Cell Senescence Regulating Osteoarthritis Progression: Sex-dependent Mechanisms

细胞衰老调节骨关节炎进展：性别依赖性机制

基本信息

批准号：
10567551
负责人：
QIAN CHEN
金额：
$ 62.14万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-15 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10567551
关键词：
Address Aging Antiviral Agents Bone remodeling Cartilage Cell Aging Cells Chondrocytes Chronic Clinical Code Complex DNA Transposable Elements Data Degenerative polyarthritis Development Disease Elderly Elements FDA approved Female Fibrosis Genes Goals Health Human Inflammation Injury Interleukin-1 beta Intervention Joints Knee Osteoarthritis Knowledge Lamivudine Length Lesion Medial meniscus structure Medical Mission Molecular Mus Nuclear Nucleosides Outcome Pathway interactions Patients Pattern Pharmaceutical Preparations Phenotype Population Predisposition Prevalence Process Public Health Regulation Repression Research Resistance Retrotransposon Reverse Transcriptase Inhibitors Role Severities Sex Differences Signal Transduction Sterility Stress Testing Translating Traumatic Arthropathy United States National Institutes of Health Woman articular cartilage cartilage degradation clinical practice derepression disability disease disparity drug development early onset effective therapy effectiveness testing innovation joint destruction joint injury male men mesenchymal stromal cell mouse model novel marker novel strategies nucleoside inhibitor precision medicine senescence sex transcriptome sequencing transcriptomics

项目摘要

Osteoarthritis (OA), a leading cause of disability in the elderly (aging OA), is a complex degenerative joint disease involving articular cartilage degradation, chronic inflammation, and bone remodeling. In addition, joint injury can trigger post-traumatic osteoarthritis (PTOA). The prevalence and severity of knee OA are higher in women than men during aging, although female mice are more resistant to OA progression after injury. The scientific challenge is the incomplete understanding of the sex-specific mechanisms regulating OA progression, which hampers the development of disease-modifying osteoarthritis drugs that can target the process. The scientific goal of this project is to determine the molecular mechanisms underlying sex-difference in OA progression. We discovered that retrotransposon Long Interspersed Nuclear Element-1 (LINE-1, or L1), a novel marker of cell senescence, is closely associated with OA lesions in both human and mice. Further, L1 activation mechanism is sex dependent. Activation of stress-inducible miR-365 stimulates L1 and OA progression in female but not in male during aging. Furthermore, senostatics that target cell senescence inhibit OA progression by inhibiting L1, which is repressed in chondrocytes but de-repressed in senescent MSCs in the joint. These data suggest that senescent MSCs can be a key target for effective treatment of OA. The innovative hypothesis is that females are more susceptible to early-onset and progression of OA during aging because stress signals stimulate L1, which leads to MSC senescence, SASP inflammation, and joint degeneration in female. On the other hand, after OA onset is triggered by injury, males are more susceptible to OA progression because of the higher basal levels of L1 and IL-1β in male. If so, intervention of aging-OA progression in female and PTOA progression in male can be achieved by repressing L1 using FDA-approved anti-viral drug nucleoside reverse transcriptase inhibitor (NRTI). This hypothesis will be tested through three aims. First, we will define activation patterns of L1 and cell senescence in OA cartilage lesions of male and female patients. Second, we will determine sex-specific mechanisms regulating OA progression in aging OA and PTOA using the sex-specific OA progression mouse models. Third, we will develop sex-specific intervention for NRTIs to inhibit OA progression. This study has high impact because it uncovers fundamental mechanisms of OA disease disparity between men and women. It is innovative because it represents a new and distinct direction for the field by revealing sex-specific regulation of OA progression through addressing a previously unsuspected role of retrotransposons in these processes. It has significant clinical and translational values. If successful, NRTIs, which are safe and readily available, can be re-purposed for OA treatment in human. It will not only change the concepts that drive the OA research field, but also greatly impact the clinical practice of how we treat OA patients.

骨关节炎 (OA) 是导致老年人残疾（老年 OA）的主要原因，是一种复杂的退行性关节疾病此外，关节损伤可能涉及关节软骨退化、慢性炎症和骨重塑。引发创伤后骨关节炎 (PTOA) 女性膝关节 OA 的患病率和严重程度均高于女性。雄性小鼠在衰老过程中，尽管雌性小鼠在受伤后对 OA 进展具有更强的抵抗力。挑战在于对调节 OA 进展的性别特异性机制的不完全理解，阻碍了针对该过程的缓解疾病骨关节炎药物的开发。该项目的目标是确定 OA 进展中性别差异的分子机制。发现逆转录转座子长散布核元件-1（LINE-1或L1），一种新的细胞标记物衰老与人类和小鼠的 OA 损伤密切相关。此外，L1 激活机制。应激诱导型 miR-365 的激活会刺激女性的 L1 和 OA 进展，但在女性中则不然。此外，针对细胞衰老的衰老抑制剂通过抑制 L1 来抑制 OA 进展。它在软骨细胞中受到抑制，但在关节中的衰老 MSC 中却被解除抑制。这些数据表明，衰老的间充质干细胞可以成为有效治疗骨关节炎的关键靶标，这一创新假设是女性。由于压力信号会刺激 L1，因此在衰老过程中更容易受到 OA 早发和进展的影响，另一方面，这会导致女性 MSC 衰老、SASP 炎症和关节退化。 OA 发病是由损伤引发的，男性由于基础水平较高，更容易发生 OA 进展如果是这样，干预女性的衰老-OA 进展和男性的 PTOA 进展可以。通过使用 FDA 批准的抗病毒药物核苷逆转录酶抑制剂抑制 L1 来实现 (NRTI)。首先，我们将定义 L1 和细胞的激活模式。其次，我们将确定男性和女性患者的 OA 软骨病变的衰老情况。使用性别特异性 OA 进展小鼠调节衰老 OA 和 PTOA 中 OA 进展的机制第三，我们将开发针对 NRTI 的性别特异性干预措施，以抑制 OA 进展。影响，因为它揭示了男性和女性之间 OA 疾病差异的基本机制。创新，因为它通过揭示性别特异性调控，代表了该领域的一个新的、独特的方向通过解决反转录转座子在这些过程中先前未曾怀疑的作用来促进 OA 的进展。如果成功，安全且易于获得的 NRTI 具有重要的临床和转化价值。重新用于人类 OA 治疗，它不仅会改变推动 OA 研究领域的概念，但也极大地影响了我们治疗 OA 患者的临床实践。