Dietary fat-associated osteoarthritic chondrocytes gain resistance to lipotoxicity through PKCK2/STAMP2/FSP27

Abstract

Free fatty acids (FFAs), which are elevated with metabolic syndrome, are considered the principal offender exerting lipotoxicity. Few previous studies have reported a causal relationship between FFAs and osteoarthritis pathogenesis. However, the molecular mechanism by which FFAs exert lipotoxicity and induce osteoarthritis remains largely unknown. We here observed that oleate at the usual clinical range does not exert lipotoxicity while oleate at high pathological ranges exerted lipotoxicity through apoptosis in articular chondrocytes. By investigating the differential effect of oleate at toxic and nontoxic concentrations, we revealed that lipid droplet (LD) accumulation confers articular chondrocytes, the resistance to lipotoxicity. Using high fat diet-induced osteoarthritis models and articular chondrocytes treated with oleate alone or oleate plus palmitate, we demonstrated that articular chondrocytes gain resistance to lipotoxicity through protein kinase casein kinase 2 (PKCK2)—six-transmembrane protein of prostate 2 (STAMP2)—and fat-specific protein 27 (FSP27)-mediated LD accumulation. We further observed that the exertion of FFAs-induced lipotoxicity was correlated with the increased concentration of cellular FFAs freed from LDs, whether FFAs are saturated or not. In conclusion, PKCK2/STAMP2/FSP27-mediated sequestration of FFAs in LD rescues osteoarthritic chondrocytes. PKCK2/STAMP2/FSP27 should be considered for interventions against metabolic OA.

Oil droplets protect cartilage from toxic fatty acids

Cartilage tissue deals with the stress of exposure to free fatty acids by sequestering the toxic molecules into sub-cellular oil droplets. Young Hyun Yoo from Dong-A University College of Medicine in Busan, South Korea, and coworkers exposed rat cartilage cells to increasing levels of a fatty acid called oleate, a by-product of fat metabolism, and observed that the accumulation of oil droplets conferred resistance to oleate-induced toxicity. In these rat cells and in experiments involving mouse models of osteoarthritis fed a high-fat diet, the researchers then identified three of the protective proteins needed for cartilage tissue to properly quarantine fatty acids into oil droplets. Those proteins — and their connected regulatory networks — could now serve as drug targets for treating metabolic syndrome-associated osteoarthritis.

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