Paget's disease is the most flagrant example of disordered bone remodeling, with abnormalities in all phases of the bone remodeling process. Pagetic osteoclasts are abnormal and contain paramyxoviral-like nuclear and cytoplasmic inclusions. However, major questions exist about the identity of the virus, how it is propagated and maintained for many years, and the role of the strong familial predisposition to Paget's disease in this process. To address some of these questions, the applicants propose to: (1) transduce normal CFU-GM with retroviral constructs containing measles virus cDNAs and determine if these cDNAs alone, or in combination, can induce normal osteoclast precursors to express pagetic phenotypes. In addition, they will clone and sequence the paramyxoviral cDNAs present in a recently constructed cDNA subtraction library prepared from Paget's and normal peripheral blood cells, and then characterize these cDNAs in a similar manner; (2) screen peripheral blood samples from Paget's patients and age-matched controls from the U.S., England, Australia and New Zealand for paramyxoviral nuclear transcripts that have been associated with Paget's disease, in order to determine if pagetic patients from different geographical locations harbor a similar or different virus; and (3) determine if there is genetic heterogeneity of the locus for Paget's disease that has been identified on human chromosome 18q by genotyping a second large family with Paget's disease for this locus. They will seek to determine if hematopoietic precursors from individuals carrying the disease haplotype that they have associated with Paget's disease, but not yet with Paget's disease, are more susceptible to paramyxoviral infection and/or have increased osteoclast activity than first-degree relatives lacking this haplotype.
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