Engineering cartilage mechanotransduction for treatment of chondrocyte injury

工程化软骨力学信号转导治疗软骨细胞损伤 摘要 骨关节炎（OA）是一种疼痛和使人衰弱的滑膜关节疾病，影响约12%的 美国25-74岁的总人口。这种疾病的发病率随着 年龄，在超过70%的65岁以上人口中观察到放射学证据。OA研究是 重要的是，考虑到这种疾病的广泛影响和公共卫生后果。的病因 OA尚未完全了解，并且不存在疾病修饰疗法。OA的显著特征是 关节软骨的形态、组成和力学性能的进行性、退行性变化 软骨，表明软骨细胞代谢活动的正常平衡， 制造和维持所有软骨的组织都被严重破坏了虽然它们之间的关系 这种病理学中涉及的生物化学和生物力学事件尚不清楚，现在很明显， 机械因素在导致软骨代谢失衡的一系列事件中起着关键作用 在OA中。 本研究的主要目的是解构原代软骨细胞中的机械敏感信号， 更好地理解具有巨大相关性的基本机制，并提供关键的见解 以促进关节负荷性损伤（包括OA）的更合理治疗。我们做了一个令人兴奋的 在软骨细胞中发现PIEZO机械敏感通道的表达，其在软骨细胞中发挥功能， 对机械负荷的反应。因此，该补助金的具体目的是：（1）研究PIEZO的作用 控制对生理和过度机械负荷的合成代谢和分解代谢反应的通道 使用软骨的器官型制备。(2)在小鼠损伤后关节炎模型中，为了将Piezo 拮抗剂GsMTx 4作为预防软骨细胞介导的关节退行性变的一种手段。 目的1将在猪模型中，并利用蜘蛛毒素GsMTx 4，其阻断压电通道。 目标2将利用我们采用的小鼠创伤后关节炎模型， 步态改变和关节组织学。基于我们令人兴奋的发现，解决这些目标将增加我们的 以非增量方式深入了解OA病理生理学，并直接指导我们研究新的特异性 治疗

Engineering cartilage mechanotransduction for treatment of chondrocyte injury Abstract Osteoarthritis (OA) is a painful and debilitating disease of the synovial joints, affecting an estimated 12% of the total United States population 25-74 years of age. The prevalence of this disease increases significantly with age, with radiographic evidence observed in over 70% of the population over age 65. OA research is important, considering the extensive impact and public health consequences of this disease. The etiology of OA is not fully understood, and there exist no disease-modifying therapies. OA is distinctively characterized by the progressive, degenerative changes in the morphology, composition, and mechanical properties of articular cartilage, indicating that the normal balance of metabolic activities in chondrocytes, the cellular element that makes and maintains all cartilage, has been severely disrupted. While the relationships between the biochemical and biomechanical events involved in this pathology are not yet known, it is now evident that mechanical factors play a critical role in the sequence of events leading to the metabolic imbalance of cartilage in OA. The over-riding objective of this study is to deconstruct mechanosensitive signaling in primary chondrocytes to provide better understanding of a basic mechanism of enormous relevance, and also to provide critical insight to enhance more rational therapies of joint-loading-induced injuries including OA. We have made an exciting discovery of expression of PIEZO mechanosensitive channels in chondrocytes, which appear functional in response to mechanical loading. Thus, the Specific Aims of this grant are: (1) To examine the role of PIEZO channels in controlling the anabolic and catabolic response to physiologic and excessive mechanical loading using an organotypic preparation of cartilage. (2) In a mouse post-injury arthritis model, to apply the Piezo antagonist GsMTx4 to the affected joint as a means of preventing chondrocyte-mediated joint degeneration. Aim 1 will be in a porcine model and take advantage of the spider toxin GsMTx4, which blocks Piezo channels. Aim 2 will take advantage of a post-traumatic arthritis model that we have adopted to mice, with a read-out of gait change and joint histology. Based on our exciting discovery, addressing these Aims will increase our insights into OA pathophysiology in a non-incremental way, and directly guide us towards new specific therapies.