Strategies to Enhance Integrative Repair of the Meniscus

描述（由申请方提供）：股骨髁是位于股骨髁和胫骨平台之间的纤维软骨组织。这些结构对于膝关节的正常生物力学功能是必不可少的，包括承重、减震、关节一致性和关节稳定性。除了最初的关节损伤引起的疼痛和残疾外，关节组织的损伤或损失还与关节的退行性变化相关，最终导致骨关节炎（OA）。已在损伤和退行性关节中测量到炎性细胞因子（如白细胞介素-1（IL-1））水平的增加。此外，IL-1已显示上调降解酶，如基质金属蛋白酶（MMP），并且还减少结肠细胞的基质生物合成。IL-1还显示出显著降低神经修复模型系统中界面处的修复强度、细胞积累和组织形成。然而，IL-1抑制视网膜病变修复的机制尚不清楚。本研究的目的是确定IL-1阻止尿道损伤修复的机制，并开发在IL-1存在下促进尿道撕裂愈合的策略。这些研究将使用一种新的半月板综合修复体外模型，该模型由两个同心半月板外植体组成，在体外培养数周后自然表现出修复。将确定IL-1对细胞增殖、细胞迁移、胶原和蛋白聚糖合成、MMP活性以及胶原和蛋白聚糖降解的影响。在IL-1的存在下，合成代谢因子和MMPs抑制剂将用于鉴定和阻断阻止半月板整合修复的IL-1活性机制。还将评估在存在或不存在IL-1的情况下，不同大小的机械应力对尿道撕裂修复的影响。本研究的广泛、长期目标是确定IL-1活性的下游靶点，这些靶点可以通过免疫和/或机械方式靶向，从而最终在临床上可用于促进损伤后和关节炎患者的关节愈合。这一建议与公共卫生有关，因为结果将对关节损伤或关节炎患者半月板损伤的新型药理学和物理治疗产生影响。确定的潜在药物和机械治疗方法最终可以在临床上转化为未来的半月板修复治疗方法。

DESCRIPTION (provided by applicant): The menisci are fibrocartilaginous tissues situated between the femoral condyles and the tibial plateau. These structures are essential for normal biomechanical function of the knee, including load bearing, shock absorption, joint congruity, and joint stability. In addition to the pain and disability with the initial meniscal injury, damage or loss of meniscal tissue is associated with degenerative changes in the joint that ultimately lead to osteoarthritis (OA). Increased levels of the inflammatory cytokines, such as interleukin-1 (IL-1), have been measured in injured and degenerative joints. In addition, IL-1 has been shown to upregulate degradatiye enzymes, such as matrix metalloproteinases (MMPs), and also decrease matrix biosynthesis by meniscal cells. IL-1 has also been shown to significantly decrease repair strength, cell accumulation, and tissue formation at the interface in a meniscal repair model system. However, the mechanism(s) by which IL-1 inhibits repair of meniscal lesions is not yet known. The goals of this study are to identify the mechanism(s) by which IL-1 prevents the repair of meniscal lesions and to develop strategies to enhance the healing of meniscal tears in presence of IL-1. A novel in vitro model of integrative repair of the meniscus that consists of two concentric meniscus explants that naturally exhibit repair over several weeks of culture in vitro will be utilized for these studies. The effects of IL-1 on cell proliferation, cell migration, collagen and proteoglycan synthesis, MMP activity, and collagen and proteoglycan degradation will be determined. In the presence of IL-1, anabolic factors and inhibitors of MMPs will be used to identify and block the mechanisms of IL-1 activity that prevent integrative repair of the meniscus. The effects of different magnitudes of mechanical stress on the repair of a meniscal tear in the presence or absence of IL-1 will also be assessed. The broad, long-term objectives of this study are to identify downstream targets of IL-1 activity that could be targeted pharmacologically and/or mechanically and thus could ultimately be useful clinically to promote meniscal healing following injury and in patients with arthritis. This proposal is relevant to public health, as results will have implications with regard to both novel pharmacologic and physical therapy treatments for meniscus injury in patients with a joint injury or arthritis. Potential pharmacologic and mechanical treatments identified could ultimately be translated clinically to future treatments for meniscus repair.