title: Aluminum potentiates the effect of fluoride on tyrosine phosphorylation and osteoblast replication in vitro and bone mass in vivo.
abstract: Osteosclerosis in workers exposed to fluoride (F) and aluminum (Al) (industrial fluorosis) led to the use of F as a treatment to increase bone mass in osteoporosis patients. Because the influence of traces of Al on the effects of F on bone formation is heretofore unknown, we have investigated this issue both in vitro and in vivo. We have found that minute amounts of Al (< or = 10(-5) M) potentiate the effects of F in vitro such that osteoblast proliferation increased by 15 +/- 2.7% at 50 microM (p < 0.001) and by 117.6 +/- 5.1% at 750 microM (p < 0.001), concentrations of F with no mitogenic effect alone. F + Al time-dependently modulated a growth factor signaling pathway(s) associated with enhanced tyrosine phosphorylation (TyrP) of several proteins (p90 [2.9x], p77 [4.9x], p68 [9.6x], and mitogen activated protein kinases [3x]). TyrP was only slightly or not at all changed by F and Al alone, respectively. The effects of F + Al on TyrP and cell proliferation were markedly reduced by 100 microM tyrphostin-51, a tyrosine kinase inhibitor. Protein kinase A (PKA) and protein kinase C (PKC) pathways were not involved in this response. In vivo, F + Al administered for 8 months, at doses that had no effect when the minerals were administered individually, significantly enhanced proximal tibia bone mineral density (BMD) by 6.3 +/- 1% compared with initial values and by 2-fold compared with control ovariectomized rats (p < 0.0001). These effects are consistent with a crucial role of Al in osteosclerosis observed in industrial fluorosis. The results suggest that the combination of F + Al modulates a growth factor-dependent TyrP pathway enhancing mitogen-activated protein kinase and osteoblastic proliferation and bone mass.
authors.affiliation: Department of Medicine, University Hospital of Geneva, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Caverzasio
authors.forename: T
authors.initials: T
authors.lastname: Imai
authors.forename: P
authors.initials: P
authors.lastname: Ammann
authors.forename: D
authors.initials: D
authors.lastname: Burgener
authors.forename: J P
authors.initials: JP
authors.lastname: Bonjour
mesh_terms: D016475:3T3 Cells; D000535:Aluminum / Q000008:administration & dosage*; D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D002455:Cell Division; D003470:Culture Media; D000242:Cyclic AMP / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D005459:Fluorides / Q000008:administration & dosage*; D019204:GTP-Binding Proteins / Q000378:metabolism; D051379:Mice; D008934:Mitogens / Q000008:administration & dosage; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D003470:Culture Media; D008934:Mitogens; D014443:Tyrosine; D000535:Aluminum; D000242:Cyclic AMP; D020794:Receptor Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins; D005459:Fluorides