Shp2 in Osteoclastogenesis and Bone Remodeling

Shp2 在破骨细胞生成和骨重塑中的作用

• 批准号: 7788413
• 负责人: Wentian Yang
• 金额: $ 20.57万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7788413
• 关键词: Address; Adherence; Affect; Age; Albers-Schonberg disease; Alleles; American; Animals; Architecture; Biochemical; Biological; Biological Assay; Bone Density; Bone Development; Bone Marrow; Bone Marrow Cells; Bone Matrix; Bone Resorption; Bone remodeling; Breeding; Cells; Colony-forming units; Data; Defect; Degenerative Disorder; Deposition; Development; Diagnostic radiologic examination; Disease; Generations; Goals; Growth; Hematopoietic; Histology; Homeostasis; In Vitro; Lead; Ligands; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Maintenance; Marrow; Menopause; Mesenchymal Stem Cells; Minerals; Molecular; Molecular Target; Mus; Mutant Strains Mice; Mutation; Nuclear; Osteoblasts; Osteoclasts; Osteoporosis; PTPN11 gene; Pharmaceutical Preparations; Phenotype; Play; Positioning Attribute; Protein Tyrosine Phosphatase; Regulation; Research; Role; Signal Transduction; Skeletal Development; Src homology 2 domain-containing, transforming protein 1; Staining method; Stains; Surface; System; Thick; Tissues; Transgenic Organisms; United States; Woman; age related; bone; bone mass; c-fms Proto-Oncogenes; cell type; design; in vivo; insight; knockout gene; macrophage; migration; mouse model; mutant; novel; novel therapeutics; osteoclastogenesis; public health relevance; receptor; regenerative; response; skeletal; skeletal disorder; stem; tartrate-resistant acid phosphatase

DESCRIPTION (provided by applicant): Osteoclasts are the exclusive cells responsible for bone resorption. Governing their number and function can reduce bone mineral loss during ageing, and therefore treat osteoporosis and other bone degenerative diseases that affect a significant number of Americans. The long-term goal of this proposal is to elucidate the function of protein tyrosine phosphatases (PTP), specifically PTP Shp2, in osteoclastogenesis and bone remodeling. Taking a tissue/cell specific gene knockout approach, I bred Shp2 floxed allele with LysM-Cre and Ctsk-Cre transgenic lines respectively to generate mice lacking Shp2 expression specifically in osteoclast precursors and mature osteoclasts. My preliminary data demonstrate that mice lacking Shp2 in osteoclasts are osteopetrotic, and bone marrow cells from the mutant mice have impaired osteoclastogenesis ex vivo, implicating a critical role for Shp2 in osteoclast development, bone remodeling and mineral maintenance. With these unique mouse models and their cellular derivatives, I will be in an unique position to address three important questions: Aim 1: to determine how Shp2 supports the survival of osteoclast precursors and their proliferation and differentiation towards functional osteoclasts; Aim 2: to determine whether the osteopetrotic phenotype in osteoclast-specific Shp2 deficient mice is caused by reduction of osteoclast numbers, and/or function; Aim 3: to define how is the signaling evoked by macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor kB ligand (RANKL) regulated by Shp2 for osteoclastogenesis and osteoclast bone resorptive function. Understanding this molecular machinery in detail will provide insights into designing new therapeutics for ageing related bone degenerative diseases for which there are no restorative or regenerative treatment. PUBLIC HEALTH RELEVANCE: We will study the role of protein tyrosine phosphatase Shp2 in osteoclastogenesis and osteoclast functional activation. Our research will lead to a better understanding of the moceluar and cellular mechanism of Shp2 in osteoclast development and functional regulation, and identifying potential novel targets for treating osteoporosis and other bone degenerative diseases.

描述（由申请人提供）：破骨细胞是负责骨吸收的唯一细胞。控制它们的数量和功能可以减少衰老过程中骨矿物质的流失，从而治疗影响大量美国人的骨质疏松症和其他骨退行性疾病。该提案的长期目标是阐明蛋白酪氨酸磷酸酶 (PTP)，特别是 PTP Shp2，在破骨细胞生成和骨重塑中的功能。采用组织/细胞特异性基因敲除方法，我分别用 LysM-Cre 和 Ctsk-Cre 转基因品系培育 Shp2 floxed 等位基因，以产生在破骨细胞前体和成熟破骨细胞中特异性缺乏 Shp2 表达的小鼠。我的初步数据表明，破骨细胞中缺乏Shp2的小鼠是骨石症的，并且来自突变小鼠的骨髓细胞在体外破骨细胞生成受损，这表明Shp2在破骨细胞发育、骨重塑和矿物质维持中发挥着关键作用。有了这些独特的小鼠模型及其细胞衍生物，我将处于一个独特的位置来解决三个重要问题： 目标 1：确定 Shp2 如何支持破骨细胞前体的存活及其增殖和分化为功能性破骨细胞；目标2：确定破骨细胞特异性Shp2缺陷小鼠的骨石化表型是否是由破骨细胞数量和/或功能减少引起的；目标 3：明确 Shp2 调节巨噬细胞集落刺激因子 (M-CSF) 和核因子 kB 配体受体激活剂 (RANKL) 引发的信号如何促进破骨细胞生成和破骨细胞骨吸收功能。详细了解这种分子机制将为设计治疗与衰老相关的骨退行性疾病（目前尚无恢复或再生治疗方法）的新疗法提供见解。 公共健康相关性：我们将研究蛋白酪氨酸磷酸酶 Shp2 在破骨细胞生成和破骨细胞功能激活中的作用。我们的研究将有助于更好地了解Shp2在破骨细胞发育和功能调节中的分子和细胞机制，并确定治疗骨质疏松症和其他骨退行性疾病的潜在新靶点。