Regulation of Osteoclast Differentiation by Pax5

描述（由申请人提供）：破骨细胞，吸收骨的细胞，起源于造血，与其他造血谱系一样，起源于多能干细胞，并经过一系列发育阶段成熟。除了成为成熟骨吸收细胞的最终分化步骤外，这一发育途径尚不清楚。在早期发育阶段尤其如此。B淋巴细胞（B细胞）是产生抗体的细胞，表达细胞表面分子，如参与破骨细胞分化的RANKL。骨骼稳态的丧失可导致B细胞功能的改变。我们已经开始对缺乏Pax5的小鼠进行分析，Pax5是B细胞分化所需的转录因子。这些动物在B细胞分化中经历发育障碍，导致完全缺乏成熟B细胞的表型。初步数据表明，这些小鼠严重矮小，骨小梁明显减少，破骨细胞前体和破骨细胞数量增加，骨吸收增加，成骨细胞数量减少。我们的假设是，Pax5的缺失导致某些增强破骨细胞生成的基因的失调，进而产生最终的骨表型。这种放松管制也可能导致b细胞谱系承诺的丧失。三个具体目标：1)定量分析Pax5缺失小鼠的骨表型；2)体外突变型成骨细胞、基质细胞和软骨细胞的定量功能分析；3)破骨细胞前体的分离及定量功能分析。这项提议的长期目标是确定Pax5调节正常破骨细胞分化的机制。Pax5缺乏似乎是破骨细胞发育的一种新模式，应该允许对以前无法获得的破骨细胞前体发育进行详细检查。破骨细胞发育的新模型提供了发现新的、未被识别的分解代谢途径的潜力。对于具有已建立的骨表型的体内模型尤其如此。这些信息将适用于各种骨骼缺陷，包括绝经后骨质疏松症、年龄相关性骨质减少、骨折修复和假体植入物的延长生存期。

DESCRIPTION (provided by applicant): Osteoclasts, the cells that resorb bone, are hematopoietic in origin and like other hematopoietic lineages arise from pluripotential stem cells, and mature through a series of developmental stages. With the exception of the terminal differentiation step to become mature bone resorbing cells, this developmental pathway(s) is poorly understood. This is particularly true of the early developmental stages. B lymphocytes (B cells), the cells which make antibodies, express cells surface molecules such as RANKL, which are involved in osteoclast differentiation. Loss of skeletal homeostasis can result in altered B cell function. We have begun an analysis of mice deficient in Pax5, a transcription factor required for the differentiation fo B cells. These animals experience a developmental block in B cell differentiation resulting in a phenotype characterized by the complete lack of mature B cells. Preliminary data indicate these mice are severely runted, develop strikingly decreased trabecular bone, with increased numbers of osteoclast precursors and osteoclasts, increased bone resorption, and reduced numbers of osteoblasts. It is our hypothesis that the loss of Pax5 leads to the deregulation of certain genes that enhance osteoclastogenesis and this, in turn, produces the resultant bone phenotype. This deregulation may also be responsible for the concomitant loss of B-cell lineage commitment. Three Specific Aims will be pursued: 1) Quantitative analysis of the bone phenotype in Pax5 deficient mice; 2) Quantitative functional analysis of mutant osteoblasts, stromal cells, and chondrocytes in vitro; and 3) Isolation and quantitative functional analysis of the osteoclast precursors. The long-term goal of this proposal is to identify the mechanism(s) by which Pax5 regulates normal osteoclast differentiation. Pax5 deficiency appears to be a novel model for osteoclast development and should allow for a detailed examination of osteoclast precursor development previously unobtainable. New models of osteoclast development present the potential to discover new, unrecognized catabolic pathways. This is particularly true for in vivo models with an established bone phenotype. Such information would be applicable to a wide variety of skeletal defects including, post-menopausal osteoporosis, age-related osteopenia, fracture repair, and extended survival of prosthetic implants.