Mechanism Underlying the Aluminum-Induced Stimulation of Bone Nodule Formation by Rat Calvarial Osteoblasts

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The signal transduction mechanism for aluminum (Al^<3+>)-induced stimulation of bone formation and its crosstalk with the prostaglandin E_2 (PGE_2) signaling pathway were studied in calvarial osteoblasts from 25-week-old rats (MOB) and those from 90-week-old rats (AOB). Alkaline phosphatase activity, the rate of [^3H]proline incorporation into collagenase-digestible proteins, the total area and number of mineralized bone nodules (BN) and the content of calcium in BN, which are the markers for differentiation of osteoblasts, were dose-dependently stimulated by the treatment with Al^<3+> at a concentration range of 10^<-7>-10^<-5> M in the cultures of both MOB and AOB. The stimulatory effects of Al^<3+> on the differentiation markers were abolished by the pretreatment of the cells with pertussis toxin (PTX), an inhibitor of G_i protein, indicating that the effects of Al^<3+> are mediated through a receptor coupled with G_i protein. Al^<3+> increased inositol-1,4,5-triphosphate (IP_3) production and intracellular concentration of Ca^<2+>([Ca^<2+>],) in the cultures of MOB and AOB: these effects were not observed in the presence of PTX, indicating that the effects of Al^<3+> are mediated through the activation of phosphatidylinositol-specific phospholipase C (PI-PLC). We have previously shown that 17-phenyl-ω-trinor-PGE_2, a selective agonist for an EP, subtype of PGE_2 receptor (EP_1), stimulates the differentiation markers in the cultures of MOB through the activation of PI-PLC, but not in those of AOB because of the lack of EP_1. The levels of the differentiation markers obtained in the presence of the EP, agonist were increased by the addition of Al^<3+> in the cultures of MOB and AOB, while Al^<3+> increased the levels of IP_3 production and [Ca^<2+>], in the presence of the EP_1 agonist only in the cultures of AOB. These results indicate a possibility that PI-PLC molecules stimulated by the signal through G_i protein and those stimulated by the signal through EP_1 belong to the same pool and that the Al^<3+> signal through _i protein induces cell differentiation via a pathway(s) independent of PI-PLC in addition to that (those) dependent on the PI-PLC. We have also shown that 11-deoxy-PGE_1, a selective agonist for an EP_2/EP_4 subtype of PGE_2 receptor (EP_2/EP_4), inhibits cell differentiation in the cultures of both MOB and AOB. Al^<3+> had no effect on the basal levels of CAMP production, but the levels induced by the EP_2/EP_4 agonist were dose-dependently reduced by the treatment with Al^<3+> at a concentration range of 10^<-7>-10^<-5> M. The inhibitory effect of Al^<3+> on adenylyl cyclase was abolished by the pretreatment with PTX. These results indicate that Al^<3+> suppresses adenylyl cyclase activity induced by the EP_2/EP_4-mediated signal through the Gi protein-coupled receptor.
公益社団法人日本薬学会の論文
2004-02-01

Mechanism Underlying the Aluminum-Induced Stimulation of Bone Nodule Formation by Rat Calvarial Osteoblasts

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