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 健康的骨骼通过紧密结合的骨吸收在整个生命周期中不断更新自己 和以重塑为基础的骨形成。相比之下，基于模型的骨形成，即从头骨 没有预先激活骨吸收的形成，在成人骨骼中较少发现，但有 已被确定为治疗骨质疏松症的合成代谢剂的重要机制，例如间歇性 甲状旁腺激素(PTH)和甲状旁腺激素相关肽(PTHrP)，以及硬化素抗体(scl-Ab)快速诱导 新骨形成。通过开发一种新型成像平台，能够可靠地识别MBF和 在成年大鼠骨骼中进行的组织水平力学测试中，我们发现MBF对 比RBF更快地达到合成代谢治疗。此外，由MBF产生的骨组织对 与对照组相比，合成代谢治疗戒断引起的骨丢失和弹性模量的异质性增加 原存在的骨和由RBF产生的骨组织。这些令人兴奋的初步数据提供了一个强有力的 支持我们的中心假设的科学前提，即MBF是一种高效的再生机制， 在骨组织的数量和质量以及整个骨强度方面带来可持续的治疗效益。 此外，我们的数据表明，在早期停止合成代谢治疗后，正在进行的骨形成 持续在MBF部位，形成保留治疗效果的“合成代谢窗”；相比之下，大多数 在停止治疗后，在RBF部位形成的骨组织的一半被吸收。因此，我们建议一项 交替进行合成代谢和抗吸收治疗的循环和顺序治疗方案将导致 增加矿物质沉积和MBF数量，改善RBF和静止状态下骨组织的保留 改善了骨表面，改善了组织的异质性和整体骨强度。这项研究的总体目标是 是阐明MBF和RBF的细胞机制(目标1a)和力学后果(目标2a)， 并评价利用MBF改善和延长治疗效果的新治疗方案 (目标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相结合 力学测试方法的研究，本课题的提出将填补长期的关键知识空白 通过MBF和RBF形成的骨组织的力学后果，并为 调整MBF的临床设计和治疗策略的优化，一种高效但经常 忽视了再生机制。