Inhibition of osteoclastogenesis by a phosphodiesterase 4 inhibitor XT-611 through synergistic action with endogenous prostaglandin E2.
We examined the effect of a phosphodiesterase 4 (PDE4) inhibitor, 3,4-dipropyl-4,5,7,8-tetrahydro-3H-imidazo[1,2-i]-purin-5-one (XT-611) on osteoclast formation in three different mouse bone-marrow cell (BMC) culture systems. We confirmed that selective inhibitors of PDE4, including XT-611, among several PDE inhibitors decreased osteoclast formation in the BMC culture system. XT-611 also inhibited osteoclast formation in co-culture of mouse bone-marrow stromal cell line ST2 and adherent cell-depleted (ACD)-BMCs. However, it did not inhibit osteoclastogenesis in culture of ACD-BMCs alone in the presence of macrophage-colony stimulating factor (M-CSF) and soluble receptor activator of NF-kappaB ligand (sRANKL). XT-611 significantly increased prostaglandin E(2) (PGE(2)) production from ST2 cells and, in combination with PGE(2), synergistically increased cAMP concentration in osteoclast progenitors. In the ST2 co-culture system, XT-611 did not influence the expression of RANKL, osteoprotegerin and RANK mRNAs. By combined treatment with XT-611 and PGE(2) of ACD-BMCs, osteoclast multinucleation was clearly inhibited with decrease in the expression of calcitonin receptor mRNA, while the expression of RANK and c-fms (an M-CSF receptor) mRNAs was unchanged. These results indicate that the PDE4 inhibitor inhibits osteoclastogenesis by acting on osteoclast progenitors synergistically with PGE(2) secreted from stromal cells, but not by influencing the cell-to-cell interaction between stromal cells and osteoclast progenitors.
Yamagami
Hideomi
H
Department of Hospital Pharmacy, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan.
Nishioka
Tatsuo
T
Ochiai
Eiji
E
Fukushima
Kazuyo
K
Nomura
Masaaki
M
Kasugai
Shohei
S
Moritani
Shuzo
S
Yokogawa
Koichi
K
Miyamoto
Ken-ichi
K
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015232:Dinoprostone / Q000378:metabolism*; D004357:Drug Synergism; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects* / Q000502:physiology; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology; D053244:Osteoprotegerin; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor
C461440:3,4-dipropyl-4,5,7,8-tetrahydro-3H-imidazo(1,2-i)purin-5-one; D002352:Carrier Proteins; D006023:Glycoproteins; D007093:Imidazoles; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D010726:Phosphodiesterase Inhibitors; D011687:Purines; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D016173:Macrophage Colony-Stimulating Factor; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015232:Dinoprostone