MOLECULAR MECHANISM OF ACTION OF FLUORIDE ON BONE-CELLS

Fluoride is an effective anabolic agent to increase spinal bone densit y by increasing bone formation, and at therapeutically relevant (i.e., micromolar) concentrations, it stimulates bone cell proliferation and activities in vitro and in vivo. However, the fluoride therapy of ost eoporosis has been controversial, in large part because of a lack of c onsistent antifracture efficacy. However, information regarding the mo lecules mechanism of action of fluoride may improve its optimum and co rrect usage and may disclose potential targets for the development of new second generation drugs that might have a better efficacy and safe ty profile. Accordingly, this review will address the molecular mechan isms of the osteogenic action of fluoride. In this regard, we and othe r workers have proposed two competing models, both of which involve th e mitogen activated protein kinase (MAPK) mitogenic signal transductio n pathway. Our model involves a fluoride inhibition of a unique fluori de-sensitive phosphotyrosine phosphatase (PTP) in osteoblasts, which r esults in a sustained increase in the tyrosine phosphorylation level o f the key signaling proteins of the MAPK mitogenic transduction pathwa y, leading to the potentiation of the bone cell proliferation initiate d by growth factors. The competing model proposes that fluoride acts i n coordination with aluminum to form fluoroaluminate, which activates a pertussis toxin-sensitive Gi/o protein on bone cell membrane, leadin g to an activation of cellular protein tyrosine kinases (PTKs), which in turn leads to increases in the tyrosine phosphorylation of signalin g proteins of the MAPK mitogenic signal transduction pathway, ultimate ly leading to a stimulation of cell proliferation. A benefit of our mo del, but not the other model, is that it accounts for all the unique p roperties of the osteogenic action of fluoride. These include the low effective fluoride dose, the skeletal tissue specificity, the requirem ent of PTK-activating growth factors, the sensitivity to changes in me dium phosphate concentration, the preference for undifferentiated oste oblasts, and the involvement of the MAPK. Unlike fluoride, the mitogen ic action of fluoroaluminate is not specific for skeletal cells. Moreo ver, the mitogenic action of fluoroaluminate shows several important, different characteristics than that of fluoride. Thus, it is likely th at our model of a fluoride-sensitive PTP represents the actual molecul ar mechanism of the osteogenic action of fluoride.