Sphingosine 1-phosphate counteracts the effects of interleukin-1β in human chondrocytes.

摘要: In osteoarthritis (OA), repeated injury activates chondrocytes to release proinflammatory mediators, cytokines, and matrix-degrading enzymes (1,2). This chronic inflammatory process leads pathologic joint remodeling cartilage destruction (1,3). Interleukin-1β (IL-1β) plays a central role in the development progression of degradation OA. Injection IL-1β into mouse knee joints is sufficient induce damage, elevated levels are found synovial fluid OA patients (4,5). Upon stimulation with IL-1β, metalloproteases matrix metalloproteinase 1 (MMP-1), MMP-3, MMP-13, aggrecanase (ADAMTS-4), mediators such as prostaglandins nitric oxide (NO) (6,7). stimulates NO by provoking up-regulation inducible synthase (iNOS; also known NOS2). inhibits synthesis proteoglycan type II collagen (3,8,9). Furthermore, high concentrations chondrocyte apoptosis (10). animal models rheumatoid arthritis, iNOS-knockout mice exhibit less compared their wild-type littermates (11). However, another study did not confirm these results (12). Protein iNOS regulated at transcriptional level. NF-κB translocation nucleus activation MAPK pathways required for transcription iNOS, both processes have been described occur response variety stimuli, including (13–15). Physiologic mechanisms that limit excessive from human poorly understood. We previously reported endogenous bioactive sphingolipid sphingosine 1-phosphate (S1P) able counteract effects diminish expression ADAMTS-4 bovine (16). S1P generated kinase ceramide metabolite (17). It involved regulation vital functions, cell migration, inflammation, angiogenesis, wound healing (18–20). exerts its various functions binding specific G protein–coupled receptors, which 5 functionally different isoforms (termed S1P1–5) identified. others gene receptors bovine, rat, (16,21,22). present patients, tissue potential source (23,24). chondrocytes, has implicated cyclooxygenase 2 vascular endothelial growth factor (25,26). The current investigates on signaling chondrocytes. addition, we define this process.