Synthesis and release of human cartilage matrix proteoglycans are differently regulated by nitric oxide and prostaglandin-E₂

Simon C Mastbergen ^1*, Johannes WJ Bijlsma ¹ and Floris PJG Lafeber ¹

¹ UMC Utrecht, Netherlands

^* To whom correspondence should be addressed. E-mail: s.mastbergen{at}umcutrecht.nl.

Accepted 30 April 2007

Abstract

Objectives: Recent studies showed beneficial effects of COX-2 inhibition on proteoglycan turnover of both IL-/TNF damaged cartilage and of osteoarthritic cartilage. Although proteoglycan release and content normalized, proteoglycan synthesis was only partially influenced. Prostaglandin-E2 is the main product formed by COX-2. We therefore evaluate the role of prostaglandin-E2 in relation to nitric oxide in disturbing cartilage proteoglycan turnover.

Methods: Human healthy cartilage, alone or in the presence of IL-;+TNF, was cultured for 7 days with or without prostaglandin-E2 or the selective COX-2 inhibitor (celecoxib 10µM). Changes in cartilage matrix proteoglycan turnover, levels of prostaglandin-E2 and nitric oxide were determined.

Results: Proteoglycan synthesis and release of the cartilage were not affected by prostaglandin-E2 alone. Addition of IL-+TNF to healthy cartilage resulted in inhibition of proteoglycan synthesis and increase in proteoglycan release. When prostaglandin-E2 was added, in addition to IL-+TNF, proteoglycan release further increased, but proteoglycan synthesis was not further influenced. Addition of a selective COX-2 inhibitor to the IL-+TNF treated cartilage inhibited the enhanced prostaglandin-E2 production and almost complete normalized proteoglycan release, whereas synthesis remained unaffected. Also the enhanced NO-levels remained elevated. Prostaglandin-E2 levels correlated significantly with proteoglycan release whereas NO levels correlated significantly with proteoglycan synthesis.

Conclusion: The present results suggest involvement of prostaglandin-E2 in enhanced cartilage proteoglycan release but not synthesis, although healthy cartilage has to be sensitized by IL-+TNF. IL-1£]+TNF induced NO seems to be involved in inhibition of proteoglycan synthesis, independent of prostaglandin-E2 and thus seems insensitive to regulation by (selective) COX-2 inhibitors.

Keywords: COX-2, human cartilage tissue, prostaglandin-E2, proteoglycan turnover

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