Abstract
ObjectiveThe aim of this study was to determine whether hypercholesterolemia increases articular damage in a rabbit model of chronic arthritis.MethodsHypercholesterolemia was induced in 18 rabbits by administrating a high-fat diet (HFD). Fifteen rabbits were fed normal chow as controls. Chronic antigen-induced arthritis (AIA) was induced in half of the HFD and control rabbits, previously immunized, by intra-articular injections of ovalbumin. After sacrifice, lipid and systemic inflammation markers were analyzed in blood serum. Synovium was analyzed by Krenn score, multinucleated cell counting, immunohistochemistry of RAM11 and CD31, and TNF-α and macrophage chemoattractant protein-1 (MCP-1) gene expression. Active bone resorption was assessed by protein expression of receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG) and quantification of cathepsin K, contact surface and the invasive area of pannus into bone.ResultsRabbits receiving the HFD showed higher total serum cholesterol, HDL, triglycerides and CRP levels than rabbits fed a normal diet. Synovitis score was increased in HFD, and particularly in AIA and AIA + HFD groups. AIA + HFD synovium was characterized by a massive infiltration of RAM11+ cells, higher presence of multinucleated foam cells and bigger vascularization than AIA. Cathepsin K+ osteoclasts and the contact surface of bone resorbing pannus were also increased in rabbits with AIA + HFD compared with AIA alone. Synovial TNF-α and MCP-1 gene expression was increased in AIA and HFD rabbits compared with healthy animals. RANKL protein expression in AIA and AIA + HFD groups was higher compared with either HFD or normal groups.ConclusionsThis experimental model demonstrates that hypercholesterolemia increments joint tissue damage in chronic arthritis, with foam macrophages being key players in this process.
Highlights
The increased burden of cardiovascular disease in rheumatoid arthritis (RA) is only explained partly by traditional cardiovascular risk factors
Metabolic profile Rabbits fed with a hyperlipemic diet showed significant higher levels of total serum cholesterol, high-density lipoprotein (HDL) and triglycerides than healthy rabbits (P = 0.01)
C-reactive protein (CRP) levels Levels of CRP were significantly increased in sera of antigen-induced arthritis (AIA) and AIA + high-fat diet (HFD) groups (73.07 ± 32.58 and 124.2 ± 38.69) in comparison with the healthy group (7.83 ± 1.28, P = 0.011 and P
Summary
The increased burden of cardiovascular disease in rheumatoid arthritis (RA) is only explained partly by traditional cardiovascular risk factors. They seem to have similar prevalence in RA and non-RA patients, suggesting that other factors contribute significantly to this health issue [1,2]. In addition to the production of most of these pro-inflammatory cytokines, there is increasing evidence concerning the contribution of dysregulated adipose tissue through adipokine secretion to systemic RA inflammation [3]. Leptin has been shown to promote phagocytic function and induce production of several pro-inflammatory cytokines in macrophages and monocytes [5]. An increase of leptin and resistin (pro-atherogenic hormones) and the decrease of adiponectin (anti-atherogenic hormone) may alter endothelial homeostasis in RA patients [7]
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