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

• 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
• 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

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）是老年人（老化OA）的主要原因，是一种复杂性的关节疾病 涉及关节软骨降解，慢性感染和骨骼重塑。另外，关节损伤可以 触发创伤后骨关节炎（PTOA）。膝盖OA的患病率和严重程度高于 在衰老中的男性，尽管雌性小鼠受伤后对OA的进展更具耐药性。科学 挑战是对调节OA进展的性别特定机制的不完全理解，这 阻碍了可以针对该过程的疾病改良骨关节炎药物的发展。科学 该项目的目标是确定OA进展中性别差异的分子机制。我们 发现逆转座子长长散布核元素1（LINE-1或L1），这是细胞的新标记 衰老与人和小鼠的OA病变密切相关。此外，L1激活机制 是性依赖的。应力诱导miR-365的激活刺激女性的L1和OA进展 衰老期间的男性。此外，通过抑制L1，靶向细胞感应靶向细胞感应的鼻刺激学抑制OA的进展 它反映在软骨细胞中，但在关节中的感觉MSC中取消了替代。这些数据表明 感觉MSC可以是有效治疗OA的关键目标。创新的假设是女性 在衰老过程中更容易受到早期发作和OA的进展，因为压力信号刺激L1， 导致女性的MSC感应，SASP炎症和关节变性。另一方面，之后 OA发作是由受伤触发的，雄性更容易受到OA的进展，因为较高的基本水平 男性的L1和IL-1β。如果是这样，雌性衰老-OA进展的干预和男性PTOA进展的干预措施可以 可以通过使用FDA批准的抗病毒药物核苷逆转录酶抑制剂来反映L1来实现 （NRTI）。该假设将通过三个目标进行检验。首先，我们将定义L1和细胞的激活模式 男性和女性患者的OA软骨病变中的感受。第二，我们将确定特定于性别的 使用性别特定的OA进展小鼠在老化OA和PTOA中调节OA进展的机制 型号。第三，我们将开发针对NRTI的性别干预措施，以抑制OA的进展。这项研究很高 影响是因为它发现了男性和女性之间OA疾病差异的基本机制。这是 创新性是因为它通过揭示特定于性别的调节来代表该领域的新方向 OA通过在这些过程中解决了逆转录座子的先前未经刺激的作用。它 具有明显的临床和翻译值。如果成功的话，安全且容易获得的NRTI可以 在人类的OA治疗中重新使用。它不仅会改变驱动OA研究领域的概念，还会改变 但也极大地影响了我们如何治疗OA患者的临床实践。