BMP2 regulation of the intramembranous bone stem cell niche

描述（由申请人提供）：最近的研究表明，新生动物中发生的快速骨形成和骨重建（成人骨骼最重要的功能）需要成骨形态发生蛋白（BMP）。似乎BMP 4、5、6和7不是成人骨形成的必需介质，因为缺乏这些BMP中的任何一种的小鼠维持正常的骨量。相比之下，缺乏BMP 2的小鼠在出生后无法维持足够的骨形成，并且患有自发性骨折，这些骨折不会随着时间的推移而消退。在我们的实验室中，我们目前正在研究自发性骨折的分子机制，以及在缺乏BMP 2的情况下观察到的骨折修复缺乏。我们目前的数据表明，缺乏BMP 2诱导的结构表型，是负责自发性骨折。此外，缺乏BMP 2的骨骼显示Wnt信号通路抑制剂的表达增加，骨骼祖细胞数量增加。在这个提议中，我们假设BMP 2在调节骨稳态和控制膜内骨干细胞龛中具有核心作用。我们在四个具体目标中解决这个假设。在特定目标1中，我们通过将这些小鼠与Dkk 1（Wnt信号通路的拮抗剂）杂合子小鼠杂交，并通过给予LiCl（Wnt信号通路的化学激活剂）来拯救BMP 2表型。在特定目标2中，通过活体显微镜，我们探索了膜内骨干细胞龛的位置和组织。在具体目标3中，我们研究了BMP 2的存在和不存在对生态位的影响。在具体目标4中，我们研究了衰老对膜内骨干细胞龛的影响，并通过稳定表达BMP 2来挽救衰老表型。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。总之，这些研究将评估BMP 2在调节膜内骨干细胞龛中的作用，旨在为开发新的牙科和颌面骨治疗提供重要信息。 公共卫生相关性：最近的研究表明，干细胞（能够分化成不同种类细胞的未分化细胞）和干细胞龛（干细胞驻留的地方）可以调节器官或组织的稳态。干细胞分化为其他细胞的机制失调可能导致细胞类型之间的不平衡，从而导致疾病。由于我们以前的研究已经确定BMP 2是骨稳态的关键因素，我们相信，对BMP 2调节骨干细胞的方式有更深入的了解，可能会为开发新的牙科和骨科治疗提供重要信息。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Recent studies have shown that stem cells (undifferentiated cells able to differentiate into different kinds of cells) and stem cell niche (the place where stem cells reside) may regulate the homeostasis of an organ or a tissue. A dysregulation of the mechanisms by which stem cells differentiate into other cells may lead to an imbalance among cell types and therefore to diseases. Since our previous studies have identified BMP2 as a key factor for bone homeostasis, we believe that developing a greater understating of the way BMP2 regulates bone stem cells may provide important information for the development of novel dental and orthopaedic therapies.