Endogenous retrovirus in joint aging and osteoarthritis development

项目总结/摘要 骨关节炎（OA）是一种关节退行性疾病，在美国，超过16%的60岁以上的人受到影响。 年龄和损伤是OA的主要危险因素。迫切需要开发OA的治疗方法 治疗，因为目前的治疗方案主要依赖于疼痛管理和关节置换，而OA是 只会在老龄化人口中变得越来越普遍。长期暴露于细胞应激源， 破坏关节软骨细胞（AC）的体内平衡，AC是覆盖关节表面的主要细胞类型， 导致AC衰老、细胞凋亡和关节光滑表面的退化。我们知道 染色质结构的核变化影响许多组织的生物学年龄， 因此，研究人员发现了衰老表型的表现，并希望研究这是否也适用于OA。我们的初步 数据表明，OA中AC的染色质结构被破坏，可能是OA的一个促成因素 疾病进展。 本提案的总体目标是剖析衰老和压力源如何影响 染色质结构破坏AC稳态，最终引起OA。我们的初步发现表明 转座因子（TE）的异常激活优先发生在OA组织中。我们假设 细胞应激随着年龄的增长而积累，从而损害AC中的TE沉默，从而引发炎症， 最后，OA。我们将测试我们的假设：通过确定染色质可及性和TE激活 随着年龄的增长和AC中骨关节炎的存在而增加;通过确定OA模型中的TE激活是否可以 增加OA进展;以及评估压力是否会导致TE激活和骨关节炎。 影响：该项目将产生对老化，应力条件， ERV激活和OA发病机制。重要的是，这项建议有可能影响关节健康， 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.