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

• 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
• 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

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.

项目摘要 几十年来，人们已经知道，关节中的炎症和分解代谢环境加速了骨质疏松， 骨性关节炎（OA）的发展。然而，目前抑制这种环境的OA疗法是不能治愈的， 它们没有针对造成这种环境的根本原因。最近的研究表明， 软骨细胞（AC）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AC可以减轻小鼠中与年龄相关的和创伤后OA的进展。而 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，并针对那些首先阻止或减缓向衰老过渡的人。 我们的长期目标是研究导致AC衰老的机制，以便制定策略。 用于预防和/或治疗OA。为此，来自全基因组关联研究（阿科- GEN Consortium，2012）显示OA与SENP 6的强关联，SENP 6是一种酶（去糖基化酶）， 逆转特定蛋白质靶点上的SUMO修饰。我们发现这很有趣，因为类泛素化是 一种与应激反应和衰老过程相关的酶途径， 潜在的药物。我的实验室已经报道了SENP 6通路、细胞衰老和 骨骼祖细胞应激反应。此外，我们发现，这部分是通过过度sumoylation TRIM 28，一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， SENP 6在软骨中的缺失加速了小鼠的AC衰老和OA，为进一步的研究提供了理论基础。 SENP 6的作用。假设SENP 6通过抑制AC敏感性降低OA易感性。 由应激反应和表观遗传改变引起的衰老。为了验证这个假设，我们的第一个目标是阻止- 挖掘SENP 6作为治疗可能靶点的未来可行性;我们将研究在多大程度上获得 SENP 6功能降低OA进展。接下来，因为我们的初步研究表明- 在SENP 6稳定性和应激反应之间，第二个目标是确定应激如何诱导SENP 6降解。 以及潜在机制如何影响AC衰老。我们的第三个目标是识别SENP 6-orches- 晚期表观遗传改变及其在AC衰老中的作用。这是受到表观遗传改变的事实的启发- 细胞周期是衰老的标志，我们和其他人的研究结果表明SENP 6-TRIM 28的潜在作用。 轴在基因表达和炎症的表观遗传调节中的作用。预计这项拟议的工作 将通过揭示一种新的机制，将SUMO化途径与压力联系起来， 反应、表观遗传改变、衰老、关节老化和OA。这些成果将成为发展的基础- 通过选择性调节sumoylation相关通路抑制AC衰老来开发新的OA治疗方法， 方式，例如，通过增加SENP 6水平或活性。

项目成果

An Integrated View of Stressors as Causative Agents in OA Pathogenesis.

应力源作为OA发病机理中的致病剂的综合视图。

• DOI: 10.3390/biom13050721
• 发表时间: 2023-04-22
• 期刊: Biomolecules
• 影响因子: 5.5

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。

• DOI: 10.1101/2023.02.23.529728
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Liu,Huadie;Zhai,Lukai;Liu,Ye;Lu,Di;VanderArk,Alexandra;Yang,Tao;Krawczyk,ConnieM
• 通讯作者: Krawczyk,ConnieM

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

• DOI: 10.1007/s11926-021-01022-w
• 发表时间: 2021-07-03
• 期刊: Current rheumatology reports
• 影响因子: 5
• 作者: Liu Y;Molchanov V;Yang T
• 通讯作者: Yang T

SUMOylation in Skeletal Development, Homeostasis, and Disease.

• DOI: 10.3390/cells11172710
• 发表时间: 2022-08-31
• 期刊: Cells
• 影响因子: 6