Teriparatide as a Therapy for Osteoarthritis Following Meniscal Injury

本项目1建议书是CORT计划修订后的续签申请的一部分，其标题为“翻译 矫形外科创伤护理的分子信号通路“。在之前的资助期间，我们发表了研究结果。 支持不适当的关节软骨细胞(AC)肥大是一种机制的普遍假设 关于骨性关节炎发病机制的研究。鉴于PTH1-34(Teriparatide)是一种肥厚抑制和基质诱导剂 在软骨细胞中的合成，我们最近的几个突破性发现巩固了将其用作 治疗骨关节炎的新疗法。最重要的是我们的惊人发现，Terparatide具有戏剧性的软骨- 创伤性膝骨性关节炎小鼠模型中的再生效应。这在机械上是合理的，因为我们的 已发表的结果表明，Terparatide诱导软骨细胞中的Runx2依赖于细胞周期蛋白DI的降解。自.以来 FORTEO(Teriparatide)已经得到FDA的批准，而且由于参加NIH赞助的OAI的患者 服用Forteo治疗骨质疏松症的患者与匹配的对照组相比，WOMAC膝关节功能评分有所改善。 临床研究的理由是令人信服的。基于这一系列的发现，我们建议继续这样做 一个测试以下中心假设的项目：软骨保护和再生效果 Terparatide在小鼠创伤后骨性关节炎中的作用涉及刺激基质的产生 关节软骨细胞不适当成熟的抑制与一种机械上的 RUNX2的减少/抑制。为了解决这一假设，我们提出了以下三个具体目标：1) 证实特瑞帕帝对创伤性膝骨性关节炎软骨再生的影响是通过 关节软骨细胞，2)表征刺激基质产生的分子基础和 抑制Terparatide诱导的关节软骨细胞成熟，以及3)探讨其作用。 Terparatide对关节软骨影响的Jag1/Notch信号转导。如果成功，这些目标的实现 将建立Teriparatide作为治疗OA的候选疗法，这是一种目前只能姑息治疗的疾病。

This Project 1 proposal is part of a revised renewal application for the CORT Program entitled "Translating molecular signal pathways to orthopaedic trauma care". During the previous funding period, we published results contributing to the general hypothesis that inappropriate articular chondrocyte (AC) hypertrophy is a mechanism of OA pathogenesis. Given that PTH 1-34 (teriparatide) is an inhibitor of hypertrophy and inducer of matrix synthesis in chondrocytes, several of our recent breakthrough discoveries have solidified rationale for its use as a novel therapy for OA. Most important is our remarkable finding that teriparatide has dramatic chondro- regenerative effects in a mouse model of injury-induced knee OA. This is plausible mechanistically based on our published result that teriparatide induces the cyclinDI-dependent degradation of Runx2 in chondrocytes. Since Forteo (teriparatide) is already FDA-approved, and since patients enrolled in the NIH-sponsored OAI that were prescribed Forteo for osteoporosis had improved WOMAC knee function scores compared to matched controls, the rationale for clinical study is compelling. Based on this series of findings, we propose a continuation of this project that involves testing the following central hypotheses: The chondro-protective and -regenerative effect of teriparatide in murine posttraumatic OA involves stimulation of matrix production coupled with the inhibition of inappropriate articular chondrocytes maturation that is mechanistically linked to a reduction/inhibition of RUNX2. To address this hypothesis, we propose the following 3 Specific Aims: 1) To establish that the chondro-regenerative effects of teriparatide in posttraumatic knee OA are mediated by articular chondrocytes, 2) To characterize the molecular basis for the stimulation of matrix production and the inhibition of maturation induced by teriparatide in articular chondrocytes, and 3) To investigate the role of Jag1/Notch signaling in the effects of teriparatide on arthritic cartilage. If successful, completion of these aims will establish teriparatide as a candidate therapy for OA, a disease that currently is only treated palliatively.