Abstract : Paget's disease (PD) of bone occurs in 3-4% of population over the age of 50. We have identified expression of measles virus nucleocapsid transcripts in osteoclast (OCL) precursors and that MVNP expression induces pagetic phenotype in osteoclasts with increased bone resorption activity as seen in patients with Paget's disease. We previously cloned and identified osteoclast inhibitory peptide-1 (OIP-1/hSca) which inhibits osteoclast formation and bone resorption. We hypothesize that MVNP expression in osteoclast precursors modulates RANK receptor signaling leading to Pagetic OCL development. OIP-1 blocks these signaling events and inhibits MVNP induced osteoclastogenesis and elevated bone resorption activity. We demonstrated that MVNP increases TNF-alpha induced OCL differentiation and activation by increasing NF-kB signaling through increased expression of p62, and IKK-gama and increased MAPK signaling. Our results also suggest that MVNP's effects on TNF-alpha signaling contribute to the increased OCL formation in PD. Furthermore, expression of MVNP gene in OCL in vivo induces a pagetic-like phenotype. RANKL stimulation of OIP-1 mice derived bone marrow cells resulted in significantly decreased osteoclast formation. Furthermore, OIP-1 transgenic mouse bones demonstrated an osteopetrotic phenotype. These data suggest that OIP-1 is an important physiologic regulator of osteoclast development and bone resorption in vivo and may have therapeutic utility to control excess bone turnover in patients with Paget's disease.