Shp2 in Osteoclastogenesis and Bone Remodeling

描述(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的骨骼矿物质流失，从而治疗骨质疏松症和其他影响大量美国人的骨骼退行性疾病。这项建议的长期目标是阐明蛋白酪氨酸磷酸酶(PTP)，特别是PTP Shp2，在破骨细胞形成和骨重建中的作用。我采用组织/细胞特异性基因敲除的方法，分别用LysM-Cre和CTSK-Cre转基因系培育Shp2等位基因，产生破骨细胞前体和成熟破骨细胞中Shp2特异性表达缺失的小鼠。我的初步数据显示，在破骨细胞中缺乏Shp2的小鼠是成骨的，来自突变小鼠的骨髓细胞在体外损害了破骨细胞的生成，这意味着Shp2在破骨细胞发育、骨重建和矿物质维持中起着关键作用。利用这些独特的小鼠模型及其细胞衍生物，我将以独特的身份回答三个重要问题：目的1：确定Shp2如何支持破骨细胞前体细胞的存活以及它们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Shp2缺陷小鼠的破骨细胞表型是否是由破骨细胞数量和/或功能减少引起的；目的3：确定Shp2如何调控巨噬细胞集落刺激因子(M-CSF)和核因子kB受体激活剂(RANKL)对破骨细胞生成和破骨细胞骨吸收功能的信号传导。详细了解这一分子机制将为设计新的治疗衰老相关骨骼退行性疾病的方法提供洞察力，这些疾病没有恢复性或再生性治疗。 公共卫生相关性：我们将研究蛋白酪氨酸磷酸酶Shp2在破骨细胞形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，并找到治疗骨质疏松症和其他骨骼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.