Phosphodiesterase 3 and 4 Negatively Regulate Receptor Activator of Nuclear Factor-.KAPPA.B Ligand-Mediated Osteoclast Formation by Prostaglandin E2
| Autor: | Mijung Yim, Jung-Min Lee, Mihye Yang, A Long Sae Mi Noh, Dong-Seok Lee, Hyojung Park |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
musculoskeletal diseases
medicine.medical_specialty Prostaglandin E2 receptor Phosphodiesterase 3 Osteoclasts Pharmaceutical Science p38 Mitogen-Activated Protein Kinases Dinoprostone Mice Osteoclast Internal medicine medicine Animals RNA Messenger Prostaglandin E2 Cells Cultured Pharmacology biology Activator (genetics) Chemistry RANK Ligand Phosphodiesterase Osteoblast General Medicine Blotting Northern Cyclic Nucleotide Phosphodiesterases Type 3 Cyclic Nucleotide Phosphodiesterases Type 4 Cell biology Endocrinology medicine.anatomical_structure RANKL biology.protein Electrophoresis Polyacrylamide Gel lipids (amino acids peptides and proteins) medicine.drug |
| Zdroj: | Biological and Pharmaceutical Bulletin. 32:1844-1848 |
| ISSN: | 1347-5215 0918-6158 |
| DOI: | 10.1248/bpb.32.1844 |
| Popis: | Prostaglandin E2 (PGE2) stimulates osteoclast formation by increasing receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) mRNA expression via cAMP-protein kinase A (PKA) pathways in osteoblasts. Since phosphodiesterases (PDEs) balance the concentration of intracellular cAMP stimulated by PGE2, we investigated the role of PDEs in PGE2-mediated osteoclast formation using various cAMP-specific PDEs inhibitors. In the presence of PGE(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 PGE2-induced cAMP production followed by increased RANKL mRNA expression in osteoblasts, suggesting that PDE3 and 4 negatively regulate PGE2-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 PGE2-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 PGE2-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. |
| Databáze: | OpenAIRE |
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