Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 2002 Mar 1;362(Pt 2):367–373. doi: 10.1042/0264-6021:3620367

Differentiation regulates interleukin-1beta-induced cyclo-oxygenase-2 in human articular chondrocytes: role of p38 mitogen-activated protein kinase.

Béatrice Thomas 1, Sylvie Thirion 1, Lydie Humbert 1, Lujian Tan 1, Mary B Goldring 1, Gilbert Béréziat 1, Francis Berenbaum 1
PMCID: PMC1222396  PMID: 11853544

Abstract

Chondrocyte dedifferentiation has been noted in osteoarthritic cartilage, but the contribution of this phenomenon is poorly understood. Interleukin (IL)-1beta, the major pro-inflammatory cytokine found in osteoarthritic synovial fluid, induces the dedifferentiation of cultured articular chondrocytes, whereas E-series prostaglandins (PGE) are capable of inducing cell differentiation. Since PGE(2) synthesis is up-regulated by IL-1beta, we addressed the question of whether the state of chondrocyte differentiation may influence the production of IL-1-induced PGE(2) by modulating cyclooxygenase (COX)-2 expression. Immortalized human articular chondrocytes, (tsT/AC62) cultured in monolayer after passage through alginate matrix (alg+) produced 5-fold greater amounts of PGE(2) than continuous monolayer cultures (alg-) after stimulation with IL-1beta. Moreover, IL-1beta induced COX-2 expression at 0.01 ng/ml in (alg+) cells, whereas a 100-fold higher dose of cytokine was necessary for stimulation in (alg-) cells. SB203580, a selective p38 mitogen-activated protein kinase (MAPK) inhibitor, completely abolished the IL-1beta-induced COX-2 mRNA. Overexpression of p38 MAPK induces a COX-2 reporter, whereas overexpression of dominant negative p38 MAPK represses IL-1beta-induced promoter expression. Interestingly, IL-1beta-induced p38 MAPK activity was greatly enhanced in (alg+) compared with (alg-) cells. Our results suggest that differentiated articular chondrocytes are highly responsive to IL-1beta and that p38 MAPK mediates this response by inducing COX-2 gene expression.

Full Text

The Full Text of this article is available as a PDF (223.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aigner T., Frischholz S., Dertinger S., Beier F., Girkontaité I., von der Mark K. Type X collagen expression and hypertrophic differentiation in chondrogenic neoplasias. Histochem Cell Biol. 1997 Jun;107(6):435–440. doi: 10.1007/s004180050130. [DOI] [PubMed] [Google Scholar]
  2. Aigner T., Zhu Y., Chansky H. H., Matsen F. A., 3rd, Maloney W. J., Sandell L. J. Reexpression of type IIA procollagen by adult articular chondrocytes in osteoarthritic cartilage. Arthritis Rheum. 1999 Jul;42(7):1443–1450. doi: 10.1002/1529-0131(199907)42:7<1443::AID-ANR18>3.0.CO;2-A. [DOI] [PubMed] [Google Scholar]
  3. Amin A. R., Attur M., Patel R. N., Thakker G. D., Marshall P. J., Rediske J., Stuchin S. A., Patel I. R., Abramson S. B. Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. Influence of nitric oxide. J Clin Invest. 1997 Mar 15;99(6):1231–1237. doi: 10.1172/JCI119280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Badger A. M., Griswold D. E., Kapadia R., Blake S., Swift B. A., Hoffman S. J., Stroup G. B., Webb E., Rieman D. J., Gowen M. Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis. Arthritis Rheum. 2000 Jan;43(1):175–183. doi: 10.1002/1529-0131(200001)43:1<175::AID-ANR22>3.0.CO;2-S. [DOI] [PubMed] [Google Scholar]
  5. Bartlett S. R., Sawdy R., Mann G. E. Induction of cyclooxygenase-2 expression in human myometrial smooth muscle cells by interleukin-1beta: involvement of p38 mitogen-activated protein kinase. J Physiol. 1999 Oct 15;520(Pt 2):399–406. doi: 10.1111/j.1469-7793.1999.00399.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Berenbaum F., Jacques C., Thomas G., Corvol M. T., Béréziat G., Masliah J. Synergistic effect of interleukin-1 beta and tumor necrosis factor alpha on PGE2 production by articular chondrocytes does not involve PLA2 stimulation. Exp Cell Res. 1996 Feb 1;222(2):379–384. doi: 10.1006/excr.1996.0047. [DOI] [PubMed] [Google Scholar]
  7. Bordji K., Grillasca J. P., Gouze J. N., Magdalou J., Schohn H., Keller J. M., Bianchi A., Dauça M., Netter P., Terlain B. Evidence for the presence of peroxisome proliferator-activated receptor (PPAR) alpha and gamma and retinoid Z receptor in cartilage. PPARgamma activation modulates the effects of interleukin-1beta on rat chondrocytes. J Biol Chem. 2000 Apr 21;275(16):12243–12250. doi: 10.1074/jbc.275.16.12243. [DOI] [PubMed] [Google Scholar]
  8. Børglum J. D., Richelsen B., Darimont C., Pedersen S. B., Négrel R. Expression of the two isoforms of prostaglandin endoperoxide synthase (PGHS-1 and PGHS-2) during adipose cell differentiation. Mol Cell Endocrinol. 1997 Jul 4;131(1):67–77. doi: 10.1016/s0303-7207(97)00094-4. [DOI] [PubMed] [Google Scholar]
  9. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  10. Crofford L. J., Lipsky P. E., Brooks P., Abramson S. B., Simon L. S., van de Putte L. B. Basic biology and clinical application of specific cyclooxygenase-2 inhibitors. Arthritis Rheum. 2000 Jan;43(1):4–13. doi: 10.1002/1529-0131(200001)43:1<4::AID-ANR2>3.0.CO;2-V. [DOI] [PubMed] [Google Scholar]
  11. Del Toro F., Jr, Sylvia V. L., Schubkegel S. R., Campos R., Dean D. D., Boyan B. D., Schwartz Z. Characterization of prostaglandin E(2) receptors and their role in 24,25-(OH)(2)D(3)-mediated effects on resting zone chondrocytes. J Cell Physiol. 2000 Feb;182(2):196–208. doi: 10.1002/(SICI)1097-4652(200002)182:2<196::AID-JCP8>3.0.CO;2-E. [DOI] [PubMed] [Google Scholar]
  12. Evans C. B., Pillai S., Goldyne M. E. Endogenous prostaglandin E2 modulates calcium-induced differentiation in human skin keratinocytes. Prostaglandins Leukot Essent Fatty Acids. 1993 Oct;49(4):777–781. doi: 10.1016/0952-3278(93)90025-r. [DOI] [PubMed] [Google Scholar]
  13. Fahmi H., Di Battista J. A., Pelletier J. P., Mineau F., Ranger P., Martel-Pelletier J. Peroxisome proliferator--activated receptor gamma activators inhibit interleukin-1beta-induced nitric oxide and matrix metalloproteinase 13 production in human chondrocytes. Arthritis Rheum. 2001 Mar;44(3):595–607. doi: 10.1002/1529-0131(200103)44:3<595::AID-ANR108>3.0.CO;2-8. [DOI] [PubMed] [Google Scholar]
  14. Frank G. R., Brar A. K., Cedars M. I., Handwerger S. Prostaglandin E2 enhances human endometrial stromal cell differentiation. Endocrinology. 1994 Jan;134(1):258–263. doi: 10.1210/endo.134.1.7506205. [DOI] [PubMed] [Google Scholar]
  15. Geng Y., Valbracht 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 Nov 15;98(10):2425–2430. doi: 10.1172/JCI119056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Goldring M. B., Birkhead J., Sandell L. J., Kimura T., Krane S. M. Interleukin 1 suppresses expression of cartilage-specific types II and IX collagens and increases types I and III collagens in human chondrocytes. J Clin Invest. 1988 Dec;82(6):2026–2037. doi: 10.1172/JCI113823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Goldring M. B., Fukuo K., Birkhead J. R., Dudek E., Sandell L. J. Transcriptional suppression by interleukin-1 and interferon-gamma of type II collagen gene expression in human chondrocytes. J Cell Biochem. 1994 Jan;54(1):85–99. doi: 10.1002/jcb.240540110. [DOI] [PubMed] [Google Scholar]
  18. Goldring M. B., Sohbat E., Elwell J. M., Chang J. Y. Etodolac preserves cartilage-specific phenotype in human chondrocytes: effects on type II collagen synthesis and associated mRNA levels. Eur J Rheumatol Inflamm. 1990;10(1):10–21. [PubMed] [Google Scholar]
  19. Goldring Mary B., Suen Lii-Fang, Yamin Rina, Lai Wen-Fu Thomas. Regulation of Collagen Gene Expression by Prostaglandins and Interleukin-1beta in Cultured Chondrocytes and Fibroblasts. Am J Ther. 1996 Jan;3(1):9–16. doi: 10.1097/00045391-199601000-00003. [DOI] [PubMed] [Google Scholar]
  20. Guan Z., Baier L. D., Morrison A. R. p38 mitogen-activated protein kinase down-regulates nitric oxide and up-regulates prostaglandin E2 biosynthesis stimulated by interleukin-1beta. J Biol Chem. 1997 Mar 21;272(12):8083–8089. doi: 10.1074/jbc.272.12.8083. [DOI] [PubMed] [Google Scholar]
  21. Guan Z., Buckman S. Y., Miller B. W., Springer L. D., Morrison A. R. Interleukin-1beta-induced cyclooxygenase-2 expression requires activation of both c-Jun NH2-terminal kinase and p38 MAPK signal pathways in rat renal mesangial cells. J Biol Chem. 1998 Oct 30;273(44):28670–28676. doi: 10.1074/jbc.273.44.28670. [DOI] [PubMed] [Google Scholar]
  22. Guan Z., Buckman S. Y., Pentland A. P., Templeton D. J., Morrison A. R. Induction of cyclooxygenase-2 by the activated MEKK1 --> SEK1/MKK4 --> p38 mitogen-activated protein kinase pathway. J Biol Chem. 1998 May 22;273(21):12901–12908. doi: 10.1074/jbc.273.21.12901. [DOI] [PubMed] [Google Scholar]
  23. Guo J. F., Jourdian G. W., MacCallum D. K. Culture and growth characteristics of chondrocytes encapsulated in alginate beads. Connect Tissue Res. 1989;19(2-4):277–297. doi: 10.3109/03008208909043901. [DOI] [PubMed] [Google Scholar]
  24. Harrison J. R., Kelly P. L., Pilbeam C. C. Involvement of CCAAT enhancer binding protein transcription factors in the regulation of prostaglandin G/H synthase 2 expression by interleukin-1 in osteoblastic MC3T3-E1 cells. J Bone Miner Res. 2000 Jun;15(6):1138–1146. doi: 10.1359/jbmr.2000.15.6.1138. [DOI] [PubMed] [Google Scholar]
  25. Hill E. M., Eling T., Nettesheim P. Differentiation dependency of eicosanoid enzyme expression in human tracheobronchial cells. Toxicol Lett. 1998 Aug;96-97:239–244. doi: 10.1016/s0378-4274(98)00078-2. [DOI] [PubMed] [Google Scholar]
  26. Kliewer S. A., Lenhard J. M., Willson T. M., Patel I., Morris D. C., Lehmann J. M. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell. 1995 Dec 1;83(5):813–819. doi: 10.1016/0092-8674(95)90194-9. [DOI] [PubMed] [Google Scholar]
  27. Kujubu D. A., Fletcher B. S., Varnum B. C., Lim R. W., Herschman H. R. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem. 1991 Jul 15;266(20):12866–12872. [PubMed] [Google Scholar]
  28. LaPointe M. C., Isenović E. Interleukin-1beta regulation of inducible nitric oxide synthase and cyclooxygenase-2 involves the p42/44 and p38 MAPK signaling pathways in cardiac myocytes. Hypertension. 1999 Jan;33(1 Pt 2):276–282. doi: 10.1161/01.hyp.33.1.276. [DOI] [PubMed] [Google Scholar]
  29. Lasa M., Mahtani K. R., Finch A., Brewer G., Saklatvala J., Clark A. R. Regulation of cyclooxygenase 2 mRNA stability by the mitogen-activated protein kinase p38 signaling cascade. Mol Cell Biol. 2000 Jun;20(12):4265–4274. doi: 10.1128/mcb.20.12.4265-4274.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lefebvre V., Peeters-Joris C., Vaes G. Modulation by interleukin 1 and tumor necrosis factor alpha of production of collagenase, tissue inhibitor of metalloproteinases and collagen types in differentiated and dedifferentiated articular chondrocytes. Biochim Biophys Acta. 1990 May 22;1052(3):366–378. doi: 10.1016/0167-4889(90)90145-4. [DOI] [PubMed] [Google Scholar]
  31. Lemare F., Steimberg N., Le Griel C., Demignot S., Adolphe M. Dedifferentiated chondrocytes cultured in alginate beads: restoration of the differentiated phenotype and of the metabolic responses to interleukin-1beta. J Cell Physiol. 1998 Aug;176(2):303–313. doi: 10.1002/(SICI)1097-4652(199808)176:2<303::AID-JCP8>3.0.CO;2-S. [DOI] [PubMed] [Google Scholar]
  32. Leong J., Hughes-Fulford M., Rakhlin N., Habib A., Maclouf J., Goldyne M. E. Cyclooxygenases in human and mouse skin and cultured human keratinocytes: association of COX-2 expression with human keratinocyte differentiation. Exp Cell Res. 1996 Apr 10;224(1):79–87. doi: 10.1006/excr.1996.0113. [DOI] [PubMed] [Google Scholar]
  33. Liu H., Lee Y. W., Dean M. F. Re-expression of differentiated proteoglycan phenotype by dedifferentiated human chondrocytes during culture in alginate beads. Biochim Biophys Acta. 1998 Nov 27;1425(3):505–515. doi: 10.1016/s0304-4165(98)00105-6. [DOI] [PubMed] [Google Scholar]
  34. Lyons-Giordano B., Pratta M. A., Galbraith W., Davis G. L., Arner E. C. Interleukin-1 differentially modulates chondrocyte expression of cyclooxygenase-2 and phospholipase A2. Exp Cell Res. 1993 May;206(1):58–62. doi: 10.1006/excr.1993.1120. [DOI] [PubMed] [Google Scholar]
  35. Melchiorri C., Meliconi R., Frizziero L., Silvestri T., Pulsatelli L., Mazzetti I., Borzì R. M., Uguccioni M., Facchini A. Enhanced and coordinated in vivo expression of inflammatory cytokines and nitric oxide synthase by chondrocytes from patients with osteoarthritis. Arthritis Rheum. 1998 Dec;41(12):2165–2174. doi: 10.1002/1529-0131(199812)41:12<2165::AID-ART11>3.0.CO;2-O. [DOI] [PubMed] [Google Scholar]
  36. Mestre J. R., Mackrell P. J., Rivadeneira D. E., Stapleton P. P., Tanabe T., Daly J. M. Redundancy in the signaling pathways and promoter elements regulating cyclooxygenase-2 gene expression in endotoxin-treated macrophage/monocytic cells. J Biol Chem. 2000 Nov 22;276(6):3977–3982. doi: 10.1074/jbc.M005077200. [DOI] [PubMed] [Google Scholar]
  37. Miller C., Zhang M., He Y., Zhao J., Pelletier J. P., Martel-Pelletier J., Di Battista J. A. Transcriptional induction of cyclooxygenase-2 gene by okadaic acid inhibition of phosphatase activity in human chondrocytes: co-stimulation of AP-1 and CRE nuclear binding proteins. J Cell Biochem. 1998 Jun 15;69(4):392–413. [PubMed] [Google Scholar]
  38. Nakamura K., Shirai T., Morishita S., Uchida S., Saeki-Miura K., Makishima F. p38 mitogen-activated protein kinase functionally contributes to chondrogenesis induced by growth/differentiation factor-5 in ATDC5 cells. Exp Cell Res. 1999 Aug 1;250(2):351–363. doi: 10.1006/excr.1999.4535. [DOI] [PubMed] [Google Scholar]
  39. O'Neill L. A., Greene C. Signal transduction pathways activated by the IL-1 receptor family: ancient signaling machinery in mammals, insects, and plants. J Leukoc Biol. 1998 Jun;63(6):650–657. [PubMed] [Google Scholar]
  40. Oh C. D., Chang S. H., Yoon Y. M., Lee S. J., Lee Y. S., Kang S. S., Chun J. S. Opposing role of mitogen-activated protein kinase subtypes, erk-1/2 and p38, in the regulation of chondrogenesis of mesenchymes. J Biol Chem. 2000 Feb 25;275(8):5613–5619. doi: 10.1074/jbc.275.8.5613. [DOI] [PubMed] [Google Scholar]
  41. Ridley S. H., Dean J. L., Sarsfield S. J., Brook M., Clark A. R., Saklatvala J. A p38 MAP kinase inhibitor regulates stability of interleukin-1-induced cyclooxygenase-2 mRNA. FEBS Lett. 1998 Nov 13;439(1-2):75–80. doi: 10.1016/s0014-5793(98)01342-8. [DOI] [PubMed] [Google Scholar]
  42. Robbins J. R., Thomas B., Tan L., Choy B., Arbiser J. L., Berenbaum F., Goldring M. B. Immortalized human adult articular chondrocytes maintain cartilage-specific phenotype and responses to interleukin-1beta. Arthritis Rheum. 2000 Oct;43(10):2189–2201. doi: 10.1002/1529-0131(200010)43:10<2189::AID-ANR6>3.0.CO;2-S. [DOI] [PubMed] [Google Scholar]
  43. Scherle P. A., Pratta M. A., Feeser W. S., Tancula E. J., Arner E. C. The effects of IL-1 on mitogen-activated protein kinases in rabbit articular chondrocytes. Biochem Biophys Res Commun. 1997 Jan 23;230(3):573–577. doi: 10.1006/bbrc.1996.5985. [DOI] [PubMed] [Google Scholar]
  44. Schwartz Z., Gilley R. M., Sylvia V. L., Dean D. D., Boyan B. D. The effect of prostaglandin E2 on costochondral chondrocyte differentiation is mediated by cyclic adenosine 3',5'-monophosphate and protein kinase C. Endocrinology. 1998 Apr;139(4):1825–1834. doi: 10.1210/endo.139.4.5919. [DOI] [PubMed] [Google Scholar]
  45. Sylvia V. L., Del Toro F., Jr, Hardin R. R., Dean D. D., Boyan B. D., Schwartz Z. Characterization of PGE(2) receptors (EP) and their role as mediators of 1alpha,25-(OH)(2)D(3) effects on growth zone chondrocytes. J Steroid Biochem Mol Biol. 2001 Sep;78(3):261–274. doi: 10.1016/s0960-0760(01)00099-1. [DOI] [PubMed] [Google Scholar]
  46. Thomas B., Berenbaum F., Humbert L., Bian H., Béréziat G., Crofford L., Olivier J. L. Critical role of C/EBPdelta and C/EBPbeta factors in the stimulation of the cyclooxygenase-2 gene transcription by interleukin-1beta in articular chondrocytes. Eur J Biochem. 2000 Dec;267(23):6798–6809. doi: 10.1046/j.1432-1033.2000.01778.x. [DOI] [PubMed] [Google Scholar]
  47. Wadleigh D. J., Reddy S. T., Kopp E., Ghosh S., Herschman H. R. Transcriptional activation of the cyclooxygenase-2 gene in endotoxin-treated RAW 264.7 macrophages. J Biol Chem. 2000 Mar 3;275(9):6259–6266. doi: 10.1074/jbc.275.9.6259. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES