Obesity is among the most significant and preventable risk factors for developing osteoarthritis (OA). Efforts to identify the causes of this risk have traditionally focused on obesity-induced triggers of joint stress, such as mechanical and inflammatory factors. However, there is a fundamental gap in our understanding about how obesity impairs chondrocyte cellular defense mechanisms resulting in inappropriate or insufficient responses to joint stresses. The applicant's long-term goal is to develop strategies t either up-regulate chondroprotective pathways or down-regulate cell catabolic pathways that become dysregulated with obesity and aging. The objective here is to determine how obesity increases the acetylation of mitochondrial proteins that ultimately regulate cartilage catabolism under aging and inflammatory conditions. This focus is derived from the applicant's exciting preliminary data linking an age-related decline in the regulation of mitochondrial protein acetylation by the mitochondrial deacetylase SIRT3 to impaired antioxidant defense and OA. The central hypothesis is that obesity exacerbates an age-related increase in chronic mitochondrial hyper-acetylation resulting in chondrocyte redox stress and cartilage catabolism. It is proposed that this imbalance is driven by an aging-dependent decline in SIRT3 expression coupled with an obesity-driven increase in acetyl-CoA production and inflammation. Preliminary data show that the mitochondrial antioxidant, SOD2, is a key target of hyper-acetylation in chondrocytes. Guided by these and additional preliminary data, the hypothesis will be tested by three specific aims: 1) Determine how obesity induces metabolic changes that promote mitochondrial protein acetylation; 2) Determine the aging and obesity-dependent effects of manipulating SIRT3 expression, positively or negatively, on chondrocyte redox homeostasis and cartilage catabolism; and 3) Identify the mechanisms by which SIRT3 regulates mitochondrial redox homeostasis and activation of cartilage catabolic pathways following a pro-inflammatory challenge. Well-established mouse models of diet-induced obesity and OA will be used in combination with genetically modified mice that allow for the conditional deletion or over- expression of SIRT3 in cartilage. Targeted genomic, proteomic, and metabolite detection methods are in place for aims 1 and 2 to determine the factors that promote mitochondrial acetylation, alter antioxidant capacity, and induce OA.
Aim 3 will use ex vivo interleukin-1 stimulation assays to identify SIRT3-sensitive cartilage catabolic pathways. Mice with cartilage-specific deletion of SOD2 will provide a reference for evaluating the effect of SOD2 hyper-acetylation on chondrocyte oxidative stress and activation of downstream catabolic pathways. This approach is innovative because it shifts the focus of obesity research on OA from cellular stress triggers to stress susceptibility. The proposed research is significant because it will initiate the systematic study of how reversible post-translational lysine acetylation of mitochondrial proteins may be manipulated, either positively or negatively, to promote chondroprotection with aging and obesity.
The proposed research is relevant to public health because understanding how obesity impairs chondrocyte stress defense mechanisms under aging and inflammatory conditions is expected to lead to new disease-modifying drugs for preventing osteoarthritis. The project is relevant to NIH's mission because it develops fundamental knowledge about the causes and potential therapies for reducing the burdens of human disability associated with trauma and aging.
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