Nmp4/CIZ regulation of bone phenotype

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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.