Phosphodiesterase 3 and 4 Negatively Regulate Receptor Activator of Nuclear Factor-[kappa]B Ligand-Mediated Osteoclast Formation by Prostaglandin E sub(2)

• Published in: Biological & pharmaceutical bulletin 2009-01, Vol.32 (11), p.1844-1844
• Main Authors: Noh, A Long Sae Mi, Yang, Mihye, Lee, Jung-Min, Park, Hyojung, Lee, Dong-Seok, Yim, Mijung
• Format: Article
• Language: English
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.32.1844

Prostaglandin E sub(2) (PGE sub(2)) stimulates osteoclast formation by increasing receptor activator of nuclear factor (NF)-[kappa]B ligand (RANKL) mRNA expression via cAMP-protein kinase A (PKA) pathways in osteoblasts. Since phosphodiesterases (PDEs) balance the concentration of intracellular cAMP stimulated by PGE sub(2), we investigated the role of PDEs in PGE sub(2)- mediated osteoclast formation using various cAMP-specific PDEs inhibitors. In the presence of PGE sub(2), PDE3 and 4 inhibitors were shown to dose- dependently increase the osteoclast formation in cocultures of mouse bone marrow cells and calvarial osteoblasts. In agreement with this finding, they stimulated PGE sub(2)-induced cAMP production followed by increased RANKL mRNA expression in osteoblasts, suggesting that PDE3 and 4 negatively regulate PGE sub(2)-mediated RANKL expression in osteoblasts. RT-PCR analysis revealed that PDE3A, 3B, 4A, 4B and 4D are expressed in osteoblasts. The PDE8 inhibitor did not increase osteoclast formation, although it stimulated PGE sub(2)-induced RANKL mRNA expression in osteoblasts. The four subtypes of PGE receptors are designated EP1, EP2, EP3, and EP4. PDE3 and 4 inhibitors were found to increase EP1/3, EP4 and/or EP2 agonist-stimulated RANKL expression, indicating that PDE3 and PDE4 negatively regulate PGE sub(2)- induced RANKL mRNA expression through four EPs. Taken together, these data suggest that PDE3 and PDE4 could have important pharmacological and clinical implications in bone-related diseases.