Depletion of gangliosides enhances cartilage degradation in mice

Objective: Glycosphingolipids (GSLs) are ubiquitous membrane components that play a functional role in maintaining chondrocyte homeostasis. We investigated the potential role of gangliosides, one of the major components of GSLs, in osteoarthritis (OA) pathogenesis. Design: Both age-associated and instability-induced OA models were generated using GM3 synthase knockout (GM3.5(-/-)) mice. A cartilage degradation model and transiently GM3S-transfected chondrocytes were analyzed to evaluate the function of gangliosides in OA development. The amount of each series of GSLs in chondrocytes after IL-1 alpha stimulation was profiled using mass spectrometry (MS). Results: OA changes in GM3.5(-/-) mice were dramatically enhanced with aging compared to those in wildtype (WT) mice. GM3.5(-/-) mice showed more severe instability-induced pathologic OA in vivo. Ganglioside deficiency also led to the induction of matrix metalloproteinase (MMP)-13 and ADAMTS-5 secretion and chondrocyte apoptosis in vitro. In contrast, transientGM3.5(-/-) transfection of chondrocytes suppressed MMP-13 and ADAMTS-5 expression after interleukin (IL)-1 alpha stimulation. GSL profiling revealed the presence of abundant gangliosides in chondrocytes after IL-1 alpha stimulation. Conclusion: Gangliosides play a critical role in OA pathogenesis by regulating the expression of MMP-13 and ADAMTS-5 and chondrocyte apoptosis. Based on the obtained results, we propose that gangliosides are potential target molecules for the development of novel OA treatments. (C) 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.