Parathyroid hormone regulates transforming growth factor beta1 and beta2 synthesis in osteoblasts via divergent signaling pathways.
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.
Wu
Y
Y
Department of Medicine, Mayo Clinic/Foundation, Rochester, Minnesota 55905, USA.
Kumar
R
R
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D017931:DNA Primers; D006801:Humans; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000502:physiology*; D020033:Protein Isoforms / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics
D017931:DNA Primers; D010281:Parathyroid Hormone; D020033:Protein Isoforms; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D017868:Cyclic AMP-Dependent Protein Kinases