Nmp4/CIZ regulation of bone phenotype

描述（由申请人提供）：骨质疏松症是一种主要的公共卫生威胁，其特征是骨量低，导致骨骼骨折的易感性增加。甲状旁腺激素（PTH）治疗是一种有前途的新疗法，刺激骨形成，但这种合成代谢反应的机制在很大程度上是未知的。PTH诱导的成骨细胞表型变化的分子基础涉及可溶性信号通路与固态支架的整合，其本身能够将信息传递到靶基因。细胞外基质、粘着斑、细胞骨架和核基质的相互连接的蛋白质构成该支架或组织基质。Nmp 4/CIZ（nuclear matrix protein 4/cas-interacting zinc finger protein，核基质蛋白4/cas相互作用锌指蛋白）可能整合了PTH激活的可溶性和固态信号通路与转录。这种蛋白质是成骨细胞组织基质的PTH应答组分和核质穿梭转录因子。作为转录因子，Nmp 4/CIZ控制转录诱导的幅度（协同控制）。例如，Nmp 4/CIZ抑制了响应PTH、前列腺素E2和骨形态发生蛋白2的特定成骨细胞基因的活性增加。这种功能的丧失可能导致Nmp 4/CIZ敲除小鼠的骨骼表型，其中包括对PTH和BMP 2的增强的骨骼反应。我们的初步研究表明，Nmp 4/CIZ协同控制涉及Nmp 4/CIZ-DNA结合活性的激素调节和Runx 2的相互作用。作为一种信号分子，Nmp 4/CIZ可能通过与p130 cas（一种参与有丝分裂的整合素相关对接蛋白）相互作用来调节成骨细胞增殖。Nmp 4/CIZ也在破骨细胞中表达，我们的初步数据表明在破骨细胞生成中的作用。我们推测Nmp 4/CIZ作为信号分子和转录因子的功能整合在介导PTH诱导的骨骼结构变化中。将使用野生型和Nmp 4/CIZ遗传修饰小鼠来研究Nmp 4/CIZ在介导PTH诱导的骨表型变化中的作用。来自这些小鼠的成骨细胞和破骨细胞将用于确定Nmp 4/CIZ作为信号分子和转录因子在介导骨细胞对激素的反应中的功能作用。这项工作与公共卫生的相关性在于，它将确定治疗骨质疏松症的潜在新治疗靶点。

DESCRIPTION (provided by applicant): Osteoporosis is a major public health threat characterized by low bone mass leading to an increased susceptibility to skeletal fractures. Parathyroid hormone (PTH) treatment is a promising new therapy that stimulates bone formation, however the mechanisms underlying this anabolic response are largely unknown. The molecular basis underlying PTH-induced changes in osteoblast phenotype involves the integration of soluble signaling pathways with a solid-state scaffold, itself capable of transmitting information to target genes. The interlinking proteins of the extracellular matrix, the focal adhesions, the cytoskeleton, and the nuclear matrix comprise this scaffold or tissue matrix. Nmp4/CIZ (nuclear matrix protein 4/cas-interacting zinc finger protein) may integrate PTH activated soluble and solid-state signaling pathways with transcription. This protein is a PTH-responsive component of the osteoblast tissue matrix and a nucleocytoplasmic shuttling transcription factor. As a transcription factor, Nmp4/CIZ governs the amplitude of transcription induction (synergy control). For example, Nmp4/CIZ suppresses the increase in activity of specific osteoblast genes responding to PTH, prostaglandin E2, and bone morphogenetic protein 2. The loss of this function may contribute to the skeletal phenotype of Nmp4/CIZ knockout mice, which includes an enhanced skeletal response to PTH and BMP2. Our preliminary studies indicate that Nmp4/CIZ synergy control involves hormone regulation of Nmp4/CIZ-DNA binding activity and an interaction with Runx2. As a signaling molecule, Nmp4/CIZ may regulate osteoblast proliferation via an interaction with p130cas, an integrin- associated docking protein involved in mitogenesis. Nmp4/CIZ is also expressed in the osteoclast and our preliminary data indicate a role in osteoclastogenesis. We hypothesize that the functions of Nmp4/CIZ as signaling molecule and transcription factor are integrated in mediating PTH-induced changes in skeletal architecture. Wild type and Nmp4/CIZ genetically modified mice will be used to study the role of Nmp4/CIZ in mediating PTH-induced changes in bone phenotype. Osteoblasts and osteoclasts derived from these mice will be used to determine the functional role of Nmp4/CIZ as a signaling molecule and transcription factor in mediating bone cell response to hormone. The relevance of this work to public health is that it will identify a potential new therapeutic target for the treatment of osteoporosis.