BMP2 Regulation of Periosteal Function

BMP2 骨膜功能调节

基本信息

批准号：
10627170
负责人：
Vicki Rosen
金额：
$ 6.4万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2022-11-08
项目状态：
已结题

项目摘要

Abstract The periosteum, a highly specialized tissue microenvironment on the outer surface of bone, has a key role in ensuring the survival and self-renewal of a unique population of resident stem/progenitor cells that are responsible for appositional bone formation and fracture repair. Injuries that disrupt periosteal function are common, with 12-15 million fractures occurring yearly in the US that lead to 18 million doctor’s visits and result in 60 million workdays lost. Although most fractures heal successfully, due in large part to the innate regenerative capacity of the periosteum, healing is slow and ineffectual (nonunion) for more than 5% of patients, and failure to heal can be as high as 10% for fractures that occur in weight-bearing long bones that are crucial for mobility. Recalcitrant fractures are challenging to treat and current therapies produce unpredictable outcomes, leaving almost 600,000 patients each year with significant disability. Unpredictability in healing is compounded for procedures that aim to replace large areas of bone lost during trauma or tumor resection and require bone grafting; almost half of the 500,000 bone grafting surgeries performed each year fail over time, due in large part to the absence of live periosteal cells that orchestrate the new bone formation needed to successfully unite the graft to the host bone. Our published work identifies BMP2 as a potent physiological regulator of periosteal function. Mice lacking BMP2 expression in Prx1+ stem/progenitor cells exhibit severe defects in all known periosteal activities. In the absence of BMP2, bones fail to grow in width proportional to their growth in length, creating structural instability that results in spontaneous fracture; once fractured, the periosteum fails to initiate repair and cannot support bone graft incorporation. In addition, treatment with anabolic agents such as intermittent PTH or anti-sclerostin antibody fail to stimulate cortical bone formation in the absence of periosteal BMP2. As such, we hypothesize that the dynamic spatio/temporal expression pattern of Bmp2 within the periosteal niche constitutes an essential mechanism determining active versus quiescent states of the periosteum throughout postnatal life. We propose 3 aims to test this hypothesis. In Aim 1, we will validate the functional role of pathways identified in a recently completed periosteum RNAseq as downstream mediators of BMP2 signaling during appositional growth and fracture repair. In Aim 2, we will examine the requirement for BMP2 resident in the ECM of the periosteal niche versus BMP2 produced by periosteal cell during appositional bone growth. In Aim 3, we will determine if increasing endogenous BMP2 production by periosteal cells is beneficial for periosteal function. Completion of these studies will result in a more in depth understanding of the cellular and molecular mechanisms coordinated by BMP2 signaling in periosteal stem/progenitor cells, and should lead to the development of novel therapies for enhancing bone repair. Knowledge gained through this proposal also has the potential to increase the utility of anabolic agents targeted to the periosteum to prevent fractures.

抽象的骨膜是骨骼外表面高度专业化的组织微环境，在确保独特的常驻干细胞/祖细胞群的生存和自我更新破坏骨膜功能的损伤负责并置骨形成和骨折修复。在美国，每年发生 12-1500 万起骨折，导致 1800 万人次就诊并得到结果尽管大多数骨折都能成功愈合，但很大程度上是由于先天因素。骨膜的再生能力，超过 5% 的患者愈合缓慢且无效（骨不连）对于患者来说，发生在负重长骨上的骨折无法愈合的比例可能高达 10%。顽固性骨折的治疗具有挑战性，目前的治疗方法也难以实现。不可预测的结果，每年导致近 600,000 名患者患有严重残疾。对于旨在替换创伤或肿瘤期间损失的大面积骨质的手术来说，愈合过程是复杂的每年进行的 50 万例骨移植手术中，几乎有一半需要进行骨移植；随着时间的推移会失败，很大程度上是由于缺乏协调新骨形成的活骨膜细胞我们发表的研究表明 BMP2 是一种有效的药物。 Prx1+干细胞/祖细胞中缺乏BMP2表达的小鼠骨膜功能的生理调节剂。所有已知的骨膜活动都表现出严重缺陷。如果缺乏 BMP2，骨骼的宽度就无法生长。与它们的长度增长成正比，造成结构不稳定，一旦发生就会导致自发断裂；骨折后，骨膜无法开始修复，并且不能支持骨移植物合并。使用合成代谢药物（例如间歇性 PTH 或抗硬化素抗体）治疗无法刺激皮质在没有骨膜 BMP2 的情况下骨形成因此，我们认为是动态的。 Bmp2 在骨膜生态位内的时空表达模式构成了重要的决定整个出生后骨膜活跃与静止状态的机制。提议 3 旨在检验这一假设。在目标 1 中，我们将验证在 a 中确定的途径的功能作用。最近完成的骨膜 RNAseq 作为并置过程中 BMP2 信号传导的下游介质在目标 2 中，我们将检查 BMP2 驻留在 ECM 中的要求。骨膜生态位与骨膜细胞在骨生长过程中产生的 BMP2 的比较在目标 3 中，我们将进行比较。确定增加骨膜细胞内源性 BMP2 的产生是否有利于骨膜功能。完成这些研究将导致对细胞和分子的更深入的了解骨膜干细胞/祖细胞中 BMP2 信号传导协调的机制，并且应该导致通过该提案获得的知识也有助于开发增强骨修复的新疗法。增加针对骨膜的合成代谢药物的效用以预防骨折的潜力。