Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenylyl Cyclases / metabolism*
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Adjuvants, Immunologic / pharmacology
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Animals
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Animals, Newborn
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Bucladesine / metabolism
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Bucladesine / pharmacology*
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Carbazoles / pharmacology
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Cells, Cultured / cytology
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Cells, Cultured / drug effects
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Cells, Cultured / metabolism
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Cholera Toxin / pharmacology
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Colforsin / pharmacology
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Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Indoles / pharmacology
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Mice
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Nerve Growth Factors / pharmacology
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Neuropeptides / pharmacology
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Neurotransmitter Agents / pharmacology
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Osteoblasts / cytology
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Osteoblasts / drug effects*
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Osteoblasts / metabolism
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Osteocalcin / metabolism*
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Phosphorylation / drug effects
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Pituitary Adenylate Cyclase-Activating Polypeptide
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Protein Kinase C / antagonists & inhibitors
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Pyrroles / pharmacology
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Triiodothyronine / pharmacology*
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Adcyap1 protein, mouse
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Adjuvants, Immunologic
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Carbazoles
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Enzyme Inhibitors
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Indoles
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Nerve Growth Factors
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Neuropeptides
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Neurotransmitter Agents
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Pituitary Adenylate Cyclase-Activating Polypeptide
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Pyrroles
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Triiodothyronine
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Osteocalcin
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Colforsin
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KT 5720
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Bucladesine
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Cholera Toxin
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Cyclic AMP-Dependent Protein Kinases
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Protein Kinase C
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p38 Mitogen-Activated Protein Kinases
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Adenylyl Cyclases