Osteoarthritis (OA) is a painful and debilitating disease of the synovial joints, affecting an estimated 21million people in the United States. There is increasing evidence that local and systemic inflammatorycytokines such as interleukin 1 (IL-1) and inflammatory mediators such as free fatty acids, nitric oxide, orprostaglandins play a major role in OA pathogenesis and pain. Additionally, biomechanical loading plays animportant role in the normal homeostatic maintenance of the cartilage extracellular matrix, and underabnormal conditions, mechanical stress may be a significant factor in the initiation and progression of OA.Our governing hypothesis is that obesity causes OA through synergistic interactions of dietary and systemicpro-inflammatory mediators, cytokines, and mechanical stress acting on the chondrocytes. The goal of thisproject is to examine the influence of dietary fatty acids on obesity-associated OA in mice, and to examinetheir interaction with altered biomechanical and pro-inflammatory cytokines using various in vivo and in vitromodels. We propose that low-grade chronic systemic inflammation due to obesity or pro-inflammatoryfatty acids in the diet acts in synergy with local inflammatory cytokines or altered mechanical loading (dueto obesity or joint instability) to promote a state of inflammation and matrix degradation in the articularcartilage. We will pursue the following aims:
In Aim 1, we will examine the role of a high-fat (lard-based) dietin the development of OA in a leptin-receptor deficient mouse (db/db), and we will also measureosteoarthritic changes in diet-induced obese mice fed high-fat diets high in saturated and monounsaturatedfatty acids, or omega-3 or omega-6 poly-unsaturated fatty acids.
In Aim 2, we will examine the effects ofobesity (via high-fat diet or leptin deficiency) on the progression of OA in a destabilized medial meniscusmodel of mouse OA.
In Aim 3, we will use controlled in vitro models of cartilage explant loading to examinethe effects of mechanical stress in combination with pro-inflammatory cytokines (e.g., IL-1, leptin, TNF-a)and fatty acids on the anabolic and catabolic activities of the chondrocytes, as measured by biomarkerproduction, real-time PCR measurements of mRNA transcription, and protein synthesis of collagen II andaggrecan. Detailed studies of the interactions between specific biomechanical factors, pro-inflammatorymediators, and tissue metabolism in articular cartilage will improve our understanding of the pathology of theOA, particularly as it relates in vivo to 'biomechanical' factors such as obesity, injury, or weight loss. Theresults of this study will provide new insights into key elements of the pathogenesis of OA, and ultimatelycould lead to new treatments that exploit mechanical, psychosocial, and biochemical therapies to preventdisease.
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