In the first four projects of this Program Project Application, we have concentrated our efforts on studies of the normal bone resorption process and its regulation. In this project we will examine Paget's disease, a bone disorder in which osteoclast behavior is grossly distorted with greatly increased bone resorption followed by abundant new bone formation. The primary cellular abnormality occurs in osteoclasts. However, the mechanisms responsible for the abnormal bone remodeling the Paget's disease are unknown. We will use our recently developed human long term marrow cultures which form cells with osteoclast characteristics to investigate the pathobiology of Pagetic osteoclasts. Paget's disease offers a unique and ideal opportunity to study abnormal bone cells since the precursors for the abnormal cells, osteoclasts, can now be studied directly in long-term human marrow cultures. Therefore, we will determine: 1) the ultrastructure and light microscopic appearance of osteoclast-like cells from involved and uninvolved bone of patients with Paget's disease and contrast them to those from normals, 2) if viral inclusions are present in osteoclast-like cells using monoclonal antibodies and DNA probes for paramyxoviruses, 3) if conditioned media from long-term marrow cultures from patients with Paget's disease contain viral material and if coculture this conditioned media with marrow cells or osteoclasts results in transfer of the virus to these cells, 4) dose-response relationships for osteoclast-like cell formation with osteotropic hormones and inhibitors of osteoclast formation in cultures from Pagetic bone and uninvolved bone from the same patients and normal controls, and 5) if conditioned media from long-term marrow cultures of patients with Paget's disease contain factors which stimulate the growth, alkaline phosphatase activity and collagen production of osteoblasts from human bone biopsies as well as osteoblastic cell lines. In this manner we will for the first time critically examine the pathobiology of osteoclasts in Paget's disease.
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