The role of the osteocyte in responses to osteoporosis anabolic treatment in humans and mice

骨细胞在人类和小鼠骨质疏松合成代谢治疗反应中的作用

• 批准号: 10404416
• 负责人: ROLAND E BARON
• 金额: $ 41.69万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404416
• 关键词: Address; Affect; Antibodies; Behavior; Bioinformatics; Biology; Biopsy Specimen; Bone Diseases; Bone Marrow; Bone remodeling; Cells; Center for Translational Science Activities; Complement; Data; Deposition; Forteo; Gene Expression; Goals; Homeostasis; Human; Imaging Techniques; Injections; Investigation; Link; Mediating; Methods; Modeling; Molecular; Morphology; Mus; Osteocytes; Osteoporosis; Osteoporotic; Outcome; Pathway interactions; Pharmaceutical Preparations; Play; Postmenopause; Preparation; Process; Regulation; Research; Role; Safety; Sampling; Skeleton; Source; TNFSF11 gene; Testing; Therapeutic; Three-dimensional analysis; Time; Woman; analog; bisphosphonate; bone; bone fragility; bone mass; cell behavior; fracture risk; improved; microCT; mouse model; new therapeutic target; novel; novel therapeutics; osteoprogenitor cell; parathyroid hormone (1-34); parathyroid hormone-related protein; preclinical study; prevent; receptor; response; skeletal; skeletal stem cell; transcriptome; transcriptome sequencing; treatment response; treatment strategy; ultra high resolution

Osteoporosis and other diseases of bone fragility are treated with two classes of drugs: Anti-resorptives (bisphosphonates, antibodies to RANKL) or anabolics, and their sequential or combined use. Anabolics include PTH analogs (Teriparatide and Abaloparatide) and sclerostin antibody (Scl-Ab, Romosozumab) and increase BMD and reduce fracture risk, but they have limitations and their activity wanes over time. Understanding the mechanisms underlying their anabolic action and their decrease in efficacy over time could help identify novel therapeutic targets and lead to better osteo-anabolic drugs. This application focuses on the role of osteocytes, the most abundant cells in bone and “orchestrator” of bone modeling and remodeling, in mediating the effects of PTH1-34 and Scl-Ab in humans and in mice. Importantly, osteocytes are target cells of PTH/PTHrP and the source of sclerostin. In mice, osteocyte specific deletion of the PTH receptor or the WNT receptors (LRP5/6) prevents the anabolic response to PTH1-34 or Scl-Ab treatment, respectively, establishing firmly that osteocytes play a major role in the responses to anabolic treatments. How they contribute to the responses and to the decline in anabolic activity in humans is not known. Here, we propose to determine the response of osteocyte to anabolic treatments, in humans and in mice, comparing early and late time points responses. For this purpose, human biopsy samples from post-menopausal osteoporotic (PMOP) women will be analyzed by histomorphometry, ultra-high resolution µ-CT and back-scattered EM (BSEM). Osteocyte-enriched preparations from these samples will be analyzed by RNA sequencing. In parallel, similar methods will be applied to OVX mice, a PMOP model, treated with the same agents. Our specific aims are: 1) Specific Aim1. Determine and compare the changes in the human osteocyte network in early responses to PTH(1-34) (Teriparatide) and early and late responses to sclerostin antibody (romosozumab) in PMOP. 2) Specific Aim 2. Determine and compare the changes in the mouse osteocyte network in early and late responses to the same anabolic drugs (PTH 1-34 and Scl-Ab) in a mouse model of PMOP and compare these changes to the observations made in Aim 1 in PMOP women. This project contributes to the translational theme of the CORT and addresses critical questions identified by the CORT to advance the overall translational objectives. It may reveal novel therapeutic mechanisms and targets that could significantly improve the efficacy, and possibly safety, of anabolic therapies. Further, this project relates to Project 1, since osteocytes influence bone homeostasis and the bone marrow micro-environment, and to the Bioinformatics Research Core, essential in the transcriptome analysis. The outcomes of this project will inform the other projects proposed in the CORT by linking changes in osteocytes to the regulation of bone modeling/remodeling and skeletal stem cells behavior. These studies will help generate novel hypothesis for the therapeutic induction of an anabolic response in diseases of bone fragility.

骨质疏松症和其他骨脆性疾病可使用两类药物治疗： 抗骨吸收药物 （二磷酸盐、RANKL 抗体）或合成代谢药物，以及它们的顺序或组合使用。合成代谢包括 PTH 类似物（特立帕肽和 Abaloparatide）和硬化蛋白抗体（Scl-Ab、Romosozumab）并增加 BMD 并降低骨折风险，但它们有局限性，并且它们的活性会随着时间的推移而减弱。了解 其合成代谢作用背后的机制及其随时间的推移功效下降可能有助于识别新的 治疗目标并导致更好的骨合成代谢药物。该应用程序的重点是角色 骨细胞是骨骼中最丰富的细胞，也是骨骼建模和重塑的“协调者”，在介导 PTH1-34 和 Scl-Ab 对人类和小鼠的影响。重要的是，骨细胞是 PTH/PTHrP 和硬化素的来源。在小鼠中，骨细胞特异性删除 PTH 受体或 WNT 受体 (LRP5/6) 分别阻止对 PTH1-34 或 Scl-Ab 治疗的合成代谢反应，从而建立 坚定地认为骨细胞在合成代谢治疗的反应中发挥着重要作用。他们如何为 人类合成代谢活性下降的反应和下降尚不清楚。在此，我们建议确定 人类和小鼠骨细胞对合成代谢治疗的反应，比较早期和晚期时间 点回应。为此，我们从绝经后骨质疏松症 (PMOP) 中提取人体活检样本 女性将通过组织形态计量学、超高分辨率 µ-CT 和背散射电子显微镜 (BSEM) 进行分析。 这些样品中富含骨细胞的制剂将通过 RNA 测序进行分析。平行、相似 方法将应用于 OVX 小鼠（一种 PMOP 模型），并用相同的药物治疗。 我们的具体目标是： 1) 具体目标1。测定并比较人类骨细胞的变化 对 PTH(1-34)（特立帕肽）的早期​​反应以及对硬化素抗体的早期和晚期反应的网络 PMOP 中的（romosozumab）。 2) 具体目标2. 测定并比较小鼠骨细胞的变化 在小鼠模型中对相同合成代谢药物（PTH 1-34 和 Scl-Ab）的早期和晚期反应网络 PMOP 并将这些变化与目标 1 中在 PMOP 女性中进行的观察结果进行比较。 该项目有助于 CORT 的翻译主题，并解决 CORT 确定的关键问题 CORT 推进总体转化目标。它可能揭示新的治疗机制和靶点 这可以显着提高合成代谢疗法的功效和可能的安全性。此外，本项目 与项目 1 相关，因为骨细胞影响骨稳态和骨髓微环境，并且 生物信息学研究核心，在转录组分析中至关重要。该项目的成果将 通过将骨细胞的变化与骨的调节联系起来，为 CORT 中提出的其他项目提供信息 建模/重塑和骨骼干细胞行为。这些研究将有助于产生新的假设 骨脆性疾病中合成代谢反应的治疗诱导。