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的治疗有两类药物： （二膦酸盐、RANKL抗体）或合成代谢物，以及它们的顺序或组合使用。同化包括 PTH类似物（Teriparlatin和Abaloparlatin）和硬化蛋白抗体（Scl-Ab，Romosozumab），并增加 骨密度和降低骨折风险，但他们有局限性，他们的活动随着时间的推移减弱。了解 其合成代谢作用的潜在机制及其随时间推移而降低的功效可以帮助识别新的 治疗目标，并导致更好的骨合成代谢药物。此应用程序侧重于以下角色 骨细胞是骨中最丰富的细胞，是骨建模和重建的“协调者”， PTH 1 -34和Scl-Ab在人类和小鼠中的作用。重要的是，骨细胞是骨形成的靶细胞。 PTH/PTHrP和硬化素的来源。在小鼠中，骨细胞特异性缺失PTH受体或WNT 受体（LRP 5/6）分别阻止对PTH 1 -34或Scl-Ab治疗的合成代谢反应， 骨细胞在对合成代谢治疗的反应中起主要作用。他们是如何为 反应和合成代谢活性下降在人类中是未知的。在这里，我们建议确定 人和小鼠骨细胞对合成代谢治疗的反应，比较早期和晚期 点回应。为此，从绝经后乳腺癌（PMOP）患者中采集人类活检样本， 将通过组织形态计量学、超高分辨率µ-CT和反向散射EM（BSEM）对女性进行分析。 将通过RNA测序分析来自这些样本的骨细胞富集制备物。平行的，相似的 方法将应用于OVX小鼠，PMOP模型，用相同的试剂治疗。 我们的具体目标是：（1）具体目标1。测定并比较人骨细胞的变化 对PTH（1-34）（Teriparthrin）的早期应答以及对sclerostin抗体的早期和晚期应答中的网络 （罗莫珠单抗）用于PMOP。2)具体目标2。测定并比较小鼠骨细胞的变化 网络在早期和晚期反应相同的合成代谢药物（PTH 1-34和Scl-Ab）在小鼠模型中， PMOP，并将这些变化与目标1中对PMOP妇女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。它可能揭示新的治疗机制和靶点 这可以显著提高合成代谢疗法的疗效，并可能提高其安全性。此外，该项目 与项目1相关，因为骨细胞影响骨稳态和骨髓微环境， 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， 治疗性诱导骨脆性疾病中的合成代谢反应。