Adenylyl cyclase-cAMP system inhibits thyroid hormone-stimulated osteocalcin synthesis in osteoblasts.
It is generally recognized that thyroid hormone modulates osteoblast cell function. We have previously shown that triiodothyronine (T(3)) activates p38 mitogen-activated protein (MAP) kinase, resulting in the synthesis of osteocalcin in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the effect of the adenylyl cyclase-cAMP system on thyroid hormone-stimulated osteocalcin synthesis in these cells. Dibutyryl-cAMP (DBcAMP) reduced the osteocalcin synthesis stimulated by T(3). Forskolin and cholera toxin suppressed the osteocalcin synthesis while dideoxyforskolin, a forskolin derivative that does not activate adenylyl cyclase, had little effect on the synthesis. KT5720, a selective inhibitor of protein kinase A, reversed the inhibitory effect of forskolin or DBcAMP. DBcAMP and forskolin markedly reduced the phosphorylation of p38 MAP stimulated by T(3). Pituitary adenylate cyclase-activating polypeptide (PACAP) significantly inhibited the T(3)-stimulated osteocalcin synthesis. These results strongly suggest that the adenylyl cyclase-cAMP system has an inhibitory role in thyroid hormone-stimulated osteocalcin synthesis via suppression of p38 MAP kinase activation in osteoblasts.
Kanno
Yosuke
Y
Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
Ishisaki
Akira
A
Yoshida
Minoru
M
Nakajima
Keiichi
K
Tokuda
Haruhiko
H
Numata
Osamu
O
Kozawa
Osamu
O
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D003994:Bucladesine / Q000378:metabolism / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D009414:Nerve Growth Factors / Q000494:pharmacology; D009479:Neuropeptides / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015675:Osteocalcin / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000494:pharmacology; D014284:Triiodothyronine / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C495402:Adcyap1 protein, mouse; D000276:Adjuvants, Immunologic; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D009414:Nerve Growth Factors; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011758:Pyrroles; D014284:Triiodothyronine; D015675:Osteocalcin; D005576:Colforsin; C057416:KT 5720; D003994:Bucladesine; D002772:Cholera Toxin; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D000262:Adenylyl Cyclases