BMP2 regulation of the intramembranous bone stem cell niche

摘要 最近的研究表明，成骨性骨形态发生蛋白(BMPs)是快速修复骨损伤所必需的。 在新生动物中发生的骨形成，以及对于骨重建来说，最重要的功能是 成人骨架。BMP4、BMP5、BMP6和BMP7似乎不是成人骨形成的重要介质，因为 缺乏其中任何一种BMP的小鼠保持正常的骨量。相比之下，缺乏BMP2的小鼠无法 在出生后保持足够的骨形成，并患有自发性骨折，但不能通过 时间到了。在我们的实验室里，我们目前正在研究导致自发性的分子机制 在缺乏BMP2的情况下观察到骨折和缺乏骨折修复。我们目前的数据表明，缺乏 BMP2的表达诱导了一种结构表型，从而导致了自发性骨折。此外，骨骼 缺乏BMP2表明Wnt信号通路抑制物的表达增加， 骨骼祖细胞的数量。在这个提议中，我们假设BMP2在 骨内平衡的调节和膜内骨干细胞生态位的控制。我们致力于 这一假设有四个具体目的。在特定的目标1中，我们通过杂交这些小鼠来挽救BMP2的表型 用Wnt信号通路的拮抗剂Dkk1杂合的小鼠，并通过给予LiCl2， Wnt信号通路的化学激活剂。在特定的目标2中，通过活体显微镜 探索膜内骨干细胞巢的位置和组织。在具体目标3中，我们 研究BMP2的存在和不存在对生态位的影响。在具体目标4中，我们检查 衰老对膜内骨干细胞生态位的影响及稳定期挽救衰老表型 骨形态发生蛋白2的表达。在奖项的初始指导阶段，我们将利用具体的目标1和2。 具体目标3和4将在颁奖的独立阶段制定。总而言之，这些 研究将评估BMP2在调节膜内骨干细胞生态位中的作用 旨在为牙科和颌面部骨疗法的发展提供重要信息。

Abstract Recent studies suggest that osteogenic bone morphogenetic proteins (BMPs) are required for the rapid bone formation that occurs in neonatal animals, and for bone remodeling, the most important function of the adult skeleton. It appears that BMPs 4, 5, 6 and 7 are not essential mediators of bone formation in adults, as mice lacking any one of these BMPs maintain normal bone mass. In contrast, mice lacking BMP2 are unable to maintain adequate bone formation after birth and suffer of spontaneous fractures that do not resolve with time. In our laboratory we are currently investigating the molecular mechanisms responsible for spontaneous fractures and lack of fracture repair observed in the absence of BMP2. Our current data suggest that the lack of BMP2 induces a structural phenotype that is responsible for the spontaneous fractures. Additionally, bones lacking BMP2 show an increased expression of inhibitors of the Wnt signaling pathway and an increased number of skeletal progenitor cells. In this proposal we hypothesize that BMP2 has a central role in the regulation of bone homeostasis and in the control of the intramembranous bone stem cell niche. We address this hypothesis in four specific aims. In Specific Aim 1 we rescue the BMP2 phenotype by crossing these mice with mice heterozygous for Dkk1, an antagonist of the Wnt signaling pathway and by administering LiCl, a chemical activator of the Wnt signaling pathway. In Specific Aim 2, by means of intravital microscopy we explore the location and the organization of the intramembranous bone stem cell niche. In Specific Aim 3, we investigate the effects of the presence and absence of BMP2 on the niche. In Specific Aim 4, we examine the effects of aging on the intramembranous bone stem cell niche and rescue the aging phenotype by steady expression of BMP2. During the initial Mentored phase of the award we will exploit Specific Aims 1 and 2. Specific Aims 3 and 4 will be developed during the Independent phase of the award. In summary, these studies will evaluate the role of BMP2 in the regulation of the intramembranous bone stem cell niche with the intent of providing important information for the development of novel dental and maxillofacial bone therapies.