Endogenous retrovirus in joint aging and osteoarthritis development

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Project Summary/Abstract Osteoarthritis (OA) is a degenerative disease of the joints, that affects over 16% of people over 60 in the US. Age and injury are the primary risk factors for OA. There is a critical need to develop therapies for OA treatment, as current treatment options rely primarily on pain management and joint replacement, while OA is only becoming increasingly prevalent in our aging population. Chronic exposure to cellular stressors profoundly disrupts the homeostasis of articular chondrocytes (ACs), the primary cell type covering the surface of the joint, leading to AC senescence, apoptosis, and degeneration of the smooth surface of the joint. We know that nuclear changes to chromatin structure impacts the biological age of many tissues and contributes to the manifestation of aging phenotypes and wanted to investigate whether this is also true in OA. Our preliminary data suggests that chromatin structure is disrupted in ACs in OA and may be a contributing factor to OA disease progression. The overall objective of this proposal is to dissect the mechanism(s) of how aging and stressors influence chromatin structure to disrupt AC homeostasis to ultimately give rise to OA. Our preliminary findings suggest that abnormal activation of transposable elements (TEs) occurs preferentially in OA tissue. We hypothesize that cellular stresses accumulate with age to impair TE silencing in ACs, thereby triggering inflammation and eventually, OA. We will test our hypothesis: by determining if chromatin accessibility and TE activation increase with age and presence of osteoarthritis in ACs; by determining if TE activation in OA models can augment OA progression; and by evaluating if stress causes TE activation and osteoarthritis. Impact: This project will yield a mechanistic understanding of the connection between aging, stress conditions, ERV activation, and OA pathogenesis. Importantly, this proposal has the potential to impact joint health and mobility of our aging population.