Leveraging modeling-based bone formation for osteoporosis treatment

利用基于模型的骨形成治疗骨质疏松症

• 批准号: 10366040
• 负责人: Xiaowei Sherry Liu
• 金额: $ 42.04万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-05 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366040
• 关键词: Adult; Anabolic Agents; Antibodies; Bone Resorption; Bone Surface; Bone Tissue; Bone remodeling; Bone structure; Chronic; Clinical; Collagen; Coupled; Data; Deposition; Development; Hardness; Heterogeneity; Image; Image Analysis; Knowledge; Length; Life; Longevity; Mechanics; Minerals; Modeling; Modulus; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; PTH gene; Periodicity; Predisposition; Rattus; Regimen; Research Project Grants; Resistance; Sequential Treatment; Site; Skeleton; Structure; Structure-Activity Relationship; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; Treatment Protocols; Withdrawal; base; bone; bone loss; bone mass; bone strength; design; imaging platform; improved; innovation; insight; mechanical properties; mineralization; novel; novel therapeutics; parathyroid hormone-related protein; recruit; regenerative; response; standard care; treatment duration; treatment effect; treatment optimization; treatment strategy

Project Summary The healthy skeleton continuously renews itself throughout the lifespan via closely coupled bone resorption and remodeling-based bone formation. In contrast, modeling-based bone formation, i.e., de novo bone formation without prior activation of bone resorption, is less commonly found in the adult skeleton, but has been identified as an important mechanism by which anabolic agents for osteoporosis, e.g., intermittent parathyroid hormone (PTH) and PTH related peptide (PTHrP), and sclerostin antibody (Scl-Ab), rapidly elicit new bone formation. By developing a novel imaging platform that enables reliable identification of MBF and RBF and subsequent tissue-level mechanical testing in adult rat bone, we discovered that MBF responds faster than RBF to anabolic treatments. Moreover, bone tissue resulting from MBF has a greater resistance to anabolic treatment withdrawal-induced bone loss and increased heterogeneity of elastic modulus compared to pre-existing bone and bone tissue resulting from RBF. These exciting preliminary data provide a strong scientific premise to support our central hypothesis that MBF is a highly efficient regenerative mechanism that leads to sustainable therapeutic benefits on bone tissue quantity and quality, and whole bone strength. Furthermore, our data suggest that, upon early withdrawal from anabolic treatment, ongoing bone formation continues at MBF sites, forming an “anabolic window” that retains the treatment effect; In contrast, the majority of bone tissue formed at RBF sites were resorbed following treatment withdrawal. Therefore, we propose that a cyclic and sequential treatment regimen with alternating anabolic and anti-resorptive treatments will lead to increased mineral deposition and number of MBF, improved retention of bone tissue at RBF and quiescent bone surface, and improved tissue heterogeneity and whole bone strength. The overall objective of this study is to elucidate the cellular mechanisms (Aim 1a) and mechanical consequences (Aim 2a) of MBF and RBF, and to evaluate the new treatment regimen which leverages MBF to improve and extend treatment efficacy (Aim 2a and 2b) using a rat model. By combining our innovative imaging and image analyses with tissue-level mechanical testing approaches, this proposed research project will fill the critical knowledge gap of long-term mechanical consequences of bone tissue formed through MBF and RBF, and provide important insight for the clinical design and optimization of treatment strategies that modulate MBF, a highly efficient but often overlooked regenerative mechanism.

项目摘要 健康的骨骼在整个生命周期中通过紧密结合的骨吸收不断更新自身 和基于重塑的骨形成。相反，基于建模的骨形成，即，新生骨 在没有预先激活骨吸收的情况下形成，在成人骨骼中不太常见，但 被认为是骨质疏松症的合成代谢剂，例如，间歇 甲状旁腺激素（PTH）和PTH相关肽（PTHrP）以及硬化素抗体（Scl-Ab），迅速引起 新骨形成。通过开发一种新的成像平台，能够可靠地识别MBF， RBF和随后的成年大鼠骨组织水平的力学测试，我们发现MBF响应 比RBF更快的合成代谢治疗。此外，由MBF产生的骨组织具有更大的抵抗力， 与对照组相比，合成代谢治疗撤药诱导的骨丢失和弹性模量的异质性增加 由RBF引起的既存骨和骨组织。这些令人兴奋的初步数据提供了一个强有力的 科学前提来支持我们的中心假设，即MBF是一种高效的再生机制， 导致对骨组织数量和质量以及全骨强度的可持续治疗益处。 此外，我们的数据表明，在早期停止合成代谢治疗后， 在MBF部位继续，形成保留治疗效果的“合成代谢窗口”;相反， 在治疗停止后，在RBF部位形成的骨组织被再吸收。因此，我们建议， 交替进行合成代谢和抗吸收治疗的周期性和序贯治疗方案将导致 增加矿物质沉积和MBF数量，改善RBF和静态骨组织保留 骨表面，并改善组织异质性和全骨强度。本研究的总体目标 阐明MBF和RBF的细胞机制（目标1a）和机械后果（目标2a）， 并评估利用MBF改善和延长治疗疗效的新治疗方案 (Aim图2a和2b）使用大鼠模型。通过将我们的创新成像和图像分析与组织水平 机械测试方法，这项拟议的研究项目将填补长期的关键知识空白 通过MBF和RBF形成的骨组织的机械后果，并提供重要的见解， 临床设计和优化治疗策略，调节MBF，一个高效，但往往 被忽视的再生机制