Regulation of Osteoclast Differentiation by Pax5

Pax5 对破骨细胞分化的调节

• 批准号: 7241553
• 负责人: MARK C HOROWITZ
• 金额: $ 28.42万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7241553
• 关键词: Adoptive Transfer; Affect; Age; Age-Related Bone Loss; Alkaline Phosphatase; Anabolic Agents; Animals; Antibodies; Appearance; Ascorbic Acid; B cell differentiation; B-Lymphocytes; Biochemical; Biochemistry; Bone Marrow; Bone Morphogenetic Proteins; Bone Resorption; C-KIT Gene; Caliber; Calvaria; Cell Differentiation process; Cell Line; Cell Lineage; Cell physiology; Cell surface; Cells; Cessation of life; Characteristics; Chondrocytes; Collagen; Collagen Type I; Commit; Count; Cyclophosphamide; DEXA; Data; Defect; Development; Dexamethasone; Enzyme-Linked Immunosorbent Assay; Epiphysial cartilage; Femur; Fetus; Fracture; Gene Expression; Gene Transfer; Genes; Goals; Hematopoietic; Histology; Homeostasis; Immune; Implant; In Vitro; Insulin-Like Growth Factor I; Length; Macrophage Colony-Stimulating Factor; Mature B-Lymphocyte; Mature Bone; Measures; Mesenchymal Stem Cells; Minerals; Modeling; Molecular; Mus; Mutant Strains Mice; Neonatal; Northern Blotting; Numbers; Osteoblasts; Osteocalcin; Osteoclasts; Osteogenesis; Osteoid; Osteonectin; Parathyroid Hormones; Pathway interactions; Phenotype; Population; Postmenopausal Osteoporosis; Proliferating; Prosthesis; Proteins; Proto-Oncogene Protein c-kit; Rattus; Regulation; Rest; Retroviridae; Reverse Transcriptase Polymerase Chain Reaction; Role; Series; Serum; Site; Skeletal system; Source; Spleen; Staging; Stem cells; Sternum; Stromal Cells; T-Lymphocyte; TNFSF11 gene; Thinking; Time; Urine; Weight; Western Blotting; beta-glycerophosphate; bone; bone epiphysis; bone loss; bone sialoprotein; c-fms Proto-Oncogenes; day; established cell line; experience; human PTH protein; in vivo; in vivo Model; long bone; mRNA Expression; macrophage; mineralization; monocyte; mutant; neonate; novel; osteoclastogenesis; osteopontin; precursor cell; repaired; research study; response; rib bone structure; size; spine bone structure; substantia spongiosa; success; tibia; transcription factor

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.

描述（由申请人提供）：破骨细胞是吸收骨的细胞，其起源是造血的，并且与其他造血谱系一样，由多能干细胞产生，并通过一系列发育阶段成熟。除了终末分化步骤成为成熟的骨吸收细胞外，对这种发育途径的了解很少。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RANKL，其参与破骨细胞分化。骨骼稳态的丧失可导致B细胞功能改变。我们已经开始分析Pax 5缺陷的小鼠，Pax 5是B细胞分化所需的转录因子。这些动物经历B细胞分化的发育阻滞，导致以完全缺乏成熟B细胞为特征的表型。初步数据表明，这些小鼠严重矮小，骨小梁显著减少，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Pax 5的缺失导致某些增强破骨细胞生成的基因的失调，这反过来又产生了骨表型。这种失调也可能是B细胞谱系定型的伴随损失的原因。将追求三个特定目标：1）Pax 5缺陷小鼠中骨表型的定量分析; 2）体外突变成骨细胞、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和定量功能分析。该提案的长期目标是确定Pax 5调节正常破骨细胞分化的机制。Pax 5缺乏似乎是一种新的破骨细胞发育模型，并应允许详细检查破骨细胞前体发育以前无法获得。破骨细胞发育的新模型有可能发现新的、未被认识的分解代谢途径。这对于具有确定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、年龄相关的骨质减少、骨折修复和假体植入物的延长生存期。