BMP2 regulation of the intramembranous bone stem cell niche

摘要 最近的研究表明，成骨骨形态发生蛋白（BMP）是快速骨形成所必需的。 新生动物中发生的骨形成，以及骨重建， 成人骨骼BMP4、5、6和7似乎不是成人骨形成的必需介质， 缺乏这些BMP中的任何一种的小鼠维持正常的骨质量。相比之下，缺乏BMP 2的小鼠不能 出生后保持足够的骨形成，并患有自发性骨折， 时间在我们的实验室中，我们目前正在研究负责自发的分子机制。 在没有BMP 2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， BMP 2诱导的结构表型是负责自发性骨折。此外，bones 缺乏BMP 2的小鼠显示Wnt信号通路抑制剂的表达增加， 骨骼祖细胞的数量。在这个提议中，我们假设BMP 2在细胞凋亡中起核心作用。 调节骨稳态和控制膜内骨干细胞龛。我们解决 这一假设有四个具体目标。在特定目标1中，我们通过杂交这些小鼠来拯救BMP 2表型。 用Wnt信号通路拮抗剂Dkk1杂合子小鼠， Wnt信号通路的化学激活剂。在具体目标2中，通过活体显微镜，我们 探讨膜内骨干细胞龛的位置和组织结构。在具体目标3中，我们 研究BMP 2的存在和不存在对生态位的影响。在具体目标4中，我们检查了 衰老对膜内骨干细胞生态位的影响及稳定的细胞因子对衰老表型的挽救作用 BMP 2的表达。在该奖项的初始指导阶段，我们将利用具体目标1和2。 具体目标3和4将在奖项的独立阶段制定。总而言之， 研究将评估BMP 2在调节膜内骨干细胞龛中的作用， 旨在为新型牙科颌面骨治疗方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.