Osteoporosis is a skeletal disorder in which the level of bone resorption exceeds that of bone formation resulting in a loss of bone mass. Both bone formation and the local control of bone resorption are functions of the osteoblast, a cell that also produces growth factors and cytokines that apparently work in an autocrine and paracrine fashion to influence both osteoblasts and osteoclasts. Among the most important of these agents is transforming growth factor-beta (TGF-beta), a protein known to stimulate cell proliferation, differentiation and matrix synthesis and capable of osteoinductive activity in vivo. With advancing age, osteoblast biosynthetic activity declines and with it, we suggest, the level or effective action of TGF-beta necessary for sustaining further matrix synthesis and osteoblast precursor proliferation and maturation. However, the linkage between a decline in TGF-beta synthesis and/or diminished TGF-beta effector activity and a reduction in the osteoblastic precursor pool and further matrix synthesis has not been fully documented. It is the overall objective of the studies described in this application to provide this documentation. Specifically, we propose to test the hypothesis that age-related (Type II) osteoporosis results, in part, from a decline in the endogenous synthesis and/or effective autocrine action of TGF-beta on OPCs resulting in a diminution in OPC number and a reduction in bone matrix protein synthesis. This hypothesis will be tested by pursuing the following specific aims: (1) completing our analysis of OPC number and osteogenic activity in cells recovered from the bone marrow and periosteal compartments of young (y. 4 month), middle age (m. 12 month) and old (o. 24 month) BALBc mice. (2) determining the steady state mRNA abundance of TGF-beta1,beta2,beta3 and related bone morphogenetic proteins (BMPs), and the secreted levels of TGF-beta protein in OPCs cultured from y and o mice. (3) establishing the mRNA abundance and number and overall binding affinity of the three types of TGF-beta receptor in cultured OPCs derived from y and o mice. (4) assessing whether TGF-beta is an autocrine/paracrine regulator of osteoprogenitor cells and differentiating osteoblasts. To this end, OPCs from o and y animals will be cultured in the presence and absence of TGF- beta, anti-TGF-beta antibodies and TGF-beta antisense oligonucleotides. (5) determining whether the OPC census in old mice can be increased, perhaps to y levels, by introducing exogenous TGF-beta in vivo. Collectively, the results of the proposed studies should provide an initial direct assessment of the often proposed feedback relationship between TGF-beta and osteogenic cell function and of the hypothesis that age-related osteoporotic bone loss is the result of a disruption in this relationship.
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| Gazit, D; Zilberman, Y; Ebner, R et al. (1998) Bone loss (osteopenia) in old male mice results from diminished activity and availability of TGF-beta. J Cell Biochem 70:478-88 |
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