This Program Project Grant application was initiated originally to develop a team approach to clarify the mechanisms by which local factors regulate bone remodeling, and in particular osteoclastic bone resorption. It is our hypothesis that bone remodeling is mediated by local factors generated in the bone and bone marrow microenvironment, and that bone loss associated with aging and many disease states results from abnormalities in the interactions between local factors and bone cells. Recent studies by ourselves and others indicate that these local factors are heterogeneous, and the complete characterization of their effects on bone cells will require a broadly-based approach involving Investigators with expertise in widely disparate but related areas. Our studies during the first 2 1/2 years of this grant have led to the identification of new factors and mechanisms of osteoclast formation and function both In the normal state and in Paget's disease, and we wish to continue and expand these studies in this application.
The specific aims of this current application are: 1. To identity the specific cellular and molecular events involved in normal osteoclastic bone resorption, including a) the signaling mechanisms involved in osteoclast activation, and in particular the role of newly described osteoclastpoietic factors and arachidonic acid metabolites in this process. b) the regulation of expression of the BMPs, which are members of the TGFbeta superfamily, by bone cells. 2. To determine how these cellular and molecular mechanisms are disordered in Paget's disease. We plan to use the rapidly expanding techniques of bone cell biology, protein chemistry and molecular biology to clarify the mechanisms by which these local factors interact with bone cells. Since the expertise required to identify and characterize these various mechanisms will require the attention of investigators with different types of skills, a team approach will continue to be used to unite a number of diverse approaches around the tightly focused goal of clarifying the mechanisms by which local factors regulate normal and abnormal bone remodeling.
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