Phosphodiesterase (PDE) 4 is an enzyme that degrades intracellular cAMP. In the present study, the effect of rolipram, a specific phosphodiesterase (PDE) 4 inhibitor, on osteoclast formation was investigated. Rolipram induced osteoclast formation in cocultures of mouse bone marrow cells and calvarial osteoblasts. This activity was not observed in the absence of calvarial osteoblasts, suggesting that calvarial osteoblasts are likely target cells of rolipram. Osteoclast formation by rolipram was completely blocked by the addition of osteoprotegerin (OPG), a soluble decoy receptor for the osteoclast differentiation factor, TNF-related activation-induced cytokine (TRANCE, identical to RANKL, ODF, and OPGL). Northern blot analysis revealed the effect of rolipram to be associated with the increased expression of TRANCE mRNA in mouse calvarial osteoblasts. Collectively, these data indicate that PDE4 inhibitor up-regulates the TRANCE mRNA expression in osteoblasts, which in turn controls osteoclast formation.
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Conti, M. and Jin, S. L., The molecular biology of cyclic nucleotide phosphodiesterases.Prog. Nucleic. Acid Res. Mol. Biol., 63, 1–38 (1999).
Essayan, D. M., Cyclic nucleotide phosphodiesterases.J. Allergy Clin. Immunol., 108, 671–680 (2001).
Fu, Q., Jilka, R. L., Manolagas, S. C., and O’Brien, C. A., Parathyroid hormone stimulates receptor activator of NF kappa B ligand and inhibits osteoprotegerin expressionvia protein kinase A activation of cAMP-response elementbinding protein.J. Biol. Chem., 277, 48868–48875 (2002).
Houslay, M. D. and Adams, D. R., PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling crosstalk, desensitization and compartmentalization.Biochem. J., 370, 1–18 (2003).
Houslay, M. D., Sullivan, M., and Bolger, G. B., The multienzyme PDE4 cyclic adenosine monophosphate-specific phosphodiesterase family: intracellular targeting, regulation, and selective inhibition by compounds exerting anti-inflammatory and antidepressant actions.Adv. Pharmacol., 44, 225–342 (1998).
Kinoshita, T., Kobayashi, S., Ebara, S., Yoshimura, Y., Horiuchi, H., Tsutsumimoto, T., Wakabayashi, S., and Takaoka, K., Phosphodiesterase inhibitors, pentoxifylline and rolipram, increase bone mass mainly by promoting bone formation in normal mice.Bone, 27, 811–817 (2000).
Kondo, H., Guo, J., and Bringhurst, F. R., Cyclic adenosine monophosphate/protein kinase A mediates parathyroid hormone/parathyroid hormone-related protein receptor regulation of osteoclastogenesis and expression of RANKL and osteoprotegerin mRNAs by marrow stromal cells.J. Bone Miner. Res., 17, 1667–1679 (2002).
Miyamoto, K., Waki, Y., Horita, T., Kasugai, S., and Ohya, K., Reduction of bone loss by denbufylline, an inhibitor of phosphodiesterase 4.Biochem. Pharmacol., 54, 613–617 (1997).
Suda, T., Jimi, E., Nakamura, I., and Takahashi, N., Role of 1 alpha, 25-dihydroxyvitamin D3 in osteoclast differentiation and function.Methods Enzymol., 282, 223–235 (1997).
Suda, T., Takahashi, N., Udagawa, N., Jimi, E., Gillespie, M. T., and Martin, T. J., Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families.Endocr. Rev., 20, 345–357 (1999).
Takahashi, N., Akatsu, T., Udagawa, N., Sasaki, T., Yamaguchi, A., Moseley, J. M., Martin, T. J., and Suda, T., Osteoblastic cells are involved in osteoclast formation.Endocrinology, 123, 2600–2602 (1988).
Takahashi, N., Udagawa, N., and Suda, T. A., New member of tumor necrosis factor ligand family, ODF/OPGL/TRANCE/ RANKL, regulates osteoclast differentiation and function.Biochem. Biophys. Res. Commun., 256, 449–455 (1999).
Tarn, C. S., Heersche, J. N., Murray, T. M., and Parsons, J. A., Parathyroid hormone stimulates the bone apposition rate independently of its resorptive action: differential effects of intermittent and continuous administration.Endocrinology, 110, 506–512 (1982).
Tsutsumimoto, T., Wakabayashi, S., Kinoshita, T., Horiuchi, H., and Takaoka, K., A phosphodiesterase inhibitor, pentoxifylline, enhances the bone morphogenetic protein-4 (BMP-4)-dependent differentiation of osteoprogenitor cells.Bone, 31, 396–401 (2002).
Väänänen, H. K., Zhao, H., Mulari, M., and Halleen, J. M., The cell biology of osteoclast function.J. Cell Sci., 113, 377–381 (2000).
Wakabayashi, S., Tsutsumimoto, T., Kawasaki, S., Kinoshita, T., Horiuchi, H., and Takaoka, K., Involvement of phosphodiesterase isozymes in osteoblastic differentiation.J. Bone Miner. Res., 17, 249–56 (2002).
Waki, Y., Horita, T., Miyamoto, K., Ohya, K., and Kasugai, S., Effects of XT-44, a phosphodiesterase 4 inhibitor, in osteoblastgenesis and osteoclastgenesis in culture and its therapeutic effects in rat osteopenia models.Jpn. J. Pharmacol., 79, 477–483 (1999).
Wong, B. R., Rho, J., Arron, J., Robinson, E., Orlinick, J., Chao, M., Kalachikov, S., Cayani, E., Bartlett 3rd, F. S., Frankel, W. N., Lee, S. Y., and Choi, Y., TRANCE is a novel ligand of the tumor necrosis factor receptor family that activatesc-JunN-terminal kinase in T cells.J. Biol. Chem., 272, 25190–25194 (1997).
An erratum to this article is available at http://dx.doi.org/10.1007/BF02975149.
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Cho, E.S., Yu, J.H., Kim, M.S. et al. Rolipram, a Phosphodiesterase 4 inhibitor, stimulates osteoclast formation by inducing TRANCE expression in mouse calvarial cells. Arch Pharm Res 27, 1258 (2004). https://doi.org/10.1007/BF02975891
- Phosphodiesterase 4 inhibitor