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.

骨关节炎是导致老年人残疾的主要原因之一，是一种复杂的退行性关节疾病 涉及关节软骨退化、慢性炎症和骨重建。此外，关节损伤可能 引发创伤后骨关节炎(PTOA)。女性膝关节骨性关节炎的患病率和严重程度高于 雄性小鼠在衰老过程中，尽管雌性小鼠在损伤后对OA进展更具抵抗力。科学的 挑战是对调节骨性关节炎进展的特定性别机制的不完全理解，这 阻碍了可以针对这一过程的疾病修改骨性关节炎药物的开发。科学的 该项目的目标是确定在骨性关节炎进展过程中存在性别差异的分子机制。我们 发现反转录转座子长穿插核元件-1(LINE-1，或L1)，这是一种新的细胞标记 衰老与人类和小鼠的骨性关节炎病变密切相关。此外，L1激活机制 是性依赖的。应激诱导的miR-365激活可刺激女性L1和OA进展，但不能 男性在衰老过程中。此外，靶细胞衰老的抗衰老药物通过抑制L1来抑制OA的进展， 它在软骨细胞中被抑制，但在关节中衰老的MSCs中被解除抑制。这些数据表明 衰老的骨髓间充质干细胞可以成为有效治疗骨性关节炎的关键靶点。创新的假设是女性 在衰老过程中更容易发生早发性和进行性骨性关节炎，因为应激信号刺激L1， 这会导致女性MSC衰老、SASP炎症和关节退变。另一方面，在 骨性关节炎的发病是由损伤引发的，男性由于基础水平较高而更容易发生骨性关节炎的进展 男性L1和IL-1β的表达。如果是这样的话，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实现 (NRTI)。这一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 男性和女性患者骨性关节炎软骨病变的衰老。第二，我们将确定具体的性别 利用性别特异性的骨性关节炎进展小鼠调节老年性骨性关节炎和PTOA的骨性关节炎进展的机制 模特们。第三，我们将为NRTI开发针对性别的干预措施，以抑制OA的进展。这项研究具有很高的 影响，因为它揭示了男女之间骨性关节炎疾病差异的基本机制。它是 创新，因为它代表了该领域的一个新的和独特的方向，揭示了针对性别的监管 通过解决反转录转座子在这些过程中以前未被怀疑的作用来实现OA的进展。它 具有重要的临床和翻译价值。如果成功，安全和容易获得的非传染性药物可以 被重新用于治疗人类的骨性关节炎。它不仅将改变推动办公自动化研究领域的概念， 而且也极大地影响了我们临床治疗骨性关节炎患者的方式。