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.
Highlights
Osteoarthritis (OA) is a multifactorial disease characterised by degradation of the extracellular matrix and the destruction of articular cartilage
Our results demonstrated that protein kinase casein kinase 2 (PKCK2), six-transmembrane protein of prostate 2 (STAMP2)‐ and fat-specific protein 27 (FSP27)-mediated sequestration of Free fatty acids (FFAs) in lipid droplets (LDs) confers articular chondrocytes the ability to resist lipotoxicity
It is clear that lipids naturally accumulate in chondrocytes,[9,13] it was recently reported that the accumulation of FFAs contributes to chondrocyte dysfunction related to the pathogenesis of OA
Summary
Osteoarthritis (OA) is a multifactorial disease characterised by degradation of the extracellular matrix and the destruction of articular cartilage. Stimuli involved in chondrocyte death and their signalling pathways have been highlighted as pathogenetic factors leading to joint cartilage degradation.[1,2,3,4,5]. OA is considered a complex disease with different clinical subtypes. Among these subtypes, metabolic OA is distinguished from other subtypes by the presence of obesity or metabolic syndrome, low-grade systemic inflammation, earlier onset and a faster progression.[6] the concept of the disease as a 'wear-and-tear disease', which is traditionally accepted for the pathophysiology of OA, does not seem to account for the cartilage destruction in metabolic OA. Recent studies led to the discovery of pro-inflammatory cytokines and adipokines produced by the adipose tissue as central contributors to metabolic OA of the hand and potentially other locations.[7]
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