Regulation of Osteoclast Differentiation by Pax5

描述(申请人提供)：破骨细胞，即吸收骨的细胞，起源于造血细胞，与其他造血祖细胞一样，起源于多潜能干细胞，并通过一系列发育阶段成熟。除了成熟骨吸收细胞的终末分化步骤外，人们对这一发育途径(S)知之甚少。对于早期发育阶段来说，情况尤其如此。B淋巴细胞(B细胞)是制造抗体的细胞，表达细胞表面分子，如RANKL，参与破骨细胞分化。骨骼动态平衡的丧失会导致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细胞分化所需的一种转录因子。这些动物经历了B细胞分化的发育障碍，导致了以完全缺乏成熟B细胞为特征的表型。初步数据显示，这些小鼠严重疲劳，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的缺失导致促进破骨细胞生成的某些基因的失控，从而产生最终的骨表型。这种放松管制也可能是伴随而来的B细胞谱系承诺丧失的原因。我们将追求三个具体目标：1)定量分析Pax5基因缺陷小鼠的骨表型；2)体外定量分析突变的成骨细胞、基质细胞和软骨细胞；3)分离和定量分析破骨细胞前体。这项建议的长期目标是确定Pax5调节正常破骨细胞分化的机制(S)。Pax5缺乏似乎是破骨细胞发育的一种新模式，应该可以对以前无法获得的破骨细胞前体发育进行详细的检查。破骨细胞发育的新模型提供了发现新的、未知的分解代谢途径的潜力。对于已有骨表型的活体模型尤其如此。这些信息将适用于各种各样的骨骼缺陷，包括绝经后骨质疏松症、年龄相关性骨量减少、骨折修复和假体存活期延长。

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.