Prostaglandin E2 synthesis in cartilage explants under compression: mPGES-1 is a mechanosensitive geneReport as inadecuate




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Arthritis Research and Therapy

, 8:R135

First Online: 27 July 2006Received: 21 February 2006Revised: 05 July 2006Accepted: 27 July 2006

Abstract

Knee osteoarthritis OA results, at least in part, from overloading and inflammation leading to cartilage degradation. Prostaglandin E2 PGE2 is one of the main catabolic factors involved in OA. Its synthesis is the result of cyclooxygenase COX and prostaglandin E synthase PGES activities whereas NAD+-dependent 15 hydroxy prostaglandin dehydrogenase 15-PGDH is the key enzyme implicated in the catabolism of PGE2. For both COX and PGES, three isoforms have been described: in cartilage, COX-1 and cytosolic PGES are constitutively expressed whereas COX-2 and microsomal PGES type 1 mPGES-1 are inducible in an inflammatory context. COX-3 a variant of COX-1 and mPGES-2 have been recently cloned but little is known about their expression and regulation in cartilage, as is also the case for 15-PGDH. We investigated the regulation of the genes encoding COX and PGES isoforms during mechanical stress applied to cartilage explants. Mouse cartilage explants were subjected to compression 0.5 Hz, 1 MPa for 2 to 24 hours. After determination of the amount of PGE2 released in the media enzyme immunoassay, mRNA and proteins were extracted directly from the cartilage explants and analyzed by real-time RT-PCR and western blotting respectively. Mechanical compression of cartilage explants significantly increased PGE2 production in a time-dependent manner. This was not due to the synthesis of IL-1, since pretreatment with interleukin 1 receptor antagonist IL1-Ra did not alter the PGE2 synthesis. Interestingly, COX-2 and mPGES-1 mRNA expression significantly increased after 2 hours, in parallel with protein expression, whereas COX-3 and mPGES-2 mRNA expression was not modified. Moreover, we observed a delayed overexpression of 15-PGDH just before the decline of PGE2 synthesis after 18 hours, suggesting that PGE2 synthesis could be altered by the induction of 15-PGDH expression. We conclude that, along with COX-2, dynamic compression induces mPGES-1 mRNA and protein expression in cartilage explants. Thus, the mechanosensitive mPGES-1 enzyme represents a potential therapeutic target in osteoarthritis.

Abbreviations15-PGDHNAD+-dependent 15 hydroxy prostaglandin dehydrogenase

BSAbovine serum albumin

C-EBPCAAT enhancer binding protein C-EBP

COXcyclooxygenase

cPGEScytosolic PGES

CREcyclic AMP response element

CREBcyclic AMP response element-binding protein

ERKextracellular signal regulated kinases

FGFfibroblast growth factor

HPRThypoxanthine-guanine phosphoribosyltransferase

ILinterleukin

IL1-Rainteleukin 1 receptor antagonist

JNKc-jun-N-terminal kinase

LPSlipopolysaccharides

MAPKmitogen-associated protein kinase

mPGESmicrosomal PGES

NFkBnuclear factor kappa-B

NOnitric oxide

OAosteoarthritis

PBSphosphate-buffered saline

PGEprostaglandin E2

PGESprostaglandin E synthase

RT-PCRreverse transcription PCR

SEMstandard error of the mean

SSREshear stress response element.

Electronic supplementary materialThe online version of this article doi:10.1186-ar2024 contains supplementary material, which is available to authorized users.

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Author: Marjolaine Gosset - Francis Berenbaum - Arlette Levy - Audrey Pigenet - Sylvie Thirion - Jean-Louis Saffar - Claire Jacques

Source: https://link.springer.com/







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