Mechanical stress and prostaglandin E₂ synthesis in cartilage

Issue title: Selected papers of the 5th International Symposium on Mechanobiology of Cartilage and Chondrocyte, Athens, May 2007

Article type: Research Article

Authors: Gosset, Marjolaine | Berenbaum, Francis^{; ;} | Levy, Arlette | Pigenet, Audrey | Thirion, Sylvie | Cavadias, Simeon | Jacques, Claire

Affiliations: Physiology and Physiopathology Laboratory, Paris Universitas–UPMC Paris VI and CNRS (UMR 7079), 75252 Paris, Cedex 5, France | Department of Rheumatology, APHP Saint-Antoine Hospital, 75012 Paris, France | C.N.E. Neuroendocrine Cellular Interactions, UMR CNRS 6544, Faculty of Medicine, Mediterranean University, 13916 Marseille, Cedex 20, France | Laboratoire de Génie des procédés plasmas et traitements de surface, Ecole Nationale de Chimie de Paris, 75231 Paris, Cedex 5, France

Note: [] Address for correspondence: Dr. F. Berenbaum, UMR 7079 CNRS, Physiology and Physiopathology Laboratory, University Paris 6, 7 quai St.-Bernard, 75252 Paris, Cedex 5, France. Tel.: +33 144 27 22 83; Fax: +33 144 27 51 40; E-mail: [email protected].

Abstract: NOTE: Several parts of this article were copied verbatim or close to verbatim from an article that was published in Arthritis Research & Therapy, 2006, 8:R135, doi:10.1186/ar2024. No acknowledgement of, or reference to, the previously published article in Arthritis Research & Therapy was made at the time of publication of the article in Biorheology. In this updated version of the article all the copied parts are highlighted. An Erratum has been published in Biorheology 49(4) (2012), 299. 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 in which metalloproteinase (MMP) is crucial for cartilage degradation. 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. Among the isoforms described, COX-1 and cytosolic PGES are constitutively expressed whereas COX-2 and microsomal PGES type 1 (mPGES-1) are inducible in an inflammatory context. We investigated the regulation of the COX, PGES and 15-PGDH and MMP-2, MMP-9 and MMP-13 genes by mechanical stress applied to cartilage explants. Mouse cartilage explants were subjected to compression (0.5 Hz, 1 MPa) from 2 to 24 h. After determination of the PGE2 release in the media, mRNA and proteins were extracted directly from the cartilage explants and analyzed by real-time RT-PCR and western blot 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 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. 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. MAPK are involved in signaling, since specific inhibitors partially inhibited COX-2 and mPGES-1 expressions. Lastly, compression induced MMP-2, -9, -13 mRNA expressions in cartilage. We conclude that dynamic compression induces pro-inflammatroy mediators release and matrix degradating enzymes synthesis. Notably, compression increases mPGES-1 mRNA and protein expression in cartilage explants. Thus, the mechanosensitive mPGES-1 enzyme represents a potential therapeutic target in osteoarthritis.

Keywords: PGE_2, mPGES-1, COX-2, 15-PGDH, MMP, murine cartilage, mechanical stress, osteoarthritis

DOI: 10.3233/BIR-2008-0494

Journal: Biorheology, vol. 45, no. 3-4, pp. 301-320, 2008