• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Mar 15, 1997; 99(6): 1231–1237.
PMCID: PMC507937

Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. Influence of nitric oxide.

Abstract

Cartilage specimens from osteoarthritis (OA)-affected patients spontaneously released PGE2 at 48 h in ex vivo culture at levels at least 50-fold higher than in normal cartilage and 18-fold higher than in normal cartilage + cytokines + endotoxin. The superinduction of PGE2 production coincides with the upregulation of cyclooxygenase-2 (COX-2) in OA-affected cartilage. Production of both nitric oxide (NO) and PGE2 by OA cartilage explants is regulated at the level of transcription and translation. Dexamethasone inhibited only the spontaneously released PGE2 production, and not NO, in OA-affected cartilage. The NO synthase inhibitor HN(G)-monomethyl-L-arginine monoacetate inhibited OA cartilage NO production by > 90%, but augmented significantly (twofold) the spontaneous production of PGE2 in the same explants. Similarly, addition of exogenous NO donors to OA cartilage significantly inhibited PGE2 production. Cytokine + endotoxin stimulation of OA explants increased PGE2 production above the spontaneous release. Addition of L-NMMA further augmented cytokine-induced PGE2 production by at least fourfold. Inhibition of PGE2 by COX-2 inhibitors (dexamethasone or indomethacin) or addition of exogenous PGE2 did not significantly affect the spontaneous NO production. These data indicate that human OA-affected cartilage in ex vivo conditions shows (a) superinduction of PGE2 due to upregulation of COX-2, and (b) spontaneous release of NO that acts as an autacoid to attenuate the production of the COX-2 products such as PGE2. These studies, together with others, also suggest that PGE2 may be differentially regulated in normal and OA-affected chondrocytes.

Full Text

The Full Text of this article is available as a PDF (279K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Crofford LJ, Wilder RL, Ristimäki AP, Sano H, Remmers EF, Epps HR, Hla T. Cyclooxygenase-1 and -2 expression in rheumatoid synovial tissues. Effects of interleukin-1 beta, phorbol ester, and corticosteroids. J Clin Invest. 1994 Mar;93(3):1095–1101. [PMC free article] [PubMed]
  • Bombardieri S, Cattani P, Ciabattoni G, Di Munno O, Pasero G, Patrono C, Pinca E, Pugliese F. The synovial prostaglandin system in chronic inflammatory arthritis: differential effects of steroidal and nonsteroidal anti-inflammatory drugs. Br J Pharmacol. 1981 Aug;73(4):893–901. [PMC free article] [PubMed]
  • Davies P, Bailey PJ, Goldenberg MM, Ford-Hutchinson AW. The role of arachidonic acid oxygenation products in pain and inflammation. Annu Rev Immunol. 1984;2:335–357. [PubMed]
  • Robinson DR, Tashjian AH, Jr, Levine L. Prostaglandin-stimulated bone resorption by rheumatoid synovia. A possible mechanism for bone destruction in rheumatoid arthritis. J Clin Invest. 1975 Nov;56(5):1181–1188. [PMC free article] [PubMed]
  • Palmer RM, Hickery MS, Charles IG, Moncada S, Bayliss MT. Induction of nitric oxide synthase in human chondrocytes. Biochem Biophys Res Commun. 1993 May 28;193(1):398–405. [PubMed]
  • Geng Y, Blanco FJ, Cornelisson M, Lotz M. Regulation of cyclooxygenase-2 expression in normal human articular chondrocytes. J Immunol. 1995 Jul 15;155(2):796–801. [PubMed]
  • Amin AR, Di Cesare PE, Vyas P, Attur M, Tzeng E, Billiar TR, Stuchin SA, Abramson SB. The expression and regulation of nitric oxide synthase in human osteoarthritis-affected chondrocytes: evidence for up-regulated neuronal nitric oxide synthase. J Exp Med. 1995 Dec 1;182(6):2097–2102. [PMC free article] [PubMed]
  • Sakurai H, Kohsaka H, Liu MF, Higashiyama H, Hirata Y, Kanno K, Saito I, Miyasaka N. Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritides. J Clin Invest. 1995 Nov;96(5):2357–2363. [PMC free article] [PubMed]
  • McCartney-Francis N, Allen JB, Mizel DE, Albina JE, Xie QW, Nathan CF, Wahl SM. Suppression of arthritis by an inhibitor of nitric oxide synthase. J Exp Med. 1993 Aug 1;178(2):749–754. [PMC free article] [PubMed]
  • Stefanovic-Racic M, Meyers K, Meschter C, Coffey JW, Hoffman RA, Evans CH. N-monomethyl arginine, an inhibitor of nitric oxide synthase, suppresses the development of adjuvant arthritis in rats. Arthritis Rheum. 1994 Jul;37(7):1062–1069. [PubMed]
  • Anderson GD, Hauser SD, McGarity KL, Bremer ME, Isakson PC, Gregory SA. Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis. J Clin Invest. 1996 Jun 1;97(11):2672–2679. [PMC free article] [PubMed]
  • Gilliam MB, Sherman MP, Griscavage JM, Ignarro LJ. A spectrophotometric assay for nitrate using NADPH oxidation by Aspergillus nitrate reductase. Anal Biochem. 1993 Aug 1;212(2):359–365. [PubMed]
  • Adams ME, Huang DQ, Yao LY, Sandell LJ. Extraction and isolation of mRNA from adult articular cartilage. Anal Biochem. 1992 Apr;202(1):89–95. [PubMed]
  • Wu KK. Inducible cyclooxygenase and nitric oxide synthase. Adv Pharmacol. 1995;33:179–207. [PubMed]
  • Ristimäki A, Garfinkel S, Wessendorf J, Maciag T, Hla T. Induction of cyclooxygenase-2 by interleukin-1 alpha. Evidence for post-transcriptional regulation. J Biol Chem. 1994 Apr 22;269(16):11769–11775. [PubMed]
  • Hajra A, Liu PP, Wang Q, Kelley CA, Stacy T, Adelstein RS, Speck NA, Collins FS. The leukemic core binding factor beta-smooth muscle myosin heavy chain (CBF beta-SMMHC) chimeric protein requires both CBF beta and myosin heavy chain domains for transformation of NIH 3T3 cells. Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):1926–1930. [PMC free article] [PubMed]
  • Tetsuka T, Daphna-Iken D, Srivastava SK, Baier LD, DuMaine J, Morrison AR. Cross-talk between cyclooxygenase and nitric oxide pathways: prostaglandin E2 negatively modulates induction of nitric oxide synthase by interleukin 1. Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12168–12172. [PMC free article] [PubMed]
  • Lorenz JJ, Furdon PJ, Taylor JD, Verghese MW, Chandra G, Kost TA, Haneline SA, Roner LA, Gray JG. A cyclic adenosine 3',5'-monophosphate signal is required for the induction of IL-1 beta by TNF-alpha in human monocytes. J Immunol. 1995 Jul 15;155(2):836–844. [PubMed]
  • Lowe GN, Fu YH, McDougall S, Polendo R, Williams A, Benya PD, Hahn TJ. Effects of prostaglandins on deoxyribonucleic acid and aggrecan synthesis in the RCJ 3.1C5.18 chondrocyte cell line: role of second messengers. Endocrinology. 1996 Jun;137(6):2208–2216. [PubMed]
  • DiBattista JA, Martel-Pelletier J, Cloutier JM, Pelletier JP. Modulation of glucocorticoid receptor expression in human articular chondrocytes by cAMP and prostaglandins. J Rheumatol Suppl. 1991 Feb;27:102–105. [PubMed]
  • Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell. 1995 Nov 3;83(3):493–501. [PubMed]
  • Dinchuk JE, Car BD, Focht RJ, Johnston JJ, Jaffee BD, Covington MB, Contel NR, Eng VM, Collins RJ, Czerniak PM, et al. Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature. 1995 Nov 23;378(6555):406–409. [PubMed]
  • Salvemini D, Misko TP, Masferrer JL, Seibert K, Currie MG, Needleman P. Nitric oxide activates cyclooxygenase enzymes. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7240–7244. [PMC free article] [PubMed]
  • Corbett JA, Kwon G, Turk J, McDaniel ML. IL-1 beta induces the coexpression of both nitric oxide synthase and cyclooxygenase by islets of Langerhans: activation of cyclooxygenase by nitric oxide. Biochemistry. 1993 Dec 21;32(50):13767–13770. [PubMed]
  • Tetsuka T, Daphna-Iken D, Miller BW, Guan Z, Baier LD, Morrison AR. Nitric oxide amplifies interleukin 1-induced cyclooxygenase-2 expression in rat mesangial cells. J Clin Invest. 1996 May 1;97(9):2051–2056. [PMC free article] [PubMed]
  • Salvemini D, Currie MG, Mollace V. Nitric oxide-mediated cyclooxygenase activation. A key event in the antiplatelet effects of nitrovasodilators. J Clin Invest. 1996 Jun 1;97(11):2562–2568. [PMC free article] [PubMed]
  • Blanco FJ, Lotz M. IL-1-induced nitric oxide inhibits chondrocyte proliferation via PGE2. Exp Cell Res. 1995 May;218(1):319–325. [PubMed]
  • Salvemini D, Manning PT, Zweifel BS, Seibert K, Connor J, Currie MG, Needleman P, Masferrer JL. Dual inhibition of nitric oxide and prostaglandin production contributes to the antiinflammatory properties of nitric oxide synthase inhibitors. J Clin Invest. 1995 Jul;96(1):301–308. [PMC free article] [PubMed]
  • Stadler J, Harbrecht BG, Di Silvio M, Curran RD, Jordan ML, Simmons RL, Billiar TR. Endogenous nitric oxide inhibits the synthesis of cyclooxygenase products and interleukin-6 by rat Kupffer cells. J Leukoc Biol. 1993 Feb;53(2):165–172. [PubMed]
  • Swierkosz TA, Mitchell JA, Warner TD, Botting RM, Vane JR. Co-induction of nitric oxide synthase and cyclo-oxygenase: interactions between nitric oxide and prostanoids. Br J Pharmacol. 1995 Apr;114(7):1335–1342. [PMC free article] [PubMed]
  • Janabi N, Chabrier S, Tardieu M. Endogenous nitric oxide activates prostaglandin F2 alpha production in human microglial cells but not in astrocytes: a study of interactions between eicosanoids, nitric oxide, and superoxide anion (O2-) regulatory pathways. J Immunol. 1996 Sep 1;157(5):2129–2135. [PubMed]
  • Amin AR, Attur MG, Thakker GD, Patel PD, Vyas PR, Patel RN, Patel IR, Abramson SB. A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):14014–14019. [PMC free article] [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...