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

这项A1翻译治疗研究提案旨在通过在当地交付的 甲状旁腺素(hPTH1-34)作为骨折修复促进因子在受损骨折中的应用 以避免骨折为目标的糖尿病患者、长期吸烟者和老年人的治愈- 相关并发症。 现有文献(临床前提)和我们的初步数据(科学前提)表明，骨软骨 骨折激活干细胞(FASCs)在老年T2 DM患者中数量较少或功能较差 患者和慢性吸烟者比年轻的健康受试者更多。 尽管荷尔蒙通常通过第二信使或第二信使作用于远程部位的靶细胞 直接来说，PTH是一种矛盾的荷尔蒙。从内分泌的角度来看，甲状旁腺激素是众所周知的有骨的。 分解代谢或合成代谢功能取决于高剂量与低剂量或持续性与间歇性全身 行政管理。尽管全身间歇性甲状旁腺激素治疗对骨折有推定的益处 愈合方面，局部注射甲状旁腺素对骨折愈合的影响尚不清楚。这是科学上合乎逻辑的AND 如果FASCs表达PTH受体，则在骨折处局部注射PTH具有临床实用价值。 这项研究计划的目标是建立一种新的务实和成本效益高的方式来增强 局部应用PTH1-34直接通过PTH受体促进FASCs的骨折愈合 FASC增殖分化早期关键阶段的骨折部位。 我们的初步数据显示FASCs与PTH受体有关；PTH局部释放的优化 体内和体外的动力学和最佳剂量调整；FASCs的数量或功能减少和 局部应用PTH1-34抢救老年、2型糖尿病或慢性骨折愈合障碍 以及体内局部传递甲状旁腺素产生BMP2/4。 我们提出了一个中心假设，即局部应用PTH通过增加骨折愈合时间来促进骨折愈合。 老年2型糖尿病患者骨折激活干细胞(FASCs)的数量和分化增强 或长期吸烟者。为了最大限度地发挥临床效果，我们将测试hPTH1-34是否能增强 老年人FASCs的增殖和早期骨/软骨/血管生成分化(目标1)，3 不同临床相关的T2 DM小鼠模型和慢性吸烟小鼠(目标3)。 我们的剂量递增实验和分析将是盲目的，以模拟严格的临床试验。 翻译的创新和影响在于建立一种简单、实用、成本效益高的治疗方法 使用局部注射的甲状旁腺素作为老年人骨折愈合受损的骨折愈合促进剂的平台， 2型糖尿病和长期吸烟的对象，这是最常见的三种受损骨折类型 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.