Teriparatide as a Therapy for Osteoarthritis Following Meniscal Injury

本项目1提案是CORT计划修订后的更新申请的一部分，标题为“翻译 分子信号通路的骨科创伤护理”。在上一个资助期间，我们公布了结果， 有助于一般假设，不适当的关节软骨细胞（AC）肥大是一种机制， OA的发病机制。鉴于PTH 1-34（特立帕肽）是肥大抑制剂和基质诱导剂， 在软骨细胞中的合成，我们最近的几个突破性发现已经巩固了其作为一种 OA的新疗法。最重要的是我们的发现，teriparbal有戏剧性的软骨- 在损伤诱导的膝关节OA小鼠模型中的再生作用。这在机械上是合理的， 已发表的结果表明，特立哌酮诱导软骨细胞中Runx 2的细胞周期蛋白D1依赖性降解。以来 Forteo（teriparlitazone）已经获得FDA批准，由于患者参加了NIH赞助的OAI， 与匹配的对照组相比，为骨质疏松症开具的Forteo改善了WOMAC膝关节功能评分， 临床研究的理由是令人信服的。基于这一系列的发现，我们建议继续这一点， 该项目涉及测试以下中心假设：软骨保护和再生作用 特立帕鲁肽在小鼠创伤后OA中的作用涉及刺激基质产生， 抑制不适当的关节软骨细胞成熟，这是机械连接到一个 减少/抑制RUNX 2。为了解决这一假设，我们提出了以下3个具体目标：1） 确定特立帕肽在创伤后膝关节OA中的软骨再生作用是由以下因素介导的： 关节软骨细胞，2）为了表征刺激基质产生的分子基础， 抑制关节软骨细胞中由特立哌酮诱导的成熟，以及3）研究 Jag 1/Notch信号通路在特立帕肽对关节炎软骨的作用中的作用如果成功，完成这些目标 将建立特立帕妥作为OA的候选疗法，OA是一种目前仅进行姑息治疗的疾病。

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.