Parathyroid hormone regulates transforming growth factor β1 and β2 synthesis in osteoblasts via divergent signaling pathways

Parathyroid hormone 1-34 [PTH(1-34)] was shown to increase transforming growth factor beta 1 (TGF-beta 1) and TGF-beta 2 concentrations in supernatants of cultured human osteoblasts and to increase TGF-beta 1 and TGF-beta 2 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-beta 1 but not TGF-beta 2 concentrations in supernatants of osteoblasts. Phorbol myristate acetate (PMA), a PKC agonist, increased TGF-beta 1 but not TGF-beta 2 concentrations, Specific PKC antagonists safingol and (Go6976 attenuated PTH(1-34)-mediated increases in TGF-beta 1 but not TGF-beta 2 synthesis, PTH(1-31), which increases PKA activity in several cell culture systems, increased TGF-beta 2 but not TGF-beta 1 concentrations in human osteoblast supernatants. Forskolin, a PKA agonist, increased TGF-beta 2 but not TGF-beta 1 concentrations in supernatants of human osteoblasts. The PKA antagonist H-89 blunted PTH(1-34)-mediated increases in TGF-beta 2 but not TGF-beta 1 synthesis, Our results are consistent with the concept that PTH increases TGF-beta 1 expression and secretion by pathways that involve the PKC pathway, whereas it increases TGF-beta 2 expression and secretion via the PKA pathway.