Effects of ceramide on apoptosis, proteoglycan degradation, and matrix metalloproteinase expression in rabbit articular cartilage

Cartilage loss in osteoarthritis is characterized by matrix degradation and chondrocyte death. The lipid messenger ceramide is implicated in signal tr ansduction of the catabolic cytokines tumor necrosis factor (TNF) and inter leukin-1 (IL-1), as well as in apoptosis. The aim of this study was to exam ine the in vitro effects of ceramide on proteoglycan degradation, matrix-me talloproteinase (MMP) expression and activity, and chondrocyte apoptosis in rabbit articular cartilage. Cell-permeant ceramide C-2 stimulated proteogl ycan degradation in cartilage explants starting from 3 x 10(-5) M, with 100 % increase at the dose of 10(-4) RI. This effect was probably due to MMPs s ince it was blocked by the MMP inhibitor batimastat, Furthermore, in isolat ed chondrocytes, C-2 stimulated the expression of MMP-1, 3, and 13 at the m RNA level, MMP activity, and MMP-3 production. Ceramide also caused chondro cyte apoptosis at doses ranging from 10(-5) to 10(-4) M. This study support s the hypothesis that ceramide might play a mediatory role in both matrix d egradation and apoptosis in processes of cartilage loss such as those obser ved in osteoarthritis. (C) 2000 Academic Press.