Fluoride increases tyrosine kinase activity in osteoblast-like cells: Regulatory role for the stimulation of cell proliferation and Pi transport across the plasma membrane

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Abstract
Fluoride is one of the most effective agents for the treatment of vertebral osteoporosis because of its ability to increase osteoblast proliferation. The present study further investigates the role of protein tyrosine phosphorylation previously suggested to mediate the mitogenic effect of fluoride on bone‐forming cells. The activity of the plasma membrane Na‐coupled Pi transport system was monitored to assess the relationship between alterations in tyrosine phosphorylation and osteoblast activity induced by fluoride. The results indicate that vanadate, a selective inhibitor of tyrosine phosphatase, mimicked the stimulatory effect of fluoride on Pi transport. The change in Pi transport induced by fluoride was dose dependently inhibited by genistein, a potent inhibitor of tyrosine kinase. Genistein also inhibited the change in cell proliferation induced by fluoride. Associated with these observations, tyrosine phosphorylation activity was significantly increased in subcellular fractions isolated from UMR‐106 cells treated with fluoride as compared with those isolated from vehicle‐treated cells. This change in tyrosine phosphorylation activity was markedly blunted when genistein was added to the kinase assay buffer. It was not associated with any alteration in specific tyrosine phosphatase activity. There was also no evidence of a direct effect of fluoride on tyrosine phosphatase activity in isolated plasma membrane of UMR‐106 cells. In conclusion, the results of the present study suggest that fluoride enhances protein tyrosine phosphorylation in osteoblast‐like cells by enhancing tyrosine kinase activity. The results further support the hypothesis that this signal transduction mechanism is involved in the osteogenic effects of fluoride.
Funding Information
  • Swiss National Science Foundation (32-411.91)
  • CibaGeigy AG, Basel