Caverzasio J, Imai T, Ammann P, Burgener D, Bonjour J P
Department of Medicine, University Hospital of Geneva, Switzerland.
J Bone Miner Res. 1996 Jan;11(1):46-55. doi: 10.1002/jbmr.5650110108.
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.
接触氟（F）和铝（Al）的工人出现骨硬化（工业性氟中毒），这使得氟被用于治疗骨质疏松症患者以增加骨量。由于迄今为止微量铝对氟影响骨形成的作用尚不清楚，我们在体外和体内对这一问题进行了研究。我们发现，微量铝（≤10⁻⁵ M）在体外可增强氟的作用，使得在50 μM时成骨细胞增殖增加15±2.7%（p<0.001），在750 μM时增加117.6±5.1%（p<0.001），而单独使用这些氟浓度时无促有丝分裂作用。氟+铝可随时间依赖性地调节与几种蛋白质（p90 [2.9倍]、p77 [4.9倍]、p68 [9.6倍]和丝裂原活化蛋白激酶 [3倍]）酪氨酸磷酸化（TyrP）增强相关的生长因子信号通路。单独的氟和铝分别仅使TyrP略有变化或根本没有变化。100 μM酪氨酸激酶抑制剂 tyrphostin-51可显著降低氟+铝对TyrP和细胞增殖的影响。蛋白激酶A（PKA）和蛋白激酶C（PKC）途径不参与此反应。在体内，给予氟+铝8个月，单独给予这些矿物质时无效的剂量，与初始值相比，显著提高了胫骨近端骨矿物质密度（BMD）6.3±1%，与对照去卵巢大鼠相比提高了2倍（p<0.0001）。这些作用与铝在工业性氟中毒中观察到的骨硬化中的关键作用一致。结果表明，氟+铝的组合调节生长因子依赖性TyrP途径，增强丝裂原活化蛋白激酶和成骨细胞增殖以及骨量。
