Shp2 in Osteoclastogenesis and Bone Remodeling

描述（由申请方提供）：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的骨矿物质损失，从而治疗骨质疏松症和其他影响大量美国人的骨退行性疾病。这项提案的长期目标是阐明蛋白酪氨酸磷酸酶（PTP），特别是PTP Shp 2在破骨细胞生成和骨重建中的功能。采用组织/细胞特异性基因敲除的方法，将Shp 2 floxed等位基因分别与LysM-Cre和Ctsk-Cre转基因系杂交，获得了破骨细胞前体细胞和成熟破骨细胞特异性表达Shp 2的小鼠。我的初步数据表明，小鼠缺乏Shp 2破骨细胞是骨硬化，和骨髓细胞的突变小鼠有受损的破骨细胞体外，暗示了一个关键的作用，Shp 2破骨细胞的发展，骨重建和矿物质的维护。有了这些独特的小鼠模型和它们的细胞衍生物，我将处于一个独特的位置来解决三个重要的问题：目的1：确定Shp 2如何支持破骨细胞前体细胞的存活及其向功能性破骨细胞的增殖和分化;目的2：确定破骨细胞特异性Shp 2缺陷小鼠中的骨硬化表型是否由破骨细胞数量和/或功能的减少引起;目标3：确定Shp 2如何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）诱发的信号传导，以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新的治疗方法提供见解，用于治疗与衰老相关的骨退行性疾病，这些疾病没有恢复或再生治疗。 公共卫生相关性：我们将研究蛋白酪氨酸磷酸酶Shp 2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理解Shp 2在破骨细胞发育和功能调节中的细胞和细胞机制，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。

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.