Abstract
Objective: Several studies have linked metabolic syndrome to the development of osteoarthritis (OA) through hypercholesterolemia, one of its components. However, epidemiological studies showed contradictory results, and it is not clear how hypercholesterolemia itself, or oxidized LDL (oxLDL)—a pathological molecule potentially involved in this relationship—could be affecting OA. The objectives of this study were to investigate the effect of hypercholesterolemia induced by high-fat diet (HFD) in cartilage from OA rabbits, and how oxLDL affect human chondrocyte inflammatory and catabolic responses.Design: New Zealand rabbits were fed with HFD for 18 weeks. On week 6, OA was surgically induced. At the end of the study, cartilage damage and IL-1β, IL-6, MCP-1, MMP-13, and COX-2 expression in articular cartilage were evaluated. In addition, cultured human OA articular chondrocytes were treated with oxLDL at concentrations equivalent to those expected in synovial fluid from HFD rabbits, in the presence of IL-1β and TNFα. The effect of oxLDL on cell viability, nitric oxide production and catabolic and pro-inflammatory gene expression was evaluated.Results: HFD intake did not modify cartilage structure or pro-inflammatory and catabolic gene expression and protein presence, both in healthy and OA animals. OxLDL did not affect human chondrocyte viability, ADAMTS5 and liver X receptor (LXR) α gene expression, but decreased the induction of IL-1β, IL-6, MCP-1, MMP-13, iNOS, and COX-2 gene expression and MMP-13 and COX-2 protein presence, evoked by cytokines.Conclusions: Our data suggest that cholesterol intake per se may not be deleterious for articular cartilage. Instead, cholesterol de novo synthesis and altered cholesterol metabolism could be involved in the associations observed in human disease.
Highlights
Osteoarthritis (OA) is one of the main causes of pain and disability, with high impact on life quality and on national economies [1]
Experimental models of OA allow to analyse the specific effect of dietary cholesterol in the development of the disease, disregarding other factors that are linked to hypercholesterolemia in humans
The surgical induction of OA was successful in all knees of OA animals, with all the studied histological parameters significantly increased compared to non-OA animals (Figure 1)
Summary
Osteoarthritis (OA) is one of the main causes of pain and disability, with high impact on life quality and on national economies [1]. It is a multi-factorial disease, and several risk factors like trauma, aging, gender, obesity and genetic predisposition have been associated with the development and progression of OA. This phenotype arises from the wide association of OA with metabolic syndrome, with higher incidence of this condition in OA patients than in the population without the disease, and a more severe progression of OA in patients with metabolic syndrome [3]. Dysregulated lipid metabolism and cholesterol accumulation have been found in chondrocytes during OA [6, 7], and knockout mice with altered HDL metabolism have higher predisposition to the development of OA [8]
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