Depletion of gangliosides enhances cartilage degradation in mice

作者：Sasazawa F; Onodera T^*; Yamashita T; Seito N; Tsukuda Y; Fujitani N; Shinohara Y; Iwasaki N

来源：Osteoarthritis and Cartilage, 2014, 22(2): 313-322.

DOI：10.1016/j.joca.2013.11.015

• Osteoarthritis
• Mice
• Gangliosides
• Glycosphingolipids
• Interleukin-1 alpha

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.

• 出版日期2014-2