Role of Desumoylase SENP6 in Joint Aging and Osteoarthritis Development

项目总结 几十年来，人们已经知道，关节中的炎症和分解代谢环境会加速骨质疏松。 骨关节炎(OA)的发展。然而，目前抑制这种环境的OA疗法并不能治愈，因为 他们没有针对这种环境的根本原因。最近有研究表明，衰老的关节 软骨细胞是炎症和分解代谢因子的主要来源。去年，据报道， 消除衰老的急性冠脉综合征可以减缓年龄相关性和创伤后骨性关节炎的进展。而当 这表明了一种潜在的治疗途径，理想情况下，我们还可以确定根本原因(即途径) 这会导致AC衰老，并首先针对那些防止或减缓向衰老过渡的人。 我们的长期目标是研究导致交流老化的机制，以便制定策略-- 用于预防和/或治疗骨性关节炎的开放教育。为此，来自全基因组关联研究(Arco- Gen Consortium，2012)显示，OA与SENP6有很强的关联，SENP6是一种酶(Desumoylase) 这逆转了相扑对特定蛋白质靶标的修饰。我们发现这一点很有趣，因为相扑是 一种与应激反应和衰老过程相关的酶途径，并且是 可能会被下药。我的实验室已经报告了SENP6途径、细胞衰老和 骨骼祖细胞的应激反应。此外，我们还表明，这部分是通过过度和甲基化来实现的。 TRIM28，一种与衰老相关的表观遗传调控因子。此外，我们的初步工作发现， 软骨中SENP6的丢失加速了小鼠的AC衰老和骨关节炎，为进一步研究SENP6提供了理论基础。 发挥SENP6的作用。目前的假说是SENP6通过抑制AC SEs来降低骨性关节炎的易感性。 由应激反应和表观遗传变化引起的后果。为了检验这一假设，我们的第一个目标是阻止- 挖掘SENP6作为可能的治疗靶点的未来生存能力；我们将检查获得 SENP6功能的缺失可减少骨性关节炎的进展。下一步，因为我们的初步工作表明相互作用是- 在SENP6稳定性和应激反应之间，第二个目标是确定应激是如何诱导SENP6退化的。 年龄和潜在的机制如何影响交流衰老。我们的第三个目标是确定SENP6-ORECS- 表观遗传学改变及其在AC衰老中的作用。这是受到表观遗传改变-- 衰老是衰老的标志，我们和其他人的发现表明SENP6-TRIM28可能起到作用 AXIS在表观遗传调控中的基因表达和炎症。预计这项拟议的工作 将会产生广泛的影响，因为它揭示了一种新的机制，这种机制将相扑通路与压力联系起来。 反应、表观遗传改变、衰老、关节老化和骨性关节炎。这些结果将成为开发-- 通过选择性调节苏莫化相关途径抑制AC衰老，从而寻找治疗OA的新方法 方法，例如，通过增加SENP6水平或活性。

PROJECT SUMMARY For decades, it has been known that the inflammatory and catabolic environment in the joints accelerates oste- oarthritis (OA) development. However, current OA therapies that inhibit this environment are not curative, as they do not target the underlying cause of such an environment. It was recently shown that senescent articular chondrocytes (ACs) are a major source of inflammatory and catabolic factors. Last year, it was reported that eliminating senescent ACs can alleviate the progression of age-related and post-traumatic OA in mice. While this suggests a potential treatment avenue, ideally, we would also identify the root causes (i.e. the pathways) that lead to AC senescence, and target those to prevent or slow the transition to senescence in the first place. Our long-term goal is to examine the mechanisms that lead to AC senescence, so that strategies can be devel- oped for prevention and/or treatment of OA. To that end, data from a genome-wide association study (arcO- GEN Consortium, 2012) showed a strong association of OA with SENP6, which is an enzyme (desumoylase) that reverses SUMO modifications on specific protein targets. We found this intriguing, because sumoylation is an enzymatic pathway that has been associated with both the stress response and the aging process, and is potentially druggable. My lab has reported the correlations among the SENP6 pathway, cell senescence, and stress response in skeletal progenitors. Also, we showed that this occurs partially via over-sumoylation of TRIM28, an epigenetic regulator associated with senescence. Moreover, our preliminary work found that SENP6 loss in cartilage accelerated AC senescence and OA in mice, providing a rationale for further examin- ing the role of SENP6. The hypothesis is that SENP6 reduces OA susceptibility by suppressing AC senes- cence induced by stress response and epigenetic alterations. To test this hypothesis, our first goal is to deter- mine the future viability of SENP6 as a possible target for treatment; we will examine the extent to which gain of SENP6 function reduces OA progression. Next, because our preliminary work suggested an interplay be- tween SENP6 stability and stress response, the second goal is to determine how stress induces SENP6 degra- dation and how the underlying mechanism affects AC senescence. Our third goal is to identify SENP6-orches- trated epigenetic alterations and their role in AC senescence. This is inspired by the facts that epigenetic alter- ations are a hallmark of aging and that our and other's findings suggest a potential role for the SENP6–TRIM28 axis in the epigenetic regulation of gene expression and inflammation. It is expected that this proposed work will have a broad impact by uncovering a new mechanism that connects the sumoylation pathways to stress response, epigenetic alterations, senescence, joint aging, and OA. These results will form a basis for develop- ing new OA treatments by inhibiting AC senescence through selective modulation of sumoylation-related path- ways, e.g., by increasing SENP6 level or activity.