Palmitate Has Proapoptotic and Proinflammatory Effects on Articular Cartilage and Synergizes With Interleukin‐1

Abstract

Objectives Obesity is a major risk factor for the development of osteoarthritis (OA) that is associated with a state of low-grade inflammation, and increased circulating adipokines and free fatty acids (FFA). The aim of this study was to analyze effects of saturated (palmitate) and monounsaturated (oleate) free fatty acids (FFA) on articular chondrocytes and cartilage. Methods Human articular chondrocytes and fibroblast-like synoviocytes obtained from young healthy donors, and OA chondrocytes from patients undergoing total knee replacement were treated with palmitate or oleate alone or with interleukin 1-β (IL-1β). Cell viability, caspase activation, and gene expression of proinflammatory factors, extracellular matrix proteins, and extracellular proteases were studied. In addition, chondrocyte viability, interleukin-6 (IL-6) production and matrix damage were assessed in bovine and human articular cartilage explants cultured with FFA with or without IL-1β. Results Palmitate, but not oleate, induced caspase activation and cell death in IL-1β-stimulated normal chondrocytes, and upregulated il6 and cox2 expression in chondrocytes and fibroblast-like synoviocytes through toll-like receptor-4 signaling. In cartilage explants, palmitate induced chondrocyte death, IL-6 release and extracellular matrix degradation. Palmitate synergized with IL-1β in stimulating proapoptotic and proinflammatory cellular responses. Pharmacological inhibition of caspases or TLR-4 signaling reduced palmitate and IL-1β-induced cartilage damage. Conclusions Palmitate acts as a pro-inflammatory and catabolic factor that, in synergy with IL-1β, induces chondrocyte apoptosis and articular cartilage breakdown. Collectively, our data suggest that elevated levels of saturated FFA often found in obesity may contribute to OA pathogenesis.

Characterization of diabetic osteoarthritic cartilage and role of high glucose environment on chondrocyte activation: toward pathophysiological delineation of diabetes mellitus-related osteoarthritis

“…Indeed, type 2 DM is characterized by hyperglycemia, hyperinsulinemia with insulin resistance and free fatty acids increase 45,46 . Some studies have examined the role of insulin in joint tissues and have shown an anabolic role of this hormone with the induction of the synthesis of type II collagen and proteoglycans by chondrocytes 47e49 .…”

L’arthrose, une maladie métabolique ?

“…Au genou, il est possible que les adipokines secrétées par le tissu graisseux de Hoffa diffusent jusque dans l'articulation de voisinage [25]. À côté des adipokines, on a observé aussi le rôle d'autres facteurs, tels que certains acides gras libres saturés comme le palmitate qui ont in vitro un effet pro-inflammatoire, prodégradatif et pro-apoptotique sur les chondrocytes [26].…”

Effects of Dietary Saturated Fatty Acids on the Onset and Progression of Osteoarthritis in Rat Knee Joints

“…They also play a key role in various chronic diseases such as diabetes and atherosclerosis [118,159]. It has also been recently found that 'palmitic acid exerts proapoptotic and pro-inflammatory' actions in the articular cartilage, acting in conjunction with IL-1β to facilitate chondrocyte death and cartilage destruction [153]. Wu C.L et al compared a low-fat diet and an SFA diet for wound healing properties and concluded that SFA significantly worsened OA [121].…”

“…In obesity-related OA, the SFA attract a huge interest due to their increased expression compared to other free fatty acids [153]. Dietary SFA has been known to decrease 'membrane fluidity' in the cells which in turn triggers a cascade of metabolic pathways.…”

“…Obesity-associated dyslipidemia which is caused by increased circulation of triglycerides and FFA such as SFA may contribute to the pathogenesis of OA by inducing inflammation and increasing the production of MMP in the joint tissues [60,224]. In obesity-related OA, the SFA attract a huge interest due to their increased expression compared to other free fatty acids [153]. The role of adipose tissue in both animal models of obesity and obese individuals are of significant interest.…”