Crucial role of visfatin/pre-B cell colony-enhancing factor in matrix degradation and prostaglandin E2 synthesis in chondrocytes

Objective. Prostaglandin E-2 (PGE2) is one of the main catabolic factors involved in osteoarthritis (OA), and metalloproteinases (MMPs) are crucial for cartilage degradation. PGE(2) synthesis under inflammatory conditions is catalyzed by cyclooxygenase 2 and microsomal PGE synthase 1 (mPGES-1), whereas NAD+-dependent 15-hydro4-PG dehydrogenase (15-PGDH) is the key enzyme implicated in PGE(2) catabolism. The present study was undertaken to investigate the contribution of visfatin, an adipose tissue-derived hormone, to the pathophysiology of OA, by examining its role in PGE(2) synthesis and matrix degradation. Methods. The synthesis of visfatin by human chondrocytes from OA patients, with and without stimulation with interleukin-1 beta (IL-1 beta) and the role of visfatin in PGE(2) synthesis were analyzed by real-time reverse transcriptase-polymerase chain reaction (RTPCR) and immunoblotting. The effects of visfatin (1-10 mu g/ml) on mPGES-1 and 15-PGDH synthesis, on the subsequent release of PGE(2), and on MMP-3, MMP-13, ADAMTS-4, ADAMTS-5, and PG synthesis by primary immature mouse articular chondrocytes were examined by quantitative RT-PCR, immunoblotting, and enzyme-linked immunosorbent assay. Finally, small interfering RNA (siRNA) was used to assess the influence of visfatin on IL-1 beta-induced release of PGE(2) in immature mouse articular chondrocytes. Results. Human OA chondrocytes produced visfatin, and visfatin synthesis was increased by IL-1 beta treatment. Visfatin, like IL-1 beta, triggered excessive release of PGE(2), due to increased mPGES-1 synthesis and decreased 15-PGDH synthesis. Visfatin knockout with siRNA reduced IL-1 beta-induced PGE(2) overrelease. Visfatin triggered ADAMTS-4 and ADAMTS-5 expression and MMP-3 and MMP-13 synthesis and release, and reduced synthesis of high molecular weight PG by immature mouse articular chondrocytes. Conclusion. The findings of this study indicate that visfatin has a catabolic function in cartilage and may have an important role in the pathophysiology of OA.