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健康威胁，其特征是低骨量导致对骨骼骨折的易感性增加。甲状旁腺激素（PTH）治疗是一种很有前途的新疗法，可以刺激骨形成，然而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体支架的整合，固体支架本身能够向靶基因传递信息。细胞外基质的相互连接蛋白、局灶黏附、细胞骨架和核基质组成了这个支架或组织基质。Nmp4/CIZ（核基质蛋白4/cas相互作用锌指蛋白）可能通过转录整合PTH激活的可溶性和固态信号通路。该蛋白是成骨细胞组织基质的促甲状腺素反应成分，也是核细胞质穿梭转录因子。作为一个转录因子，Nmp4/CIZ控制转录诱导的幅度（协同控制）。例如，Nmp4/CIZ抑制PTH、前列腺素E2和骨形态发生蛋白2应答的特定成骨细胞基因活性的增加。这种功能的丧失可能导致Nmp4/CIZ基因敲除小鼠的骨骼表型，包括骨骼对PTH和BMP2的反应增强。我们的初步研究表明，Nmp4/CIZ协同控制涉及激素对Nmp4/CIZ- dna结合活性的调节以及与Runx2的相互作用。作为一种信号分子，Nmp4/CIZ可能通过与p130cas（一种参与有丝分裂的整合素相关对接蛋白）的相互作用来调节成骨细胞的增殖。Nmp4/CIZ也在破骨细胞中表达，我们的初步数据表明在破骨细胞发生中起作用。我们假设Nmp4/CIZ作为信号分子和转录因子的功能在介导pth诱导的骨骼结构变化中是综合的。野生型和Nmp4/CIZ转基因小鼠将被用于研究Nmp4/CIZ在介导pth诱导的骨表型变化中的作用。这些小鼠的成骨细胞和破骨细胞将被用来确定Nmp4/CIZ作为信号分子和转录因子在介导骨细胞对激素反应中的功能作用。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.