Mechanotransduction in Meniscus Health and Repair

摘要。 半月板损伤是一个重大的临床问题，每年有850，000例半月板手术在美国进行 美国，几乎是世界的两倍。半月板无血管内带撕裂 不能很好地愈合与创伤或保守治疗，并最终导致骨关节炎的发展 （OA）。因此，需要新的策略来增强内源性半月板修复和组织再生。 踝关节在膝关节中起着关键的生物力学作用，提供负荷支撑、关节稳定性和一致性。 半月板组织通过半月板细胞的合成代谢和分解代谢活动的平衡来维持。这些 细胞活动不仅受关节中的生化因素控制， 联合加载。机械生物学，即机械因素对细胞生物反应的影响， 在将物理信号转化为半月板中的代谢和炎症反应中是重要的。然而，在这方面， 机械信号在半月板细胞中的转导机制还有待于确定。我们 总体目标是确定关键的半月板机械传导通路，并调节这些通路。 促进半月板修复和预防OA发展的途径。 我们的工作表明，瞬时受体电位香草酸4（TRPV 4）是软骨中的关键成分 机械传导和代谢。TRPV 4的激活可以阻断IL-1诱导的分解代谢反应， 还增加细胞迁移和增殖，这是增强组织修复的重要过程。而 我们已经发现TRPV 4在半月板中表达，该介导物在半月板健康中的功能， 疾病目前尚不清楚。在这个建议中，我们将确定机械转导如何通过 TRPV 4在半月板中的表达，并鉴定该途径的调节剂，其将用于增强组织修复和预防 OA开发。我们推测TRPV 4的机械转导在半月板代谢中起关键作用 并且可以被调节以增强半月板修复和预防OA的发展。在本提案中，我们将 确定机械刺激对健康半月板细胞中TRPV 4介导的代谢的影响。 接下来，我们将阐明半月板病理中TRPV 4介导的机械转导途径的改变。 最后，我们将通过调节半月板的功能来加强半月板的整体修复，预防OA的发展。 机械传导途径在这个建议中，我们将确定下游的关键信号通路， TRPV 4可作为新的药物靶点，用于1）治疗关节固定的患者以模拟运动 并维持关节健康; 2）使用组织工程策略增强半月板组织再生;以及3） 促进半月板修复，预防OA的发展。本研究中确定的新治疗靶点 建议随后可以开发成药物，以加强半月板修复和防止发展 的OA。

ABSTRACT. Meniscal injuries are a significant clinical problem as each year 850,000 meniscal surgeries are performed in the United States and nearly twice as many worldwide. Meniscal tears in the avascular inner zone of the tissue do not heal well with suturing or conservative treatments and can ultimately lead to the development of osteoarthritis (OA). Therefore, new strategies are needed to enhance endogenous meniscus repair and tissue regeneration. The menisci play a critical biomechanical role in the knee, providing load support, joint stability, and congruity. Meniscus tissue is maintained through a balance of anabolic and catabolic activities of meniscus cells. These cellular activities are controlled not only by biochemical factors in the joint but also by physical factors associated with joint loading. Mechanobiology, which is the influence of mechanical factors on the biologic response of cells, is important in converting physical signals into metabolic and inflammatory responses in meniscus. However, the mechanisms by which mechanical signals are transduced in meniscus cells have yet to be identified. Our overall goal is to identify critical meniscus mechanotransduction pathways and modulate these pathways to promote meniscus repair and prevent OA development. Our work has shown that transient receptor potential vanilloid 4 (TRPV4) is a critical component in cartilage mechanotransduction and metabolism. The activation of TRPV4 can block IL-1 induced catabolic responses and also increases cell migration and proliferation, which are important processes to enhance tissue repair. While we have found that TRPV4 is expressed in the meniscus, the function of this mediator in meniscus health and disease is currently unknown. In this proposal, we will determine how mechanotransduction occurs through TRPV4 in meniscus and identify modulators of this pathway that will be used to enhance tissue repair and prevent OA development. We hypothesize that mechanotransduction by TRPV4 plays a key role in meniscus metabolism and can be modulated to enhance meniscus repair and prevent the development of OA. In this proposal, we will determine the effects of mechanical stimulation on TRPV4-mediated metabolism in healthy meniscus cells. Next, we will elucidate alterations in TRPV4-mediated mechanotransduction pathways in meniscus pathology. Finally, we will enhance integrative meniscus repair and prevent the development of OA by modulation of mechanotransduction pathways. In this proposal, we will identify the key signaling pathways downstream of TRPV4 that may function as novel drug targets to 1) treat patients with immobilized joints to simulate exercise and maintain joint health; 2) enhance meniscus tissue regeneration using tissue engineering strategies; and 3) enhance meniscus repair and prevent the development of OA. Novel therapeutic targets identified in this proposal can subsequently be developed into drugs to enhance meniscus repair and prevent the development of OA.