Cell Senescence Regulating Osteoarthritis Progression: Sex-dependent Mechanisms

骨关节炎（OA）是一种复杂的退行性关节疾病，是老年人致残的主要原因 包括关节软骨退化、慢性炎症和骨重塑。此外，关节损伤可 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高于男性， 尽管雌性小鼠在受伤后对OA进展的抵抗力更强。科学 挑战是对调节OA进展的性别特异性机制的不完全理解， 阻碍了针对这一过程的改善疾病的骨关节炎药物的开发。科学 本项目的目的是确定OA进展中性别差异的分子机制。我们 发现逆转录转座子长散布核元件-1（LINE-1，或L1），一种新的细胞标志物， 衰老与人和小鼠的OA病变密切相关。此外，L1激活机制 是依赖性的。应激诱导型miR-365的激活刺激女性L1和OA进展，但不刺激女性L1和OA进展。 男性在衰老过程中此外，靶向细胞衰老的衰老抑制剂通过抑制L1， 其在软骨细胞中被抑制，但在关节中衰老的MSC中去抑制。这些数据表明 衰老的MSC可以是有效治疗OA的关键靶标。创新的假设是， 在衰老过程中更容易受到OA的早发和进展的影响，因为压力信号刺激L1， 导致女性MSC衰老、SASP炎症和关节退变。另一方面，在 OA发作由损伤触发，由于基础水平较高，男性更容易发生OA进展 男性L1和IL-1β的表达。如果是这样的话，女性中的老化-OA进展和男性中的PTOA进展的干预可以 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）。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OA软骨病变的衰老。其次，我们将确定性别特异性 使用性别特异性OA进展小鼠在老化OA和PTOA中调节OA进展的机制 模型第三，我们将开发针对NRTI的性别特异性干预措施，以抑制OA进展。这项研究具有高度 影响，因为它揭示了男女之间OA疾病差异的基本机制。是 创新，因为它代表了一个新的和独特的方向，为该领域揭示性别特异性调节， 通过解决逆转录转座子在这些过程中的作用，OA进展。它 具有重要的临床和转化价值。如果成功的话，安全且容易获得的NRTI可以 重新用于人类OA治疗。它不仅将改变驱动OA研究领域的概念， 也极大地影响了我们如何治疗OA患者的临床实践。

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.