Role of Desumoylase SENP6 in Joint Aging and Osteoarthritis Development

去糖化酶 SENP6 在关节衰老和骨关节炎发展中的作用

基本信息

批准号：
10609825
负责人：
Tao Yang
金额：
$ 49.85万
依托单位：
VAN ANDEL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10609825
关键词：
Acceleration Adult Affect Age Aging Biology Cartilage Cell Aging Cellular Stress Chondrocytes Chronic DNA Damage Data Degenerative polyarthritis Development Disease Endogenous Retroviruses Environment Enzymes Epigenetic Process Exhibits Future Gene Expression Gene Expression Regulation Genotoxic Stress Goals Health Homeostasis Inflammation Inflammatory Joints Knowledge Laboratories Mediating Mission Modification Mus Pathogenesis Pathway interactions Peptide Hydrolases Phenotype Predisposition Prevention Process Production Property Proteins Publishing Reporting Role Signal Transduction Site Source Stress Sumoylation Pathway Testing Tissues Translating Traumatic Arthropathy Ubiquitination United States National Institutes of Health Variant Work age related biological adaptation to stress cytokine disability epigenetic regulation epigenome genome wide association study joint injury mouse genetics mouse model novel osteoprogenitor cell palliative premature prevent response senescence skeletal stressor transcriptome treatment strategy ubiquitin-protein ligase

项目摘要

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.

项目概要几十年来，人们已经知道关节中的炎症和分解代谢环境会加速骨的形成。然而，目前抑制这种环境的 OA 疗法并不能治愈。他们没有针对这种环境的根本原因。最近的研究表明，衰老的关节。去年有报道称，软骨细胞（AC）是炎症和分解代谢因子的主要来源。消除衰老的 AC 可以缓解小鼠年龄相关性和创伤后 OA 的进展。这表明了一种潜在的治疗途径，理想情况下，我们还将确定根本原因（即途径）导致 AC 衰老的因素，并首先针对那些因素来预防或减缓衰老的转变。我们的长期目标是研究导致 AC 衰老的机制，以便制定策略。为此，来自全基因组关联研究（arcO-）的数据。 GEN Consortium，2012）表明 OA 与 SENP6 存在很强的相关性，SENP6 是一种酶（去糖化酶）我们发现这很有趣，因为苏酰化是逆转特定蛋白质靶标的相扑修饰。与应激反应和衰老过程相关的酶途径我的实验室已经报告了 SENP6 通路、细胞衰老和细胞衰老之间的相关性。此外，我们还发现，这部分是通过过度素化而发生的。 TRIM28，一种与衰老相关的表观遗传调节因子。此外，我们的初步工作发现：软骨中 SENP6 的缺失加速了小鼠 AC 衰老和 OA，这为进一步研究提供了理论依据。 SENP6 的作用假设是 SENP6 通过抑制 AC 信号来降低 OA 易感性。为了检验这一假设，我们的首要目标是阻止- 挖掘 SENP6 作为可能的治疗目标的未来可行性，我们将研究增益的程度；其次，SENP6 功能的发挥可减少 OA 的进展，因为我们的初步工作表明存在相互作用。在 SENP6 稳定性和应激反应之间，第二个目标是确定应激如何诱导 SENP6 降解我们的第三个目标是识别 SENP6-orches-。受表观遗传改变这一事实的启发，我们对表观遗传改变及其在 AC 衰老中的作用进行了研究。化是衰老的标志，我们和其他人的研究结果表明 SENP6–TRIM28 的潜在作用预计这项工作将在基因表达和炎症的表观遗传调控中发挥作用。通过揭示一种将苏素化途径与压力联系起来的新机制，将产生广泛的影响反应、表观遗传改变、衰老、关节老化和 OA。这些结果将构成发育的基础。通过选择性调节苏酰化相关路径来抑制 AC 衰老，从而开发新的 OA 治疗方法方式，例如通过增加 SENP6 水平或活性。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Enzymatic Machinery of Ubiquitin and Ubiquitin-Like Modification Systems in Chondrocyte Homeostasis and Osteoarthritis.

软骨细胞稳态和骨关节炎中泛素和泛素样修饰系统的酶机制。

DOI：
发表时间：
2021
期刊：
影响因子：
5
作者：
Liu, Ye;Molchanov, Vladimir;Yang, Tao
通讯作者：
Yang, Tao

SUMOylation in Skeletal Development, Homeostasis, and Disease.

骨骼发育、稳态和疾病中的 SUMOylation。

DOI：
发表时间：
2022-08-31
期刊：
影响因子：
6
作者：
Liu, Huadie;Craig, Sonya E L;Molchanov, Vladimir;Floramo, Joseph S;Zhao, Yaguang;Yang, Tao
通讯作者：
Yang, Tao

LRP1 Suppresses Bone Resorption in Mice by Inhibiting the RANKL-Stimulated NF-κB and p38 Pathways During Osteoclastogenesis.

LRP1 通过抑制破骨细胞生成过程中 RANKL 刺激的 NF-κB 和 p38 通路来抑制小鼠骨吸收。

DOI：
发表时间：
2018-10
期刊：
影响因子：
0
作者：
Lu, Di;Li, Jianshuang;Liu, Huadie;Foxa, Gabrielle E;Weaver, Kevin;Li, Jie;Williams, Bart O;Yang, Tao
通讯作者：
Yang, Tao

Ginkgolic Acids Impair Mitochondrial Function by Decreasing Mitochondrial Biogenesis and Promoting FUNDC1-Dependent Mitophagy.

银杏酸通过减少线粒体生物发生和促进 FUNDC1 依赖性线粒体自噬来损害线粒体功能。

DOI：
发表时间：
2019-09-11
期刊：
影响因子：
6.1
作者：
Wang, Wenjun;Wang, Miaomiao;Ruan, Yu;Tan, Junyang;Wang, Hao;Yang, Tao;Li, Jianshuang;Zhou, Qinghua
通讯作者：
Zhou, Qinghua

The histone demethylase KDM5C controls female bone mass by promoting energy metabolism in osteoclasts.

组蛋白去甲基化酶 KDM5C 通过促进破骨细胞的能量代谢来控制女性骨量。