Fluoride (F) has been considered of value in the therapy of osteoporosis since the studies of Rich and Ensink in 1961. Clinically, F is reported to increase vertebral bone mineral density and decrease the incidence of vertebral fractures. Although reported to stimulate osteoblast function in skeletal tissue, it is also known to induce hyperosteoidosis and a mineralization defect. Recognition of these facts has limited its clinical use because of concern about the induction of osteomalacia in certain patients and conflicting data regarding an increase in femoral fractures. The basis for these apparently contrasting effects of F on trabecular bone volume and bone matrix synthesis remains undefined. This is an important issue because of an interest in the expanded clinical use of F in the treatment of osteoporotic disorders. By histomorphometry, F has been observed to increase osteoblast number, osteoid volume and trabecular bone volume. However, mineralization lag time of new osteoid is also increased. In tissue culture F has been reported to stimulate osteoblast proliferation and alkaline phosphatase production. Other effects on osteoblast metabolism in vitro have been noted, including; cAMP and intercellular calcium alterations. However, F effects on type I collagen metabolism have not been consistently observed despite the observation of increased osteoid formation in vivo. We hypothesize that the F induced hyperosteroidosis and mineralization defect is a consequence of F effects on osteoblast-directed extracellular matrix (ECM) synthesis, and its subsequent mineralization. We will examine the formation of mineralizing ECM using a well defined, chicken osteoblast cell culture model. We will investigate the synthesis, processing and accumulation of osteoblast-specific proteins into a mineralizing ECM during chronic exposure to F. Knowledge gained from this model will then be applied to studies of the effect of F on cultured human osteoblast cells from normal and osteoporotic subjects. Increased knowledge of the mechanism of F action in vitro should lead to better use of the agent as a therapeutic modality in osteoporosis.
| Chipman, S D; Shapiro, J R; McKinstry, M B et al. (1992) Expression of mutant alpha (I)-procollagen in osteoblast and fibroblast cultures from a proband with osteogenesis imperfecta type IV. J Bone Miner Res 7:793-805 |
