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Parathyroid Hormone-Related Protein(1–34) Regulates Phex Expression in Osteoblasts through the Protein Kinase A Pathway

Département de Biochimie (M.Á.V., M.S.L., L.D., G.B.), Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada H3C 3J7; and Departamento de Genética del Desarrollo y Fisiología Molecular (M.A.V., J.-L.C.), Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos 62271, México

Address all correspondence and requests for reprints to: Guy Boileau, Département de Biochimie, Faculté de Médecine, Université de Montréal, C.P. 6128, Succ. Centre-Ville Montréal, Québec, Canada H3C 3J7. E-mail: guy.boileau{at}umontreal.ca.

Phex (a phosphate-regulating gene with homologies to endopeptidases on the X chromosome) is expressed predominantly in bone in which it has been implicated in the mineralization process. Multiple factors and hormones, including PTHrP, regulate formation, development, and/or homeostasis of bone. The purpose of the present study was to determine whether PTHrP(1–34) regulates Phex expression and identify the signaling pathway used. Phex mRNA and protein levels were analyzed by RT-PCR and immunoblotting, respectively. In UMR-106 cells, PTHrP(1–34) caused a time- and concentration-dependent decrease in Phex expression. Forskolin, an adenylate cyclase activator, had the same effect. Dibutiryl cAMP also decreased Phex expression, and its effect was blocked by H89, a protein kinase A (PKA) inhibitor. In contrast, 12-O-tetradecanoyl phorbol-13-acetate, a protein kinase C (PKC) activator, increased Phex expression in a time- and dose-dependent manner. This effect was reversed by bisindolylmaleimide I, a PKC inhibitor. Bovine PTH(3–34), which activates PKC but not PKA, had no effect. On the contrary, human PTH(1–31), which activates PKA but not PKC, decreased Phex expression. H89 but not bisindolylmaleimide I blocked the effect of PTHrP(1–34). PTHrP(1–34) also decreased Phex expression in cultures of fetal rat calvaria cells at d 7 of culture but not at later stages. These data demonstrate that PTHrP(1–34), through PKA, down-regulates Phex expression in osteoblasts.

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