Phosphodiesterase 4 inhibitor regulates the TRANCE/OPG ratio via COX-2 expression in a manner similar to PTH in osteoblasts.
Phosphodiesterase 4 (PDE4) inhibitors stimulate osteoclast formation by increasing the TRANCE/OPG mRNA ratio via cAMP-mediated pathways in a manner similar to parathyroid hormone (PTH) in osteoblasts. We investigated the role of cyclooxygenase-2 (COX-2) in osteoclast formation induced by the PDE4 inhibitor rolipram. Rolipram induced COX-2 expression in mRNA and protein levels, followed by increased prostaglandin E(2) production in osteoblasts. PKA, ERK, and p38 MAPK pathways regulate COX-2 mRNA expression induced by rolipram, in which PKA is a central regulator of the ERK and p38 MAPK pathways. A COX-2 inhibitor reversed the up-regulation of the TRANCE/OPG mRNA ratio induced by rolipram in osteoblasts, resulting in decreased osteoclast formation. These data suggest that COX-2 mediates rolipram induced osteoclast formation by regulating the TRANCE/OPG mRNA ratio in osteoblasts. Furthermore, the effects of the PDE4 inhibitor on osteoblasts were very similar to those of PTH, indicating that the PDE4 inhibitor largely shares the biological actions of PTH in osteoblasts.
Park
Hyojung
H
College of Pharmacy, Sookmyung Women's University, Seoul 140-742, Republic of Korea.
Young Lee
Soo
S
Lee
Dong-Seok
DS
Yim
Mijung
M
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D053244:Osteoprotegerin / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000008:administration & dosage*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage; D053245:RANK Ligand / Q000378:metabolism*; D020889:Rolipram / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D053244:Osteoprotegerin; D010281:Parathyroid Hormone; D010726:Phosphodiesterase Inhibitors; D053245:RANK Ligand; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D051546:Cyclooxygenase 2; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram