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: 10553619
• 负责人: Xiaowei Sherry Liu
• 金额: $ 42.47万
• 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/10553619
• 关键词: Adult; Anabolic Agents; Antibodies; Bone Resorption; Bone Surface; Bone Tissue; Bone remodeling; Bone structure; Chronic; Clinical; Collagen; Coupled; Data; Deposition; Development; Elasticity; Hardness; Heterogeneity; Image; Image Analysis; Knowledge; Length; 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; 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 健康的骨骼继续通过紧密耦合的骨骼分辨率在整个生命周期内恢复自身 和基于重塑的骨形成。相反，基于建模的骨形成，即从头骨 在没有事先激活骨骼的情况下形成，在成人骨骼中很少发现，但具有 被确定为一种重要机制 甲状旁腺（PTH）和PTH相关肽（PTHRP）和硬化蛋白抗体（SCL-AB），迅速引起 新的骨形成。通过开发一个新颖的成像平台，该平台可以可靠地识别MBF和 RBF和随后的成年大鼠骨骼的组织级机械测试，我们发现MBF反应 比RBF快于合成代谢治疗。此外，由MBF产生的骨组织具有更大的抗性 合成代谢治疗戒断引起的骨质流失和弹性模量的异质性增加与 由RBF引起的骨组织和骨组织。这些令人兴奋的初步数据提供了强大的 科学的前提是支持我们的中心假设，即MBF是一种高效的再生机制 导致骨组织数量和质量以及整个骨骼强度的可持续治疗益处。 此外，我们的数据表明，在早日退出代谢处理后，持续的骨形成 在MBF站点继续进行，形成了保留治疗效果的“合成代谢窗口”。相反，大多数 在戒断治疗后，在RBF部位形成的骨骼组织被放映。因此，我们建议 循环和顺序治疗方案采用替代合成代谢和抗敏感性处理将导致 增加矿物沉积和MBF数量，改善RBF骨组织的保留和静止 骨表面，改善组织异质性和全骨强度。这项研究的总体目标 是阐明MBF和RBF的细胞机制（AIM 1A）和机械后果（AIM 2A）， 并评估利用MBF提高和延长治疗效率的新治疗方案 （AIM 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级结合 机械测试方法，该提出的研究项目将填补长期的关键知识差距 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，这是一种高效但通常 被忽视的再生机制。