Endogenous retrovirus in joint aging and osteoarthritis development

项目摘要/摘要 骨关节炎(OA)是一种关节退行性疾病，在美国60岁以上的人中有超过16%的人受到影响。 年龄和损伤是骨性关节炎的主要危险因素。迫切需要开发治疗骨性关节炎的方法 治疗，因为目前的治疗选择主要依赖于疼痛管理和关节置换，而骨性关节炎是 只会在我们老龄化的人口中变得越来越普遍。长期暴露在细胞应激源下 破坏关节软骨细胞的内稳态，关节软骨细胞是覆盖关节表面的主要细胞类型， 导致AC衰老、细胞凋亡，关节表面光滑变性。我们知道 染色质结构的核变化影响许多组织的生物年龄，并有助于 衰老表型的表现，并想要调查这是否也适用于骨性关节炎。我们的预赛 数据表明，在骨性关节炎的急性冠脉综合征中，染色质结构被破坏，这可能是导致骨性关节炎的一个因素 疾病的发展。 这项建议的总体目标是剖析衰老和应激源如何影响的机制(S 染色质结构破坏AC动态平衡，最终导致骨性关节炎。我们的初步发现表明 转座元件(TES)的异常激活优先发生在骨关节炎组织中。我们假设 随着年龄的增长，细胞应激逐渐积累，从而损害急性冠脉综合征患者的沉默，从而引发炎症和 最终，OA型的。我们将检验我们的假设：通过确定染色质可及性和TE激活 在急性冠脉综合征中，随着年龄和骨关节炎的存在而增加； 通过评估压力是否会导致TE激活和骨关节炎，来促进骨性关节炎的进展。 影响：这个项目将从机械上理解衰老、压力状况、 ERV的激活与骨性关节炎的发病机制。重要的是，这项提议有可能影响联合健康和 我们老龄化人口的流动性。

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.