Obesity is one of the major risk factors for OA development, but the mechanisms involved are not clearly understood. Accumulating evidence suggests that in addition to mechanical factors, metabolic factors associated with obesity also play a role in onset of OA. Obesity is associated with increased accumulation of free fatty acids (FFA) in non-adipose tissue, resulting in endoplasmic reticulum (ER) stress and cellular dysfunction. The chondrocyte is the sole cellular constituent of cartilage and is pre-disposed to ER stress due to its secretory phenotype, which may compound obesity-related lipid toxicity. Our preliminary studies showed that human chondrocytes treated with FFA (palmitate) express CHOP/GADD153, a molecular marker of ER stress. This suggests that FFA induces ER stress in chondrocytes. The overall goal of this proposal is to determine the role of obesity-induced ER stress in the pathophysiology of OA in vivo, in a murine model of OA using a novel pharmacologic compound, 4-phenylbutyric acid (PBA) that eases ER stress. These data will form the basis for future investigations of the links between obesity, ER stress, and OA. We propose two Specific Aims: Aim 1: To determine if a high-fat diet induces ER stress and the unfolded protein response in joint tissue in vivo. Aim 2: To determine if alleviating ER stress reduces the severity of OA induced by a high-fat diet in mice. The successful completion of our project will establish the role of ER stress as a mechanistic link between a high-fat diet, obesity and OA, and provide targets for improved therapeutic treatments for OA or interventions to halt its progression.