Parathyroid hormone regulates transforming growth factor beta1 and beta2 synthesis in osteoblasts via divergent signaling pathways.

Abstract

Parathyroid hormone 1-34 [PTH(1-34)] was shown to increase transforming growth factor beta1 (TGF-beta1) and TGF-beta2 concentrations in supernatants of cultured human osteoblasts and to increase TGF-beta1 and TGF-beta2 messenger RNA (mRNA) concentrations and gene transcription in these cells. Because PTH(1-34) activates both protein kinase C (PKC) and protein kinase A (PKA) pathways in osteoblasts, we investigated the role of each kinase pathway in activation of TGF-beta isoforms. PTH(29-32), which activates the PKC pathway in rat osteoblasts, increased TGF-beta1 but not TGF-beta2 concentrations in supernatants of osteoblasts. Phorbol myristate acetate (PMA), a PKC agonist, increased TGF-beta1 but not TGF-beta2 concentrations. Specific PKC antagonists safingol and Gö6976 attenuated PTH(1-34)-mediated increases in TGF-beta1 but not TGF-beta2 synthesis. PTH(1-31), which increases PKA activity in several cell culture systems, increased TGF-beta2 but not TGF-beta1 concentrations in human osteoblast supernatants. Forskolin, a PKA agonist, increased TGF-beta2 but not TGF-beta1 concentrations in supernatants of human osteoblasts. The PKA antagonist H-89 blunted PTH(1-34)-mediated increases in TGF-beta2 but not TGF-beta1 synthesis. Our results are consistent with the concept that PTH increases TGF-beta1 expression and secretion by pathways that involve the PKC pathway, whereas it increases TGF-beta2 expression and secretion via the PKA pathway.