Phosphodiesterase 4 inhibitor rolipram potentiates the inhibitory effect of calcitonin on osteoclastogenesis.
To assess the combination effect of calcitonin and the phosphodiesterase 4 inhibitor rolipram on osteoclastogenesis, adherent cell-depleted bone marrow cells from mouse tibia and femur (ACD-BMCs), which were cultured in the presence of 25 ng/ml colony-stimulating factor 1 (CSF-1) and 100 ng/ml soluble receptor activator of NF-kappaB ligand (sRANKL), were utilized. Calcitonin inhibited formation of tartrate-resistant acid phosphatase-positive multinucleated cells, as mature osteoclasts, by 70% even at 20 pM, whereas rolipram (10 microM) scarcely affected osteoclast formation; in contrast, the combination of both agents led to significant inhibition of multinucleation and pit formation ability of osteoclasts. The combined administration of calcitonin and rolipram attenuated calcitonin receptor mRNA expression in comparison to treatment with either agent alone, whereas expression of RANK and CSF-1 receptor mRNAs was unchanged. Alone, these agents scarcely elevated intracellular cyclic AMP (cAMP) concentration; however, combination treatment with both agents significantly increased cAMP concentration in osteoclast progenitors and osteoclasts. The combination effect was abolished by H-89, an inhibitor of protein kinase A. It appears that rolipram inhibited hydrolysis of cAMP formed by calcitonin in cells and potentiated the inhibitory effect of calcitonin on osteoclastogenesis. The escape phenomenon following calcitonin treatment may also be prevented by concomitant treatment with the phosphodiesterase 4 inhibitor.
Miyamoto
Ken-ichi
K
Department of Hospital Pharmacy, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan. miyaken@pharmacy.m.kanazawa-u.ac.jp
Nishioka
Tatsuo
T
Waki
Yoshihiro
Y
Nomura
Masaaki
M
Katsuta
Hiromu
H
Yokogawa
Koichi
K
Amano
Hitoshi
H
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002116:Calcitonin / Q000819:agonists / Q000494:pharmacology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051379:Mice; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects*; D012333:RNA, Messenger; D020889:Rolipram / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D002116:Calcitonin; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram