Significance: Paget's disease is the second most common bone disease, affecting 2-3 million people in the United States. It is the most exaggerated example of bone remodeling, where increased osteoclastic bone absorption is followed by exuberant new bone formation that is of poor quality. Although Paget's disease was first described more than 100 years ago, and a potential viral etiology for Paget's disease suggested nearly 30 years ago, little is known about its pathogenesis and the role that a virus may play in Paget's disease. Thus, a P01 grant that focuses on the underlying pathophysiology of Paget's disease has important implications on all areas of bone research. Approach: This P01 application represents a concerted approach to understand the pathogenesis of Paget's disease and brings together investigators of diverse expertise to address this important problem. The P01 will employ molecular biological, cell biological, and transgenic animal approaches to understand the underlying pathophysiology of Paget's disease and the role measles virus (MV) plays in Paget's disease. The overall goals of the program project are to: 1) determine the function of the measles virus nucleocapsid gene (MVNP) in Paget's disease using structure/function, and in vivo experiments testing a recombinant MV which contains the MVNP gene derived from a Paget's patient; 2) develop an in vivo model of Paget's disease using targeted expression of the MVNP gene and the mutant p62 gene linked to familial Paget's disease to OCL in vivo. Currently no animal model of Paget's disease exists, which has severely hampered progress in understanding the pathophysiology of the disease or the roles of specific factors or genes in this process. 3) determine the mechanisms responsible for the constitutive expression of high levels of RANKL in pagetic lesions; and 4) assess the importance of VDR responsive gene expression in development of the pagetic phenotype in osteoclasts (OCL), the mechanisms responsible for the enhanced 1,25 dihydroxy vitamin D3 responsivity of OCL precursors in Paget's disease, and the effects of overexpressing coactivators of VDR, such as TAF(II)17, in OCL in vivo; and Innovation: This P01 application employs novel transgenic mouse models and recombinant MV to test the role of the MVNP gene, and genes induced by MVNP in the development of Paget's disease. Environment: This P01 application involves investigators with expertise in molecular biology, cell biology, gene transcription, histomorphometry and transgenic approaches. These investigators work in an outstanding university that has large numbers of funded investigators interested in bone biology and clinical trials for bone diseases. The knowledge gained from this P01 grant will offer important insights for normal bone cell biology especially for understanding the paracrine regulation of osteoblasts by OCLs.
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