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骼脆弱性疾病用两类药物治疗：抗敏感性 （双膦酸盐，对RANKL的抗体）或合成代谢及其顺序或合并使用。合成代谢包括 PTH类似物（Teriparatide和baloparatide）和硬化蛋白抗体（SCL-AB，Romosozumab），并增加 BMD并降低断裂风险，但随着时间的推移，它们的活动局限性且活动逐渐减弱。了解 其合成代谢作用和随着时间的效率下降的基础机制可以帮助识别新颖 治疗靶标并导致更好的骨动物代谢药物。该应用的重点是 骨细胞，骨骼建模和重塑的骨骼和“编排”中最丰富的细胞，介导 PTH1-34和SCL-AB在人类和小鼠中的影响。重要的是，骨细胞是 PTH/PTHRP和硬化蛋白的来源。在小鼠中，PTH受体或Wnt的骨细胞特异性缺失 受体（LRP5/6）分别防止对PTH1-34或SCL-AB处理的合成代谢反应，从而确定 首先，骨细胞在对合成代谢治疗的反应中起着重要作用。他们如何贡献 尚不清楚人类合成代谢活性的反应和衰落。在这里，我们建议确定 在人类和小鼠中，骨细胞对合成代谢治疗的反应，比较早期和晚期 点响应。为此，来自绝经后骨质疏松术的人体活检样本（PMOP） 妇女将通过组织形态计量学，超高分辨率µ-CT和反向散发EM（BSEM）进行分析。 从这些样品中富含骨细胞的制剂将通过RNA测序分析。并行，相似 方法将应用于用相同药物处理的PMOP模型OVX小鼠。 我们的具体目的是：1）特定目标1。确定并比较人骨细胞的变化 早期对PTH（1-34）（Teriparatide）和对硬化蛋白抗体的早期反应的网络 （Romosozumab）在PMOP中。 2）特定目标2。确定并比较小鼠骨细胞的变化 对同一合成代谢药物（PTH 1-34和SCL-AB）的早期和晚期反应的网络 PMOP并将这些更改与PMOP女性AIM 1中的观察结果进行比较。 该项目有助于Cort的翻译主题，并解决了由 Cort推进整体翻译目标。它可能揭示新的热机制和目标 这可以显着提高合成代谢疗法的效率和可能的安全性。此外，这个项目 与项目1的关系，因为骨细胞会影响骨稳态和骨髓微环境，并且 对于生物信息学研究核心，对转录组分析至关重要。这个项目的结果将 通过将骨细胞的变化与骨骼的调节联系起来，告知Cort中提出的其他项目 建模/重塑和骨骼干细胞行为。这些研究将有助于为 骨脆性疾病中合成代谢反应的治疗诱导。