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: 10208066
• 负责人: Xiaowei Sherry Liu
• 金额: $ 42.48万
• 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/10208066
• 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.

项目概要 健康的骨骼在整个生命周期中通过紧密耦合的骨吸收不断自我更新 和基于重塑的骨形成。相比之下，基于建模的骨形成，即从头骨 在没有预先激活骨吸收的情况下形成，在成人骨骼中较少见，但具有 已被确定为骨质疏松症合成代谢药物的重要机制，例如间歇性 甲状旁腺激素 (PTH) 和 PTH 相关肽 (PTHrP) 以及硬化蛋白抗体 (Scl-Ab)，快速引发 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 RBF 和随后对成年大鼠骨骼进行的组织水平机械测试，我们发现 MBF 有反应 比 RBF 更快的合成代谢治疗。此外，MBF 产生的骨组织对 与相比，合成代谢治疗戒断引起的骨质流失和弹性模量异质性增加 RBF 产生的预先存在的骨和骨组织。这些令人兴奋的初步数据提供了强有力的 支持我们中心假设的科学前提，即 MBF 是一种高效的再生机制 对骨组织的数量和质量以及整体骨强度产生可持续的治疗效果。 此外，我们的数据表明，在早期退出合成代谢治疗后，持续的骨形成 继续在 MBF 部位，形成保留治疗效果的“合成代谢窗口”；相比之下，大多数 停止治疗后，RBF 部位形成的骨组织被吸收。因此，我们建议 交替合成代谢和抗吸收治疗的循环和序贯治疗方案将导致 增加矿物质沉积和 MBF 数量，改善 RBF 和静态时骨组织的保留 骨表面，并改善组织异质性和整体骨强度。本研究的总体目标 是为了阐明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 机械测试方法，这个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，并为 调节 MBF 的治疗策略的临床设计和优化，MBF 是一种高效但经常使用的药物。 被忽视的再生机制。