Involvement of bone morphogenetic protein-4 in GH regulation by octreotide and bromocriptine in rat pituitary GH3 cells.
Here we investigated roles of the pituitary bone morphogenetic protein (BMP) system in modulating GH production regulated by a somatostatin analog, octreotide (OCT) and a dopamine agonist, bromocriptine (BRC) in rat pituitary somatolactotrope tumor GH3 cells. The GH3 cells were found to express BMP ligands, including BMP-4 and BMP-6; BMP type-1 and type-2 receptors (except the type-1 receptor, activin receptor-like kinase (ALK)-6); and Smad signaling molecules. Forskolin stimulated GH production in accordance with cAMP synthesis. BRC, but not OCT, suppressed forskolin-induced cAMP synthesis by GH3 cells. Individual treatment with OCT and BRC reduced forskolin-induced GH secretion. A low concentration (0.1 microM) of OCT in combination with BRC (1-100 microM) exhibited additive effects on reducing GH and cAMP production induced by forskolin. However, a high concentration (10 microM) of OCT in combination with BRC failed to suppress GH and cAMP production. BMP-4 specifically enhanced GH secretion and cAMP production induced by forskolin in GH3 cells. BRC, but not OCT, inhibited BMP-4-induced activation of Smad1,5,8 phosphorylation and Id-1 transcription and decreased ALK-3 expression. Of note, in the presence of a high concentration of OCT, the BRC effects suppressing BMP-4-Smad1,5,8 signaling were significantly impaired. In the presence of BMP-4, a high concentration of OCT also attenuated the BRC effects suppressing forskolin-induced GH and cAMP production. Collectively, a high concentration of OCT interferes with BRC effects by reducing cAMP production and suppressing BMP-4 signaling in GH3 cells. These findings may explain the mechanism of resistance of GH reduction to a combination therapy with OCT and BRC for GH-producing pituitary adenomas.
Miyoshi
Tomoko
T
Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama City 700-8558, Japan.
Otsuka
Fumio
F
Otani
Hiroyuki
H
Inagaki
Kenichi
K
Goto
Junko
J
Yamashita
Misuzu
M
Ogura
Toshio
T
Iwasaki
Yasumasa
Y
Makino
Hirofumi
H
D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000502:physiology*; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics / Q000502:physiology; D052004:Bone Morphogenetic Protein Receptors / Q000032:analysis / Q000235:genetics; D001971:Bromocriptine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D013006:Growth Hormone / Q000096:biosynthesis*; D015282:Octreotide / Q000494:pharmacology*; D051381:Rats; D017481:Receptors, Somatostatin / Q000235:genetics
C525818:Bmp6 protein, rat; D055415:Bone Morphogenetic Protein 4; D055418:Bone Morphogenetic Protein 6; D017481:Receptors, Somatostatin; D005576:Colforsin; D001971:Bromocriptine; D013006:Growth Hormone; D000242:Cyclic AMP; D052004:Bone Morphogenetic Protein Receptors; D015282:Octreotide