Prostaglandin E2 Exerts Catabolic Effects in Osteoarthritis Cartilage: Evidence for Signaling via the EP4 Receptor
作者： Mukundan Attur , Hayf E. Al-Mussawir , Jyoti Patel , Alison Kitay , Mandar Dave
DOI: 10.4049/JIMMUNOL.181.7.5082
关键词:
摘要: Elevated levels of PGE(2) have been reported in synovial fluid and cartilage from patients with osteoarthritis (OA). However, the functions metabolism not previously studied detail. To do so, we cultured explants, obtained undergoing knee replacement surgery for advanced OA, (0.1-10 muM). inhibited proteoglycan synthesis a dose-dependent manner (maximum 25% inhibition (p < 0.01)). also induced collagen degradation, inhibitable by matrix metalloproteinase (MMP) inhibitor ilomastat. spontaneous MMP-1, but augmented MMP-13 secretion OA explant cultures. PCR analysis chondrocytes treated or without IL-1 revealed that IL-1-induced expression was significantly cycolooygenase 2 selective celecoxib. Conversely, MMP-1 PGE(2), while celecoxib enhanced both expression. induction aggrecanase 5 (ADAMTS-5), ADAMTS-4, (10 muM) reversed (2 Quantitative screening nondiseased end-stage human articular specimens receptor EP4 up-regulated cartilage. Moreover, blocking (EP4 antagonist, AH23848) mimicked inhibiting MMP-13, ADAMST-5 expression, degradation. These results suggest inhibits stimulates degradation via receptor. Targeting EP4, rather than cyclooxygenase 2, could represent future strategy disease modification.
jimmunol.org 参考文章(42)
Heike A. Wieland, Martin Michaelis, Bernhard J. Kirschbaum, Karl A. Rudolphi, Osteoarthritis — an untreatable disease? Nature Reviews Drug Discovery. ,vol. 4, pp. 331- 344 ,(2005) , 10.1038/NRD1693
Marjolaine Gosset, Francis Berenbaum, Arlette Levy, Audrey Pigenet, Sylvie Thirion, Jean-Louis Saffar, Claire Jacques, Prostaglandin E2 synthesis in cartilage explants under compression: mPGES-1 is a mechanosensitive gene Arthritis Research & Therapy. ,vol. 8, pp. 1- 14 ,(2006) , 10.1186/AR2024
Simon C Mastbergen, Nathalie WD Jansen, Johannes WJ Bijlsma, Floris PJG Lafeber, Differential direct effects of cyclo-oxygenase-1/2 inhibition on proteoglycan turnover of human osteoarthritic cartilage: an in vitro study. Arthritis Research & Therapy. ,vol. 8, pp. 1- 9 ,(2005) , 10.1186/AR1846
H Afif, X Li, J Martel-Pelletier, J-P Pelletier, H Fahmi, Expression and regulation of microsomal prostaglandin E synthase-1 in human osteoarthritic cartilage and chondrocytes. Arthritis Research & Therapy. ,vol. 32, pp. 887- 895 ,(2004) , 10.1186/AR1439
Elena V Tchetina, Ginette Squires, A Robin Poole, Increased type II collagen degradation and very early focal cartilage degeneration is associated with upregulation of chondrocyte differentiation related genes in early human articular cartilage lesions. The Journal of Rheumatology. ,vol. 32, pp. 876- 886 ,(2005)
Xibin Wang, Paul A. Manner, Alan Horner, Lillian Shum, Rocky S. Tuan, Glen H. Nuckolls, Regulation of MMP-13 expression by RUNX2 and FGF2 in osteoarthritic cartilage Osteoarthritis and Cartilage. ,vol. 12, pp. 963- 973 ,(2004) , 10.1016/J.JOCA.2004.08.008
Steven B Abramson, Mukundan Attur, Yusuf Yazici, Prospects for disease modification in osteoarthritis Nature Reviews Rheumatology. ,vol. 2, pp. 304- 312 ,(2006) , 10.1038/NCPRHEUM0193
Ashok R. Amin, Mandar Dave, Mukundan Attur, Steven B. Abramson, COX-2, NO, and cartilage damage and repair Current Rheumatology Reports. ,vol. 2, pp. 447- 453 ,(2000) , 10.1007/S11926-000-0019-5
A R Amin, M Attur, R N Patel, G D Thakker, P J Marshall, J Rediske, S A Stuchin, I R Patel, S B Abramson, Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. Influence of nitric oxide. Journal of Clinical Investigation. ,vol. 99, pp. 1231- 1237 ,(1997) , 10.1172/JCI119280
Seiji Iimoto, Shohei Watanabe, Toshiaki Takahashi, Akira Shimizu, Haruyasu Yamamoto, The influence of Celecoxib on matrix synthesis by chondrocytes under mechanical stress in vitro International Journal of Molecular Medicine. ,vol. 16, pp. 1083- 1088 ,(2005) , 10.3892/IJMM.16.6.1083