oxide. Edited by Rubanyi GM. Richmond, CA: Harwood Academic Publishers; 1999:397–412. A comprehensive review on the regulation of nitric oxide, prostaglandins, and other inflammatory mediators in human osteoarthritisaffected cartilage. The review updates some new methods for pharmacologic intervention.
Sakurai H, Kohsaka H, Liu MF, et al.: Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritides. J Clin Invest 1995, 96:2357–2363. This is the first report on the regulation of nitric oxide in human osteoarthritis and rheumatoid arthritis.
Bellometti S, Galzigna L: Serum levels of a prostaglandin and a leukotriene after thermal mud pack therapy. J Investig Med 1998, 46:140–145.
Sawazaki Y: Leukotriene B4, leukotriene C4 and prostaglandin E2 in the serum, synovial fluid and synovium in patients with rheumatoid arthritis. Nippon Ika Daigaku Zasshi 1989, 56:559–564.
Lee YH, Choi SJ, Kim A, et al.: Expression of cyclooxygenase-1 and -2 in rheumatoid arthritis synovium. J Korean Med Sci 2000, 15:88–92.
Melchiorri C, Meliconi R, Frizziero L, et al.: Enhanced and coordinated in vivo expression of inflammatory cytokines and nitric oxide synthase by chondrocytes from patients with osteoarthritis. Arthritis Rheum 1998, 41:2165–2174. This study suggests that most of the inflammatory mediators in rheumatoid arthritis are upregulated in synovium and not cartilage, whereas in osteoarthritis, inflammation is predominantly in cartilage and less in synovium.
Amin AR, Abramson SB: The role of nitric oxide in articular cartilage breakdown in osteoarthrtis. Curr Opin Rheumatol 1998, 10:263–268. A recent review describing the role of nitric oxide in articular cartilage breakdown in osteoarthrtis, and the different mechanisms involved during this process.
Amin AR, Di Cesare P, 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, 182:2097–2102. First report on the spontaneous production of nitric oxide in human osteoarthritis-affected cartilage.
Amin AR, Attur MG, Patel RN, et al.: Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage: Influence of nitric oxide. J Clin Invest 1997, 99:1231–1237. The first report on the upregulation on COX-2 activity in human osteoarthritis-affected cartilage and its regulation by nitric oxide.
Clancy RM, Rediske J, Tang X, et al.: Outside-in signaling in the chondrocyte. Nitric oxide disrupts fibronectin-induced assembly of a subplasmalemmal actin/rho A/focal adhesion kinase signaling complex. J Clin Invest 1997, 100:1789–1796.
Mayhan WG: Role of nitric oxide in modulating permeability of hamster cheek pouch in response to adenosine 5′-diphosphate and bradykinin. Inflammation 1992, 16:295–305.
Leibovich SJ, Polverini PJ, Fong TW, et al.: Production of angiogenic activity by human monocytes requires an L-arginine/ nitric oxide-synthase-dependent effector mechanism. Proc Natl Acad Sci USA 1994, 91:4190–4194.
Cao M, Westerhausen-Larson A, Niyibizi C, et al.: Nitric oxide inhibits the synthesis of type-II collagen without altering Col2A1 mRNA abundance: prolyl hydroxylase as a possible target. Biochem J 1997, 324:305–310. Discusses inhibition of type II collagen by IL-1 via nitric oxide dependent in and independent mechanisms.
Stefanovic-Racic M, Mollers MO, Miller LA, et al.: Nitric oxide and proteoglycan turnover in rabbit articular cartilage. J Orthop Res 1997, 15:442–449.
Mehraban F, Lark MW, Ahmed FN, et al.: Increased secretion and activity of matrix metalloproteinase-3 in synovial tissues and chondrocytes from experimental osteoarthritis. Osteoarthritis Cartilage 1998, 6:286–294.
Hickery MS, Bayliss MT: Interleukin-1 induced nitric oxide inhibits sulphation of glycosaminoglycan chains in human articular chondrocytes. Biochim Biophys Acta 1998, 1425:282–290.
Arner EC, Hughes CE, Decicco CP, et al.: Cytokine-induced cartilage proteoglycan degradation is mediated by aggrecanase. Osteoarthritis Cartilage 1998, 6:214–228.
Homandberg GA: Potential regulation of cartilage metabolism in osteoarthritis by fibronectin fragments. Front Biosci 1999, 4:D713-D730.
Di Battista JA, Doré S, Morin N, 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, 63:320–333.
Blanco FJ, Lotz M: IL-1-induced nitric oxide inhibits chondrocyte proliferation via PGE2. Exp Cell Res 1995, 218:319–325. An early demonstration of the role of prostaglandin in regulation of chondrocyte function.
Turpaev KT, Amchenkova AM, Narovlyansky AN: Two pathways of the nitric oxide-induced cytotoxycal action. Biochem Mol Biol Int 1997, 41:1025–1033.
Lotz M, Hashimoto S, Kuhn K: Mechanisms of chondrocyte apoptosis. Osteoarthritis Cartilage 1999, 7:389–391.
Studer R, Jaffurs D, Stefanovic-Racic M, et al.: Nitric oxide in osteoarthritis. Osteoarthritis Cartilage 1999, 7:377–379. A comprehensive review on the role of nitric oxide in osteoarthritis.
Clancy RM, Abramson SB, Kohne C, et al.: 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.
Hukkanen M, Corbett SA, Batten J, et al.: Aseptic loosening of total hip replacement: macrophage expression of inducible nitric oxide synthase and cyclo-oxygenase-2, together with peroxynitrite formation, as a possible mechanism for ear prosthesis failure. J Bone Joint Surg Br 1997, 79:467–474.
Attur MG, Dave MN, Clancy RM, et al.: Functional genomic analysis in arthritis-affected cartilage: yin-yang regulation of inflammatory mediators by alpha5beta1 and alphaVbeta3 integrins. J Immunol 2000, 164:2684–2691. The role of matrix components in the regulation of inflammatory mediators, including nitric oxide and PGE2 in human osteoarthritisaffected cartilage.
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. An early report on the role of integrins on cartilage homeostasis.
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.
Badger AM, Cook MN, Swift BA, et al.: Inhibition of interleukin-1-induced proteoglycan degradation and nitric oxide production in bovine articular cartilage/chondrocyte cultures by the natural product, hymenialdisine. J Pharmacol Exp Ther 1999, 290:587–593.
Dingle T: Prostaglandins in human cartilage metabolism. J Lipid Mediat 1993, 6:303–312.
Di Battista JA, Martel-Pelletier J, Fujimoto N, et al.: Prostaglandins E2 and E1 inhibit cytokine-induced metalloprotease expression in human synovial fibroblasts. Mediation by cyclic-AMP signaling pathway. Lab Invest 1994, 71:270–278.
Di Battista JA, Martel-Pelletier JP, Zafarullah M, et al.: Coordinate regulation of matrix metalloproteases and tissue inhibitor of metalloporteinase expression in human synovial fibroblasts. J Rheumatol 1995, 43:123–128.
Raisz LG, Fall PM, Gabbitas BY, et al.: Effects of prostaglandin E2 on bone formation in cultured fetal rat calvariae: role of insulin-like growth factor-I. Endocrinology 1993, 133:1504–1510.
O’Keefe RJ, Crabb ID, Puzas E, et al.: Influence of prostaglandins on DNA and matrix synthesis in growth plate chondrocytes. Bone Mineral Res 1992, 7:397–404.
Di Battista JA, Doré S, Martel-Pelletier J, et al.: Prostaglandin E2 stimulates incorporation of proline into collagenase digestible proteins in human articular chondrocytes: identification of an effector autocrine loop involving insulinlike growth factor I. Mol Cell Endocrinol 1996, 123:27–35.
Lowe GN, Fu YH, McDougall S, et al.: Effects of prostaglandins on deoxyribonucleic acid and aggrecan synthesis in the RCJ 3.1C5.18 chondrocyte cell line: role of second messengers. Endocrinology 1996, 137:2208–2216.
Krupsky M, Kuang P-P, Goldstein RH: Regulation of Type 1 collagen mRNA by amino acid deprivation in human lung fibroblasts. J Biol Chem 1997, 27:13,864–13,868.
Raisz LG, Fall PM: Biphasic effects of prostaglandin E2 on bone formation in cultured fetal rat calvariae: interaction with cortisol. Endocrinology 1990, 126:1654–1659.
Zhang Y, McCluskey K, Fujii K, Wahl LM: Differential regulation of monocyte matrix metalloproteinase and TIMP-1 production by TNF-alpha, granulocyte-macrophage CSF, and IL-1beta through prostaglandin-dependent and -independent mechanisms. J Immunol 1998, 161:3071–3076.
Salvatori R, Guidon PTJ, Rapuano BE, Bockman RS: Prostaglandin E1 inhibits collagenase gene expression in rabbit synoviocytes and human fibroblasts. Endocrinology 1992, 131:21–28.
Clancy R, Varenika B, Huang W, et al.: Nitric oxide synthase/ COX cross-talk: nitric oxide activates COX-1 but inhibits COX-2 derived prostaglandin production. J Immunol 2000, 165(3):1582–1587.
Patel R, Attur MG, Dave M, et al.: Regulation of cytosolic COX-2 and prostaglandin E2 production by nitric oxide in activated murine macrophages. J Immunol 1999, 162:4191–4197.
Patel RN, Attur MG, Dave MN, et al.: Differential regulation of nitric oxide and prostaglandin E2 production by CSAIDS (SB203508) in murine macrophages and bovine chondrocytes stimulated with LPS. Inflamm Res 1999, 48:337–343.
McCartney-Francis N, Allen JB, Mizel DE, et al.: Suppresion of arthritis by an inhibitor of nitric oxide synthase. J Exp Med 1993, 178:749–754.
Stefanovic-Racic M, Meyers K, Meschter C, et al.: N-monomethyl arginine, an inhibitor of nitric oxide synthase, suppresses the development of adjuvant arthritis in rats. Arthritis Rheum 1994, 37:1062–1069.
Pelletier JP, Jovanovic DV, 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. The first demonstration of the effects of specific iNOS inhibitors in animal models of osteoarthritis. The data shows the chondroprotective effects of this inhibitor.
Pelletier JP: Pathophysiological targets in OA therapy. Osteoarthritis Cartilage 1999, 7:353–354.
Amin AR, Attur M, Abramson SB: Nitric oxide synthase and cyclooxygenases: distribution, regulation, and intervention in arthritis. Curr Opin Rheumatol 1999, 11:202–209.
Attur M, Dave M, Cipolletta C, et al.: Reversal of autocrine and paracrine effects of IL-1 in human arthritis by type II IL-1 decoy receptor: potential for pharmacological intervention. J Biol Chem 2000, in press. The paper describes the role of anti-inflammatory mediators in the regulation of nitric oxide and PGE2 in human osteoarthritis-affected cartilage, its potential for pharmacologic intervention and gene therapy.
Amin AR: Regulation of nitric oxide and inflammatory mediators in human osteoarthritis-affected cartilage. In Pathophysiology and Clinical Applications of NO. Part B. Edited by Rubanyi, G. Amsterdam; Harwood Academic Publishers: 1999: 397–412.
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Amin, A.R., Dave, M., Attur, M. et al. COX-2, NO, and cartilage damage and repair. Curr Rheumatol Rep 2, 447–453 (2000). https://doi.org/10.1007/s11926-000-0019-5
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DOI: https://doi.org/10.1007/s11926-000-0019-5