J. Caverzasio et al., ALUMINUM POTENTIATES THE EFFECT OF FLUORIDE ON TYROSINE PHOSPHORYLATION AND OSTEOBLAST REPLICATION IN-VITRO AND BONE MASS IN-VIVO, Journal of bone and mineral research, 11(1), 1996, pp. 46-55
Osteosclerosis in workers exposed to fluoride (F) and aluminum (Al) (i
ndustrial fluorosis) led to the use of F as a treatment to increase bo
ne mass in osteoporosis patients. Because the influence of traces of A
l 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 (less than or equal to 10(-5) M) potentiate the
effects of F in vitro such that osteoblast proliferation increased by
15 +/- 2.7% at 50 mu M (p < 0.001) and by 117.6 +/- 5.1% at 750 mu M (
p < 0.001), concentrations of F with no mitogenic effect alone. F + Al
time-dependently modulated a growth factor signaling pathway(s) assoc
iated with enhanced tyrosine phosphorylation (TyrP) of several protein
s (p90 [2.9x], p77 [4.9x], p68 [9.6x], and mitogen activated protein k
inases [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 prolifera
tion were markedly reduced by 100 mu M tyrphostin-51, a tyrosine kinas
e inhibitor. Protein kinase A (PKA) and protein kinase C (PKC) pathway
s were not involved in this response. In vivo, F + Al administered for
8 months, at doses that had no effect when the minerals were administ
ered individually, significantly enhanced proximal tibia bone mineral
density (BRID) by 6.3 +/- 1% compared with initial values and by 2-fol
d compared with control ovariectomized rats (p < 0.0001), These effect
s 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 mitog
en-activated protein kinase and osteoblastic proliferation and bone ma
ss.