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• W2153915876 abstract "Nitric oxide (NO) causes apoptosis and dedifferentiation of articular chondrocytes by the modulation of extracellular signal-regulated kinase (ERK), p38 kinase, and protein kinase C (PKC) α and -ζ. In this study, we investigated the effects and mechanisms of non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, ketoprofen, ibuprofen, sulindac sulfide, and flurbiprofen, in NO-induced apoptosis and dedifferentiation of articular chondrocytes. We found that all of the examined NSAIDs inhibited apoptosis and dedifferentiation. NO production in chondrocytes caused activation of ERK-1/2 and p38 kinase, which oppositely regulate apoptosis and dedifferentiation. NO production also caused inhibition of PKCα and -ζ independent of and dependent on, respectively, p38 kinase, which is required for apoptosis and dedifferentiation. Among the signaling molecules modulated by NO, NSAIDs blocked NO-induced activation of p38 kinase, potentiated ERK activation, and blocked inhibition of PKCα and -ζ. NSAIDs also inhibited some of the apoptotic signaling that is downstream of p38 kinase and PKC, such as NFκB activation, p53 accumulation, and caspase-3 activation. The inhibitory effects of NSAIDs on apoptosis and dedifferentiation were independent of the inhibition of cyclooxygenase (COX)-2 and prostaglandin E2 (PGE2) production, as evidenced by the observation that specific inhibition of COX-2 activity and PGE2 production or exogenous PGE2 did not affect NO-induced apoptosis and dedifferentiation. Taken together, our results indicate that NSAIDs block NO-induced apoptosis and dedifferentiation of articular chondrocytes by the modulation of ERK, p38 kinase, and PKCα and -ζ in a manner independent of their ability to inhibit COX-2 and PGE2 production. Nitric oxide (NO) causes apoptosis and dedifferentiation of articular chondrocytes by the modulation of extracellular signal-regulated kinase (ERK), p38 kinase, and protein kinase C (PKC) α and -ζ. In this study, we investigated the effects and mechanisms of non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, ketoprofen, ibuprofen, sulindac sulfide, and flurbiprofen, in NO-induced apoptosis and dedifferentiation of articular chondrocytes. We found that all of the examined NSAIDs inhibited apoptosis and dedifferentiation. NO production in chondrocytes caused activation of ERK-1/2 and p38 kinase, which oppositely regulate apoptosis and dedifferentiation. NO production also caused inhibition of PKCα and -ζ independent of and dependent on, respectively, p38 kinase, which is required for apoptosis and dedifferentiation. Among the signaling molecules modulated by NO, NSAIDs blocked NO-induced activation of p38 kinase, potentiated ERK activation, and blocked inhibition of PKCα and -ζ. NSAIDs also inhibited some of the apoptotic signaling that is downstream of p38 kinase and PKC, such as NFκB activation, p53 accumulation, and caspase-3 activation. The inhibitory effects of NSAIDs on apoptosis and dedifferentiation were independent of the inhibition of cyclooxygenase (COX)-2 and prostaglandin E2 (PGE2) production, as evidenced by the observation that specific inhibition of COX-2 activity and PGE2 production or exogenous PGE2 did not affect NO-induced apoptosis and dedifferentiation. Taken together, our results indicate that NSAIDs block NO-induced apoptosis and dedifferentiation of articular chondrocytes by the modulation of ERK, p38 kinase, and PKCα and -ζ in a manner independent of their ability to inhibit COX-2 and PGE2 production. nitric oxide cyclooxygenase extracellular signal-regulated protein kinase mitogen-activated protein nuclear factor κB nonsteroidal anti-inflammatory drugs prostaglandin protein kinase C sodium nitroprusside terminal deoxynucleotidyl transferase dUTP nick-end labeling 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium Chondrocytes are a unique cell type in which the differentiated phenotype is reversible. The phenotype of chondrocytes is regulated by the balance between anabolic and catabolic reactions of molecules, which are involved in the maintenance of cartilage homeostasis (1Sandell L.J. Aigner I. Arthritis Res. 2001; 3: 107-113Crossref PubMed Scopus (659) Google Scholar). Differentiated chondrocytes both in vivo and in vitro dedifferentiate into fibroblastic cells upon exposure to interleukin-1β (2Frazer A. Bunning R.A. Thavarajah M. Seid J.M. Russell R.G. Osteoarthritis Cartilage. 1994; 2: 235-245Abstract Full Text PDF PubMed Scopus (67) Google Scholar, 3Demoor-Fossard M. Redini F. Boittin M. Pujol J.P. Biochim. Biophys. Acta. 1998; 1398: 179-191Crossref PubMed Scopus (40) Google Scholar), retinoic acid (4Horton W.E. Yamada Y. Hassell J.R. Dev. Biol. 1987; 123: 508-516Crossref PubMed Scopus (101) Google Scholar), or nitric oxide (NO)1 (5Amin A.R. Abramson S.B. Curr. Opin. Rheumatol. 1998; 10: 263-268Crossref PubMed Scopus (207) Google Scholar). Although the molecular mechanism is not yet clear, dedifferentiation of articular chondrocytes is believed to play a role in the pathophysiology of arthritis. In addition to dedifferentiation, increased apoptotic death of chondrocytes was observed in arthritic cartilage, and apoptosis is closely related to cartilage destruction (6Blanco F.J. Guitian R. Vazquez-Martul E. de Toro F.J. Galdo F. Arthritis Rheum. 1998; 41: 284-289Crossref PubMed Scopus (565) Google Scholar, 7Hashimoto S. Oche R.L. Komiya S. Lotz M. Arthritis Rheum. 1998; 41: 1632-1638Crossref PubMed Scopus (453) Google Scholar), indicating that chondrocyte apoptosis plays an important role in the pathogenesis of arthritis.NO is generally believed to be an important mediator of the dedifferentiation and apoptosis of articular chondrocytes in arthritic cartilage (5Amin A.R. Abramson S.B. Curr. Opin. Rheumatol. 1998; 10: 263-268Crossref PubMed Scopus (207) Google Scholar, 8Amin A.R. Attur M. Abramson S.B. Curr. Opin. Rheumatol. 1999; 11: 202-209Crossref PubMed Scopus (157) Google Scholar, 9Abramson S.B. Attur M. Amin A.R. Clancy R. Curr. Rheumatol. Rep. 2001; 3: 535-541Crossref PubMed Scopus (219) Google Scholar). NO is produced in chondrocytes by the action of proinflammatory cytokines, such as interleukin-1β. NO production in chondrocytes causes activation of matrix metalloproteinases (10Tamura T. Nakanishi T. Kimura Y. Hattori T. Sasaki K. Norimatsu H. Takahashi K. Takigawa M. Endocrinology. 1996; 137: 3729-3737Crossref PubMed Scopus (102) Google Scholar), decreased production of interleukin-1 receptor antagonists (11Jouzeau J.Y. Pacquelet S. Boileau C. Nedelec E. Presle N. Netter P. Terlain B. Biorheology. 2002; 39: 201-214PubMed Google Scholar), inhibition of proteoglycan synthesis and type II collagen expression (12Cao M. Westerhausen-Larson A. Niyibizi C. Kavalkovich K. Georgescu H.I. Rizzo C.F. Hebda P.A. Stefanovic-Racic M. Evans C.H. Biochem. J. 1997; 324: 305-310Crossref PubMed Scopus (157) Google Scholar, 13Taskiran D. Stefanovic-Racic M. Georgescu H.I. Evans C.H. Biochem. Biophys. Res. Commun. 1994; 200: 142-148Crossref PubMed Scopus (356) Google Scholar), and apoptosis of chondrocytes (6Blanco F.J. Guitian R. Vazquez-Martul E. de Toro F.J. Galdo F. Arthritis Rheum. 1998; 41: 284-289Crossref PubMed Scopus (565) Google Scholar, 7Hashimoto S. Oche R.L. Komiya S. Lotz M. Arthritis Rheum. 1998; 41: 1632-1638Crossref PubMed Scopus (453) Google Scholar, 14Notoya K. Jovanovic D.V. Reboul P. Johanne M.P. Mineau F. Pelletier J.P. J. Immunol. 2000; 165: 3402-3410Crossref PubMed Scopus (171) Google Scholar). Indeed, inhibition of NO production protects against damage of cartilage and chondrocytes in a number of experimental models. For instance, in experimentally induced osteoarthritis in a range of animal species, a significant correlation was observed between the level of NO and the prevalence of apoptotic cells in cartilage tissue (7Hashimoto S. Oche R.L. Komiya S. Lotz M. Arthritis Rheum. 1998; 41: 1632-1638Crossref PubMed Scopus (453) Google Scholar). Moreover, inhibition of NO resulted in reduced articular cartilage damage and apoptotic cell death (11Jouzeau J.Y. Pacquelet S. Boileau C. Nedelec E. Presle N. Netter P. Terlain B. Biorheology. 2002; 39: 201-214PubMed Google Scholar, 15Pelletier J.P. Jovanovic D. Fernandes J.C. Manning P.T. Connor J.R. Currie M.G. Di Battista J.A. Martel-Pelletier J. Arthritis Rheum. 1998; 41: 1275-1286Crossref PubMed Scopus (333) Google Scholar). In our previous studies, we have shown that direct production of NO by treating chondrocytes with an NO donor, sodium nitroprusside (SNP), induces apoptosis and dedifferentiation of primary culture articular chondrocytes (16Kim S.-J. Ju J.-W. Oh C.-D. Yoon Y.-M. Song W.-K. Kim J.-H. Yoo Y.-J. Bang O.-S. Kang S.-S. Chun J.-S. J. Biol. Chem. 2002; 277: 1332-1339Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar, 17Kim S.-J. Kim H.-G. Oh C.-D. Hwang S.-G. Song W.-K. Yoo Y.-J. Kang S.-S. Chun J.-S. J. Biol. Chem. 2002; 277: 30375-30381Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 18Kim S.-J. Hwang S.-G. Shin D.-Y. Kang S.-S. Chun J.-S. J. Biol. Chem. 2002; 277: 33501-33508Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). NO-induced apoptosis and dedifferentiation of articular chondrocytes were regulated by opposite functions of mitogen-activated protein (MAP) kinase subtypes, extracellular signal-regulated protein kinase (ERK), and p38 kinase (16Kim S.-J. Ju J.-W. Oh C.-D. Yoon Y.-M. Song W.-K. Kim J.-H. Yoo Y.-J. Bang O.-S. Kang S.-S. Chun J.-S. J. Biol. Chem. 2002; 277: 1332-1339Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar). NO-induced activation of ERK-1/2 induces dedifferentiation with the inhibitory effects on apoptosis, whereas activation of p38 kinase induces apoptosis and is responsible for the maintenance of differentiated phenotype. In addition to MAP kinase signaling, NO production caused the inhibition of protein kinase C (PKC) α and -ζ activities (17Kim S.-J. Kim H.-G. Oh C.-D. Hwang S.-G. Song W.-K. Yoo Y.-J. Kang S.-S. Chun J.-S. J. Biol. Chem. 2002; 277: 30375-30381Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). The inhibition of PKCα activity is caused by inhibition of its expression, which is independent of MAP kinase signaling. In contrast, PKCζ activity is blocked as a result of p38 kinase activation, and inhibition of PKCζ activity is followed by proteolytic cleavage by caspase-3. We also found that p38 kinase induces NO-induced apoptosis by accumulating p53 via NFκB-dependent transcription and stabilization by serine 15 phosphorylation (18Kim S.-J. Hwang S.-G. Shin D.-Y. Kang S.-S. Chun J.-S. J. Biol. Chem. 2002; 277: 33501-33508Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar).NSAIDs such as aspirin and indomethacin have been used to relieve pain and inflammation in arthritic cartilage. NSAIDs exert their effects primarily by the inhibition of cyclooxygenase (COX), a key enzyme that converts arachidonic acid to prostaglandin (PG) (19Dubois R.N. Abramson S.B. Crofford L. Gupta R.A. Simon L.S. Van De Putte L.B. Lipsky P.E. FASEB J. 1998; 12: 1063-1073Crossref PubMed Scopus (2207) Google Scholar). In addition to the alleviation of inflammation, some NSAIDs also modulate homeostasis of chondrocyte and cartilage such as matrix molecule synthesis. For example, several NSAIDs, such as sodium salicylate, inhibit proteoglycan synthesis but others, such as nimesulide, induce cartilage matrix synthesis, whereas others including piroxicam have no effect on matrix synthesis (20Ding C. Inflammation. 2002; 26: 139-142Crossref PubMed Scopus (69) Google Scholar, 21Dingle J.T. Rheumatology. 1999; 58: 125-129Google Scholar). In addition, some NSAIDs, such as nimesulide and ibuprofen, have a protective effect in staurosporine-induced apoptosis of chondrocytes (22Mukherjee P. Rachita C. Aisen P.S. Pasinetti G.M. Clin. Exp. Rheumatol. 2001; 19: S7-11PubMed Google Scholar). Several lines of evidence suggest that some of the effects of NSAIDs are independent of the inhibition of COX (23Tegeder I. Pfeilschifter J. Geisslinger G. FASEB J. 2001; 15: 2057-2072Crossref PubMed Scopus (672) Google Scholar). Indeed, it has been shown that NSAIDs modulate COX-independent signaling pathways, such as Ras (24Herrmann C. Block C. Geisen C. Haas K. Weber C. Winde G. Moroy T. Muller O. Oncogene. 1998; 17: 1769-1776Crossref PubMed Scopus (113) Google Scholar), NFκB (25Kopp E. Ghosh S. Science. 1994; 265: 956-959Crossref PubMed Scopus (1597) Google Scholar), activator protein-1 (26Huang C. Ma W.Y. Hanenberger D. Cleary M.P. Bowden G.T. Dong Z. J. Biol. Chem. 1997; 272: 26325-26331Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar), ERK (26Huang C. Ma W.Y. Hanenberger D. Cleary M.P. Bowden G.T. Dong Z. J. Biol. Chem. 1997; 272: 26325-26331Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar), p38 kinase (27Schwenger P. Skolnik E.Y. Vilcek J. Mol. Cell. Biol. 1998; 18: 78-84Crossref PubMed Google Scholar), and others. Because the role of NSAIDs in the maintenance of homeostasis and apoptosis of articular chondrocytes is not clearly understood, although the action of NSAIDs in inflammation is clear, we investigated the function of various NSAIDs in NO-induced dedifferentiation and apoptosis and characterized the molecular mechanism of NSAIDs action in articular chondrocytes.DISCUSSIONNO production in articular chondrocytes plays a central role in the pathophysiology of arthritis (5Amin A.R. Abramson S.B. Curr. Opin. Rheumatol. 1998; 10: 263-268Crossref PubMed Scopus (207) Google Scholar, 8Amin A.R. Attur M. Abramson S.B. Curr. Opin. Rheumatol. 1999; 11: 202-209Crossref PubMed Scopus (157) Google Scholar, 9Abramson S.B. Attur M. Amin A.R. Clancy R. Curr. Rheumatol. Rep. 2001; 3: 535-541Crossref PubMed Scopus (219) Google Scholar, 36Martel-Pelletier J. Alaaeddine N. Pelletier J.P. Frontiers Biosci. 1999; 4: 694-703Crossref PubMed Google Scholar). High levels of nitrite/nitrate are found in the synovial fluid and serum of arthritis patients (37Farrell A.J. Blake D.R. Palmer R.M. Moncada S. Ann. Rheum. Dis. 1992; 51: 1219-1222Crossref PubMed Scopus (657) Google Scholar), and it has been shown that NO causes loss of a differentiated phenotype and apoptosis of articular chondrocytes (6Blanco F.J. Guitian R. Vazquez-Martul E. de Toro F.J. Galdo F. Arthritis Rheum. 1998; 41: 284-289Crossref PubMed Scopus (565) Google Scholar, 7Hashimoto S. Oche R.L. Komiya S. Lotz M. Arthritis Rheum. 1998; 41: 1632-1638Crossref PubMed Scopus (453) Google Scholar,12Cao M. Westerhausen-Larson A. Niyibizi C. Kavalkovich K. Georgescu H.I. Rizzo C.F. Hebda P.A. Stefanovic-Racic M. Evans C.H. Biochem. J. 1997; 324: 305-310Crossref PubMed Scopus (157) Google Scholar, 13Taskiran D. Stefanovic-Racic M. Georgescu H.I. Evans C.H. Biochem. Biophys. Res. Commun. 1994; 200: 142-148Crossref PubMed Scopus (356) Google Scholar, 14Notoya K. Jovanovic D.V. Reboul P. Johanne M.P. Mineau F. Pelletier J.P. J. Immunol. 2000; 165: 3402-3410Crossref PubMed Scopus (171) Google Scholar). We have previously shown that direct production of NO causes apoptosis and dedifferentiation of articular chondrocytes by the activation of ERK-1/2 and p38 kinase and inhibition of PKCα and -ζ (16Kim S.-J. Ju J.-W. Oh C.-D. Yoon Y.-M. Song W.-K. Kim J.-H. Yoo Y.-J. Bang O.-S. Kang S.-S. Chun J.-S. J. Biol. Chem. 2002; 277: 1332-1339Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar, 17Kim S.-J. Kim H.-G. Oh C.-D. Hwang S.-G. Song W.-K. Yoo Y.-J. Kang S.-S. Chun J.-S. J. Biol. Chem. 2002; 277: 30375-30381Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 18Kim S.-J. Hwang S.-G. Shin D.-Y. Kang S.-S. Chun J.-S. J. Biol. Chem. 2002; 277: 33501-33508Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). In this study, we investigated the effects of various NSAIDs on NO-induced apoptosis and dedifferentiation of articular chondrocytes cultured on plastic or in a 3-dimensional natural matrix (i.e. explants culture) and found that all of the examined NSAIDs inhibit apoptosis and dedifferentiation in both conditions independent of the inhibition of COX-2 expression and PGE2production. As summarized in Fig. 9, we also demonstrated that the inhibitory effects of NSAIDs on apoptosis are caused by their ability to potentiate NO-induced ERK activation, to inhibit activation of p38 kinase, and to block inhibition of PKCα and -ζ. In contrast, the inhibition of NO-induced dedifferentiation by NSAIDs is caused by the blockade of PKCα and -ζ signaling but not the modulation of ERK-1/2 and p38 kinase signaling.The cellular effects of NSAIDs are exerted primarily by the inhibition of COX and PGE2 production. PGE2 is known to regulate differentiation (34Goldring M.B. Suen L.F. Yamin R. Lai W.F. Am. J. Ther. 1996; 3: 9-16Crossref PubMed Scopus (55) Google Scholar, 35Schwartz Z. Gilley R.M. Sylvia V.L. Dean D.D. Boyan B.D. Endocrinology. 1998; 139: 1825-1834Crossref PubMed Google Scholar) and apoptosis (14Notoya K. Jovanovic D.V. Reboul P. Johanne M.P. Mineau F. Pelletier J.P. J. Immunol. 2000; 165: 3402-3410Crossref PubMed Scopus (171) Google Scholar, 38von Knethen A.V. Brune B. FASEB J. 1997; 11: 887-895Crossref PubMed Scopus (128) Google Scholar) of chondrocytes depending on the experimental system. Because NO production in chondrocytes causes COX-2 expression and PGE2production, it is possible that NSAIDs modulate NO-induced apoptosis and dedifferentiation by inhibiting COX-2. However, our current results clearly indicate that the inhibitory effects of NSAIDs on NO-induced apoptosis and dedifferentiation are independent of the inhibition of COX-2 and PGE2 production. This conclusion is clearly demonstrated by the specific inhibition of COX-2 activity and by the observation that PGE2 production or exogenous PGE2 did not affect NO-induced apoptosis and dedifferentiation. In addition, the concentration of indomethacin that is required for the inhibition of NO-induced apoptosis and dedifferentiation is higher than that needed for the inhibition of PGE2 synthesis. This is consistent with observations that the COX-independent actions of NSAIDs such as inhibition of cell cycle progression (39Shiff S.J. Qiao L. Tsai L.L. Rigas B. J. Clin. Invest. 1995; 96: 491-503Crossref PubMed Scopus (417) Google Scholar, 40Goldberg Y. Nassif I.I. Pittas A. Tsai L.L. Dynlacht B.D. Rigas B. Shiff S.J. Oncogene. 1996; 12: 893-901PubMed Google Scholar), induction of apoptosis (41Barnes C.J. Cameron I.L. Hardman W.E. Lee M. Br. J. Cancer. 1998; 77: 573-580Crossref PubMed Scopus (78) Google Scholar, 42Giardina C. Boulares H. Inan M.S. Biochim. Biophys. Acta. 1999; 1448: 425-438Crossref PubMed Scopus (92) Google Scholar, 43Shao J. Fujiwara T. Kadowaki Y. Fukazawa T. Waku T. Itoshima T. Yamatsuji T. Nishizaki M. Roth J.A. Tanaka N. Oncogene. 2000; 19: 726-736Crossref PubMed Scopus (121) Google Scholar), and inhibition of angiogenesis (44Tsujii M. Kawano S. Tsuji S. Sawaoka H. Hori M. DuBois R.N. Cell. 1998; 93: 705-716Abstract Full Text Full Text PDF PubMed Scopus (2205) Google Scholar, 45Jones M.K. Wang H. Peskar B.M. Levin E. Itani R.M. Sarfeh I.J. Tarnawski A.S. Nat. Med. 1999; 5: 1348-1349Crossref PubMed Scopus (30) Google Scholar), require high concentrations of NSAIDs that are 100- to 1000-fold higher than those needed to inhibit prostaglandin synthesis.Our results indicated that the inhibition of NO-induced apoptosis of chondrocytes by NSAIDs is related to the potentiation of ERK activation, blockade of p38 kinase activation, blockade of PKCα and -ζ inhibition, and inhibition of downstream apoptotic signaling, including NFκB, p563, and caspase-3, as summarized in Fig. 9. The modulation of MAP kinase subtypes by indomethacin (i.e.inhibition of p38 kinase and potentiation of ERK) seems to be involved in the inhibition of NO-induced apoptosis based on the observation that NO-induced activation of p38 kinase induces apoptosis, whereas ERK activation inhibits apoptosis. The inhibition of p38 kinase and apoptosis by indomethacin is consistent with the inhibition of apoptotic signaling molecules located downstream of p38 kinase, such as PKCζ, NFκB, p53, and caspase-3 (Fig. 9). In contrast to the inhibition of apoptosis, the inhibitory effects of indomethacin on NO-induced dedifferentiation are attributable to its ability to block NO-induced inhibition of PKCα and -ζ, but not its ability to modulate MAP kinase subtypes. This conclusion is based on the observations that NO-induced inhibition of PKCα and -ζ is required for the induction of dedifferentiation as well as apoptosis and that the potentiation and inhibition of ERK and p38 kinase, respectively, are the signaling events leading to the potentiation of dedifferentiation (Fig. 9). Modulation of ERK and p38 kinase by indomethacin is independent of its ability to block COX activity, consistent with previously reported results. Indeed, many studies have indicated that COX-independent effects of NSAIDs are exerted by the modulation of ERK and p38 kinase. For example, NSAIDs such as aspirin and sodium salicylate exert their effects by the inhibition ERK-1/2 (26Huang C. Ma W.Y. Hanenberger D. Cleary M.P. Bowden G.T. Dong Z. J. Biol. Chem. 1997; 272: 26325-26331Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar, 45Jones M.K. Wang H. Peskar B.M. Levin E. Itani R.M. Sarfeh I.J. Tarnawski A.S. Nat. Med. 1999; 5: 1348-1349Crossref PubMed Scopus (30) Google Scholar, 46Schwenger P. Skolnik E.Y. Vilcek J. J. Biol. Chem. 1996; 271: 8089-8094Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 47Pillinger M.H. Capodici C. Rosenthal P. Kheterpal N. Hanft S. Philips M.R. Weissmann G. Proc. Natl. Acad. Sci. U. S. A. 1998; 24: 14540-14545Crossref Scopus (159) Google Scholar), whereas p38 kinase is activated by sodium salicylate in human fibroblasts and is associated with induction of apoptosis (27Schwenger P. Skolnik E.Y. Vilcek J. Mol. Cell. Biol. 1998; 18: 78-84Crossref PubMed Google Scholar).Our current results clearly indicate that indomethacin blocked the NO-induced inhibition of PKCα and -ζ activity that is required for the induction of apoptosis and dedifferentiation of SNP-treated chondrocytes (17Kim S.-J. Kim H.-G. Oh C.-D. Hwang S.-G. Song W.-K. Yoo Y.-J. Kang S.-S. Chun J.-S. J. Biol. Chem. 2002; 277: 30375-30381Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). Because the activity of PKCζ is blocked as a result of p38 kinase activation (17Kim S.-J. Kim H.-G. Oh C.-D. Hwang S.-G. Song W.-K. Yoo Y.-J. Kang S.-S. Chun J.-S. J. Biol. Chem. 2002; 277: 30375-30381Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar), it is likely that the effects of indomethacin on PKCζ are caused by the inhibition of p38 kinase signaling. However, the possibility that indomethacin directly regulates PKCζ activity cannot be ruled out, although no evidence supports the direct action of NSAIDs in the regulation of PKC isoforms. Nevertheless, it is apparent that the blockade of the NO-induced inhibition of PKCζ by indomethacin inhibits both apoptosis and dedifferentiation of SNP-treated chondrocytes. In contrast to PKCζ, the inhibition of PKCα expression and activity is caused by the inhibition of its expression independent of ERK and p38 kinase signaling (17Kim S.-J. Kim H.-G. Oh C.-D. Hwang S.-G. Song W.-K. Yoo Y.-J. Kang S.-S. Chun J.-S. J. Biol. Chem. 2002; 277: 30375-30381Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). Based on the observation that inhibition of PKCα activity is a prerequisite for the induction of apoptosis and dedifferentiation, the MAP kinase-independent inhibition of PKCα activity by indomethacin is also essential for the inhibitory effects of indomethacin on apoptosis and dedifferentiation. The mechanisms of indomethacin regulation of PKCα expression and activity remain to be determined, although it is possible that indomethacin regulates PKCα either directly or indirectly by modulating upstream signaling events. Nevertheless, because our present results indicated that indomethacin-induced inhibition of p38 kinase and potentiation of ERK is not directly involved in the inhibition of dedifferentiation as discussed above, we conclude that the blockade of the inhibition of PKCα and -ζ activities by indomethacin plays a critical role in the inhibition of NO-induced dedifferentiation.Consistent with the inhibition of apoptotic signaling mediators such as p38 kinase and PKC, indomethacin also blocked their downstream signaling molecules such as the activation of NFκB, accumulation of p53, and activation of caspase-3. Indeed, it has been shown that some types of NSAIDs, including ibuprofen, sulindac, sulindac sulfide, and flurbiprofen, are able to inhibit NFκB activation, whereas indomethacin, ketoprofen, and ketorolac are ineffective (23Tegeder I. Pfeilschifter J. Geisslinger G. FASEB J. 2001; 15: 2057-2072Crossref PubMed Scopus (672) Google Scholar). Using a reporter gene assay and IκB degradation, we found that ectopic expression of wild type PKCα or -ζ by adenovirus infection in chondrocytes blocked the NO-induced activation of NFκB (48Kim S.-J. Chun J.-S. Biochem. Biophys. Res. Commun. 2003; 301: 206-211Crossref Scopus (44) Google Scholar), indicating that p38 kinase-dependent and -independent PKCζ and -α regulates NFκB activation. We also found that NFκB activation is required for COX-2 expression (48Kim S.-J. Chun J.-S. Biochem. Biophys. Res. Commun. 2003; 301: 206-211Crossref Scopus (44) Google Scholar). This suggests that inhibition of PKCα and -ζ is an upstream signaling event leading to NFκB activation that causes COX-2 expression as summarized in Fig. 9. Given the inability of indomethacin to inhibit NFκB (23Tegeder I. Pfeilschifter J. Geisslinger G. FASEB J. 2001; 15: 2057-2072Crossref PubMed Scopus (672) Google Scholar), it is highly likely that the inhibitory effects of indomethacin on NFκB activation observed in this study are caused by the inhibition of its upstream signaling molecules (i.e. p38 kinase and PKC) rather than by a direct action on NFκB.In summary, we found that various NSAIDs block apoptosis and dedifferentiation of articular chondrocytes caused by NO production in a manner independent of their ability to inhibit COX-2 and PGE2 production. The inhibitory effects of NSAIDs on apoptosis are derived from their ability to block NO-induced activation of p38 kinase, to potentiate ERK activation, and to block inhibition of PKCα and -ζ, whereas the inhibition of NO-induced dedifferentiation by NSAIDs is caused by the blockade of PKCα and -ζ signaling but not the modulation of ERK-1/2 and p38 kinase signaling. Additionally, the effects of NO production and NSAIDs treatment on chondrocytes derived from adult rabbit joint cartilage (from 4-month-old rabbits) or human osteoarthritic cartilage obtained from patients undergoing total knee arthroplasty are essentially same as in growth plate chondrocytes (from 2-week-old rabbits) (data not shown). Because NO production via inducible NO synthase in articular chondrocytes plays a central role in the pathophysiology of arthritis by causing inflammation, apoptosis, dedifferentiation, and the activation of matrix metalloproteinases, our results suggest that NSAIDs have protective effects on cartilage damage, not only by alleviating inflammation but also by inhibiting NO-induced apoptosis and dedifferentiation of articular chondrocytes. Chondrocytes are a unique cell type in which the differentiated phenotype is reversible. The phenotype of chondrocytes is regulated by the balance between anabolic and catabolic reactions of molecules, which are involved in the maintenance of cartilage homeostasis (1Sandell L.J. Aigner I. Arthritis Res. 2001; 3: 107-113Crossref PubMed Scopus (659) Google Scholar). Differentiated chondrocytes both in vivo and in vitro dedifferentiate into fibroblastic cells upon exposure to interleukin-1β (2Frazer A. Bunning R.A. Thavarajah M. Seid J.M. Russell R.G. Osteoarthritis Cartilage. 1994; 2: 235-245Abstract Full Text PDF PubMed Scopus (67) Google Scholar, 3Demoor-Fossard M. Redini F. Boittin M. Pujol J.P. Biochim. Biophys. Acta. 1998; 1398: 179-191Crossref PubMed Scopus (40) Google Scholar), retinoic acid (4Horton W.E. Yamada Y. Hassell J.R. Dev. Biol. 1987; 123: 508-516Crossref PubMed Scopus (101) Google Scholar), or nitric oxide (NO)1 (5Amin A.R. Abramson S.B. Curr. Opin. Rheumatol. 1998; 10: 263-268Crossref PubMed Scopus (207) Google Scholar). Although the molecular mechanism is not yet clear, dedifferentiation of articular chondrocytes is believed to play a role in the pathophysiology of arthritis. In addition to dedifferentiation, increased apoptotic death of chondrocytes was observed in arthritic cartilage, and apoptosis is closely related to cartilage destruction (6Blanco F.J. Guitian R. Vazquez-Martul E. de Toro F.J. Galdo F. Arthritis Rheum. 1998; 41: 284-289Crossref PubMed Scopus (565) Google Scholar, 7Hashimoto S. Oche R.L. Komiya S. Lotz M. Arthritis Rheum. 1998; 41: 1632-1638Crossref PubMed Scopus (453) Google Scholar), indicating that chondrocyte apoptosis plays an important role in the pathogenesis of arthritis. NO is generally believed to be an important mediator of the dedifferentiation and apoptosis of articular chondrocytes in arthritic cartilage (5Amin A.R. Abramson S.B. Curr. Opin. Rheumatol. 1998; 10: 263-268Crossref PubMed Scopus (207) Google Scholar, 8Amin A.R. Attur M. Abramson S.B. Curr. Opin. Rheumatol. 1999; 11: 202-209Crossref PubMed Scopus (157) Google Scholar, 9Abramson S.B. Attur M. Amin A.R. Clancy R. Curr. Rheumatol. Rep. 2001; 3: 535-541Crossref PubMed Scopus (219) Google Scholar). NO is produced in chondrocytes by the action of proinflammatory cytokines, such as interleukin-1β. NO production in chondrocytes causes activation of matrix metalloproteinas" @default.
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• W2153915876 title "Non-steroidal Anti-inflammatory Drugs Inhibit Nitric Oxide-induced Apoptosis and Dedifferentiation of Articular Chondrocytes Independent of Cyclooxygenase Activity" @default.
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