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

局部递送 PTH 的非激素功能可挽救骨折愈合受损

• 批准号: 10617664
• 负责人: Francis Young-In Lee
• 金额: $ 48.27万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617664
• 关键词: Aftercare; BMP2 gene; BMP4; Biomechanics; Blinded; Bone callus; Calories; Cell Differentiation process; Cells; Chronic; Clinical; Clinical Trials; Collagen; Contralateral; Data; Day Blindness; Dose; Elderly; Endocrine; Enhancers; Female; Femur; Forteo; Fracture; Gel; Goals; Harvest; Health; Hematopoietic; Heparin; Histology; Hormones; Human; Hydrogels; Hyperglycemia; Impairment; In Vitro; Injury; Intervention; Kinetics; Literature; Lung; Mesenchymal; Mesenchymal Stem Cells; Mus; Musculoskeletal; Non obese; Obesity; Orthopedic Surgery; Osteogenesis; Ovariectomy; PTH gene; Patients; Persons; Phase; Phenotype; Placebos; Population; Production; Proliferating; Proteins; Research; Research Proposals; Reverse Transcriptase Polymerase Chain Reaction; Roentgen Rays; Senility; Signal Transduction; Site; Smoker; Smoking; Testing; Therapeutic; Therapeutic Trials; Time; Tissues; Translating; Type 2 diabetic; aged; bone; bone fracture repair; cigarette smoke; cigarette smoking; clinical practice; clinically relevant; comparative; cost effective; diabetic patient; enhancing factor; experimental study; food consumption; in vivo; innovation; male; microCT; mouse model; negative affect; novel; older patient; osteochondral tissue; osteogenic; programs; receptor; skeletal stem cell; smoke inhalation; smoking exposure; stem cell function; stem cell proliferation; stem cells; therapeutically effective; translational therapeutics

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.

这项 A1 转化治疗研究提案旨在通过局部提供的药物来增强骨折修复 甲状旁腺激素（hPTH1-34）作为骨折受损情况下的骨折修复增强因子 糖尿病患者、长期吸烟者和老年人的愈合过程是为了避免骨折—— 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 老年患者、T2DM 患者中骨折激活干细胞 (FASC) 数量较少或功能较差 患者和长期吸烟者的比例高于年轻健康受试者。 尽管激素通常通过第二信使或 直接来说，PTH 是一种矛盾的激素。从内分泌角度来看，PTH众所周知与骨 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性 行政。尽管全身间歇性 PTH 治疗被认为对骨折有有益作用 愈合，局部递送 PTH 对骨折愈合的影响尚不清楚。这是有科学逻辑的 如果 FASC 表达 PTH 受体，则临床上可在骨折部位局部递送 PTH。 该研究计划的目标是建立一种新的务实且具有成本效益的方法来增强 局部递送的 PTH1-34 会损害骨折愈合，直接通过 PTH 受体增强 FASC FASC 增殖和分化早期关键期的骨折部位。 我们的初步数据显示 FASC 与 PTH 受体的鉴定；本地化PTH释放优化 体内和体外动力学和最佳剂量合理性； FASC 数量或功能减少以及 通过局部递送 PTH1-34 对老年人、T2DM 或慢性病患者骨折愈合受损进行治疗性挽救 吸烟的老鼠；以及通过体内局部递送的 PTH 产生次级合成代谢 BMP2/4。 我们提出一个中心假设，即局部递送 PTH 通过增加骨折愈合率来实现优异的骨折愈合。 老年人、2 型糖尿病、 或长期吸烟者受试者。为了最大限度地发挥临床影响，我们将测试 hPTH1-34 是否增强 老年受试者 FASC 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 T2DM 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采用盲法，以模拟严格的临床试验。 转化创新和影响在于建立一种简单、务实且具有成本效益的治疗方法 该平台使用局部递送的 PTH 作为骨折愈合促进剂，用于治疗老年人、 T2DM 和长期吸烟受试者，这是 3 种最常见的受损骨折类型 临床骨科手术中的愈合。

项目成果

Parathyroid hormone therapy improves MRSA-infected fracture healing in a murine diabetic model.

• DOI: 10.3389/fcimb.2023.1230568
• 发表时间: 2023
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7

Smoking Alters Inflammation and Skeletal Stem and Progenitor Cell Activity During Fracture Healing in Different Murine Strains.

• DOI: 10.1002/jbmr.4175
• 发表时间: 2021-01
• 期刊: JOURNAL OF BONE AND MINERAL RESEARCH
• 影响因子: 6.2
• 作者: Hao, Zichen;Li, Jun;Li, Bo;Alder, Kareme D.;Cahill, Sean, V;Munger, Alana M.;Lee, Inkyu;Kwon, Hyuk-Kwon;Back, JungHo;Xu, Shuogui;Kang, Min-Jong;Lee, Francis Y.
• 通讯作者: Lee, Francis Y.