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 perosteum是骨外表面上高度专业的组织微环境，在确保独特居民茎/祖细胞的生存和自我更新负责分配骨形成和骨折修复。破坏骨膜功能的伤害是常见的是，在美国，每年发生12.15亿个骨折，导致1800万医生的访问和结果在6000万个工作日中，损失了。尽管大多数骨折成功愈合，但很大程度上是由于先天而造成的骨膜的再生能力，愈合缓慢且无效（骨）超过5％患者和未能治愈的骨折可能高达10％对于流动性至关重要。顽固骨折的挑战是治疗和当前疗法产生的不可预测的结果，每年有近60万名患者具有严重的残疾。不可预测性旨在替代创伤或肿瘤期间骨骼损失的大部分骨骼的过程中，愈合中的愈合更加复杂切除并需要骨移植；每年进行的500,000个骨移植手术中的几乎一半随着时间的流逝失败，很大程度上是由于缺乏编排新骨形成的活骨膜细胞需要成功将移植物与宿主骨头结合在一起。我们已发表的工作将BMP2识别为有效的骨膜功能的生理调节剂。 PRX1+茎/祖细胞中缺乏BMP2表达的小鼠在所有已知的骨膜活性中均表现出严重的缺陷。在没有BMP2的情况下，骨骼无法宽度生长与它们长度的增长成正比，从而产生结构不稳定性，从而导致发起裂缝；一次断裂，per骨无法启动维修，无法支持骨移植保险。此外，用合成代谢剂（例如间歇性PTH或抗激素抗体）治疗无法刺激皮质在没有骨膜BMP2的情况下形成骨。因此，我们假设动态 BMP2在骨膜小裂中的时空表达模式构成必不可少的确定整个产后寿命的骨膜的主动与静态状态的机制。我们提案3旨在检验这一假设。在AIM 1中，我们将验证在A中识别的途径的功能作用最近完成了骨膜RNASEQ作为同名期间BMP2信号的下游介质生长和断裂修复。在AIM 2中，我们将研究对ECM中BMP2居民的要求骨膜细胞在适当的骨生长过程中产生的骨膜细胞菌与BMP2。在AIM 3中，我们将确定骨膜细胞增加内源性BMP2是否对骨膜功能有益。这些研究的完成将导致对细胞和分子的深入了解由BMP2信号在骨膜茎/祖细胞中协调的机制，应导致开发新的疗法以增强骨修复。通过该提议获得的知识也有增加针对骨膜的合成代谢剂的效用以防止骨折的潜力。