The work proposed in this grant application will extend our knowledge regarding the regulatory aspects of the bone forming cell, the osteoblast. The main thrust of this work is the description of a new role for type tartrate resistant acid phosphatase (TRAP). This enzyme is present in osteoclasts and at sites of resorption and it is our hypothesis that the molecule has growth factor-like effects on bone cells. In preliminary findings we have shown that a molecule which is homologous to osteoclastic TRAP can stimulate isolated progenitor osteoblasts to acquire a more differentiated phenotype. The significance of such an effect is that TRAP, due to its location on the resorbing surface, can act as a site-specific molecule to direct the formation of bone to resorption lacunae. Thus, along with other soluble regulatory factors released during osteoclastic activity TRAP may participate in local bone remodelling. In the first part of this project we intend 1) to characterize the effects of TRAP on bone cells and other cells, 2) to investigate whether known growth factors interact with it, and 3) to determine if it affects the production of TGF beta and bFGF. The second part of the project involves isolating and identifying the TRAP receptor and using the receptor to further characterize regulatory molecules in bone. (We currently believe that the receptor through which TRAP mediates its effects is the IGF- II/mannose-6-phosphate receptor, but this needs to be proven.) The last part of the project explores second messenger signalling mechanisms for TRAP and the possible role of intracellular calcium as a transducing agent. The importance of this work is that it may, for the first time, shed light on the localized nature of the bone remodelling process. Our central hypothesis is that the large amount of osteoclastic TRAP which remains on the surface of resorption lacunae can act as a site-directing regulatory molecule for the formation of new bone. These findings may also explain the high rates of osteoblastic activity in pathological states with high acid phosphatase content, such as prostate metastases to the skeleton.
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