CONTROL OF OSTEOGENESIS AND ADIPOGENESIS BY EBF

描述(申请人提供)：成骨细胞，即形成骨的细胞，起源于间充质，与其他间充质系一样，是由多潜能干细胞通过一系列发育转变而产生的。成骨细胞的发育途径只被部分了解，特别是在其早期阶段，人们对导致成骨细胞谱系承诺的细胞命运决定知之甚少。脂肪细胞，即产生脂肪的细胞，可能与成骨细胞共享一个共同的早期祖先，尽管对这种谱系分歧的分子控制知之甚少。越来越多的证据表明，从造血干细胞发育B淋巴细胞所需的转录因子对骨骼的正常发育至关重要，尽管到目前为止还没有发现与成骨细胞分化有关的转录因子。我们发现早期B细胞因子-1(EBF-1)是一种对B细胞发育至关重要的转录因子，在成骨细胞中表达，并在控制成骨细胞发育中发挥关键作用。EBF-1基因缺陷的小鼠发育不良，骨形成参数增加，成骨细胞数量显著增加。值得注意的是，这些小鼠还表现出长骨髓管中脂肪细胞的戏剧性扩张。支持这一建议的中心假设是EBF-1及其上游调控和下游靶基因对成骨细胞和脂肪细胞发育的控制至关重要。我们的发现表明，EBF-1和EBF-1缺陷小鼠提供了一个独特的机会，可以从分子上深入了解这两个谱系的发育。我们工作的长期目标是确定EBF-1调控成骨和脂肪生成的机制(S)。实现这一目标的第一步是在组织、形态、细胞和分子水平上对EBF-1缺陷小鼠进行仔细的分析，这将提供所需的信息，以制定EBF-1在骨和脂肪细胞发育中的作用的详细分子假说。为此，我们将追求两个特定的目标：1)确定EBF-1缺陷小鼠的骨表型；2)通过定量分析来表征EBF-1缺陷的成骨细胞、成骨细胞前体和脂肪细胞的功能和分子特性。我们预计，这些实验将导致新的成骨细胞发育模型，从而有可能发现新的合成代谢途径。这些信息将适用于各种各样的骨骼缺陷，包括年龄相关性骨量减少、绝经后骨质疏松症、骨折修复和假体存活期延长。

DESCRIPTION (provided by applicant): Osteoblasts, the cells that form bone, are mesenchymal in origin and like other mesenchymal lineages arise from pluripotential stem cells through a series of developmental transitions. The osteoblast developmental pathway is only partially understood, particularly in its early stages, where little is know about the cell fate decisions that lead to commitment to the osteoblast lineage. Adipocytes, the cells that produce fat, likely share a common early progenitor with osteoblasts, although little is known about the molecular control of this lineage bifurcation. Growing evidence indicates that transcription factors required for B lymphocyte development from hematopoietic stem cells are critical for proper skeletal development although as yet none have been implicated in osteoblast differentiation. We have discovered that Early B Cell Factor-1 (EBF-1), a transcription factor essential for B cell development, is expressed in osteoblasts and plays a critical role in controlling osteoblast development. EBF-1 deficient mice are runted, have increased bone formation parameters, and display a striking increase in numbers of osteoblasts. Remarkably, these mice also exhibit a dramatic expansion of adipocytes in the medullary canal of long bones. The central hypothesis underlying this proposal is that EBF-1 and its upstream regulatory and downstream target genes are critical for the control of osteoblast and adipocyte development. Our findings suggest that EBF-1 and EBF-1 deficient mice provide a unique opportunity to gain significant molecular insight into the development of these two lineages. The long-term goal of our work is to identify the mechanism(s) by which EBF-1 regulates osteogenesis and adipogenesis. The first step in achieving this goal is a careful analysis of the EBF-1 deficient mice at the histological, morphological, cellular, and molecular level, which will provide the information needed to formulate detailed molecular hypotheses for the role of EBF-1 in bone and fat cell development. Toward this end, we will pursue two Specific Aims: 1) To determine the bone phenotype of EBF-1 deficient mice; and 2) To characterize through a quantitative analysis the functional and molecular properties of EBF-1 deficient osteoblasts, osteoblast precursors, and adipocytes. We anticipate that these experiments will lead to new models for osteoblast development and hence for the potential to discover new anabolic pathways. Such information would be applicable to a wide variety of skeletal defects including age-related osteopenia, post-menopausal osteoporosis, fracture repair, and extended survival of prosthetic implants.