Non-hormonal function of locally delivered PTH for rescue of impaired fracture healing

这项A1转化治疗研究提案旨在通过局部递送的 甲状旁腺激素（hPTH 1 -34）作为骨折修复促进因子在受损骨折中的作用 在糖尿病患者、慢性吸烟者和老年人中看到的愈合，目的是避免骨折- 相关并发症。 现有文献（临床预测）和我们的初步数据（科学预测）表明， 在老年T2 DM患者中，再活化干细胞（FASC）数量较少或功能较弱， 患者和慢性吸烟者比年轻健康受试者。 虽然激素经典地通过第二信使或第三信使作用于远端的靶细胞， PTH是一种矛盾的激素。从内分泌的角度来看，众所周知，PTH具有骨 分解代谢或合成代谢功能取决于高剂量与低剂量或连续与间歇全身 局尽管全身性间歇性PTH治疗对骨折有假定的有益作用， 尽管局部递送PTH对骨折愈合的影响是已知的，但是局部递送PTH对骨折愈合的影响并不众所周知。这在科学上是合乎逻辑的， 如果PTH受体由FASC表达，则在骨折部位局部递送PTH在临床上是实用的。 这项研究计划的目标是建立一个新的务实和具有成本效益的方式，提高 用局部递送的PTH 1 -34直接促进FASCs与PTH受体在骨折愈合受损， FASC增殖和分化的早期关键阶段的骨折部位。 我们的初步数据显示，FASCs与PTH受体的鉴定;局部PTH释放的优化 体内和体外的动力学和最佳剂量合理性; FASC的数量或功能减少， 通过局部递送PTH 1 -34对老年人、T2 DM或慢性 吸烟小鼠;和继发性合成代谢BMP 2/4的生产，局部交付的PTH在体内。 我们证实了一个中心假设，即局部输送PTH通过增加骨密度而导致上级骨折愈合。 在老年人、2型糖尿病患者、 或慢性吸烟者受试者。为了最大限度地发挥临床影响，我们将测试hPTH 1 -34是否能增强 增殖和早期骨/软骨/血管生成分化的FASCs在老年受试者（目的1），在3 不同的临床相关T2 DM小鼠模型和慢性吸烟小鼠（目的3）。 我们的剂量递增实验和分析将设盲，以模拟严格的临床试验。 翻译创新和影响在于建立一个简单，务实，具有成本效益的治疗 使用局部递送的PTH作为老年人受损骨折愈合中的骨折愈合促进剂的平台， T2 DM和慢性吸烟受试者，这是3种最常见的受损骨折类型 临床骨科手术中的愈合。

This A1 translational therapeutic research proposal seeks to enhance fracture repair with a locally delivered parathyroid hormone (hPTH1-34) as a fracture repair enhancing factor in the setting of impaired fracture healing as seen in diabetic patients, chronic smokers, and elderly people with the goal of avoiding fracture- associated complications. Existing literature (Clinical Premise) and our preliminary Data (Scientific Premise) suggest that osteochondral fracture-activated stem cells (FASCs) are low in number or functionally less robust in elderly patients, T2DM patients, and chronic smokers than in young healthy subjects. Although hormones classically act on target cells at the remote sites through secondary messengers or directly, PTH is a paradoxical hormone. From an endocrine perspective, PTH is well known to have bone catabolic or anabolic functions depending on high vs. low doses or continuous vs. intermittent systemic administration. Despite presumed beneficial effects of systemic intermittent PTH treatments on fracture healing, effects of locally delivered PTH on fracture healing are not well known. It is scientifically logical and clinically pragmatic to deliver PTH locally at the fracture site if PTH receptors are expressed by the FASCs. The goal of this research program is to establish a new pragmatic and cost-effective way of enhancing impaired fracture healing with a locally delivered PTH1-34 that directly boost FASCs with PTH-receptors at the fracture site during the early critical phase of FASC proliferation and differentiation. Our preliminary data showed identification of FASCs with PTH receptors; optimization of localized PTH release kinetics and optimal dose justification in vivo and in vitro; decreased number or function of FASCs and therapeutic rescue of impaired fracture healing by locally delivered PTH1-34 in elderly, T2DM, or chronic cigarette-smoking mice; and secondary anabolic BMP2/4 production by locally delivered PTH in vivo. We posit a central hypothesis that locally delivered PTH results in superior fracture healing by increasing the population of and enhancing differentiation of Fracture Activated Stem Cells (FASCs) in aged, Type 2 diabetic, or chronic smoker subject. In order to maximize clinical impact, we will test whether hPTH1-34 enhances proliferation and early osteo-/chondral/angiogenic-differentiation of FASCs in elderly subjects (Aim 1), in 3 different clinically relevant T2DM mouse models, and chronic cigarette smoking mice (Aim 3). Our dose-escalated experiments and analysis will be blinded in order to simulate rigorous clinical trials. Translational innovation and impact lie in establishment of a simple, pragmatic, and cost-effective therapeutic platform to use locally delivered PTH as a fracture-healing enhancer in impaired fracture healing in aged, T2DM, and chronic cigarette smoking subjects, which are 3 most commonly seen types of impaired fracture healing in clinical orthopaedic surgery.