Diphenylhydantoin Inhibits Osteoclast Differentiation and Function Through Suppression of NFATc1 Signaling
Open Access
- 1 August 2009
- journal article
- research article
- Published by Oxford University Press (OUP) in Journal of Bone and Mineral Research
- Vol. 24 (8), 1469-1480
- https://doi.org/10.1359/jbmr.090302
Abstract
Diphenylhydantoin (DPH) is widely used as an anticonvulsant drug. We examined the effects of DPH on osteoclast differentiation and function using in vivo and in vitro assay systems. Transgenic mice overexpressing a soluble form of RANKL (RANKL Tg) exhibited increased osteoclastic bone resorption. Injection of DPH into the subcutaneous tissue overlying calvaria of RANKL Tg mice suppressed the enhanced resorption in the calvaria. In co‐cultures of mouse osteoblasts and bone marrow cells, DPH inhibited lipopolysaccharide (LPS)‐induced osteoclast formation. DPH affected neither the mRNA expression of RANKL and osteoprotegerin nor the growth of mouse osteoblasts in culture. On the other hand, DPH inhibited the RANKL‐induced formation of osteoclasts in cultures of mouse bone marrow–derived macrophages (BMMϕs) and of human peripheral blood‐derived CD14+ cells. DPH concealed LPS‐induced bone resorption in mouse calvarial organ cultures and inhibited the pit‐forming activity of mouse osteoclasts cultured on dentine slices. DPH suppressed the RANKL‐induced calcium oscillation and expression of nuclear factor of activated T cells c1 (NFATc1) and c‐fos in BMMϕs. Moreover, DPH inhibited the RANKL‐induced nuclear localization and auto‐amplification of NFATc1 in mature osteoclasts. Both BMMϕs and osteoclasts expressed mRNA of a T‐type calcium channel, Cav3.2, a target of DPH. Blocking the expression of Cav3.2 by short hairpin RNAs significantly suppressed RANKL‐induced osteoclast differentiation. These results suggest that DPH inhibits osteoclast differentiation and function through suppression of NFATc1 signaling. The topical application of DPH may be a therapeutic treatment to prevent bone loss induced by local inflammation such as periodontitis.Keywords
This publication has 48 references indexed in Scilit:
- TRPV4-Mediated Calcium Influx Regulates Terminal Differentiation of OsteoclastsCell Metabolism, 2008
- Osteoblasts induce Ca 2+ oscillation-independent NFATc1 activation during osteoclastogenesisProceedings of the National Academy of Sciences, 2008
- RGS12 Is Essential for RANKL-Evoked Signaling for Terminal Differentiation of Osteoclasts In VitroJournal of Bone and Mineral Research, 2007
- Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalaciaJCI Insight, 2006
- Apatite-mediated Actin Dynamics in Resorbing OsteoclastsMolecular Biology of the Cell, 2004
- Osteoclast differentiation and activationNature, 2003
- Transgenic mice overexpressing soluble osteoclast differentiation factor (sODF) exhibit severe osteoporosisJournal of Bone and Mineral Metabolism, 2002
- Basis of the antiseizure action of phenytoinGeneral Pharmacology: The Vascular System, 1996
- Wortmannin, a specific inhibitor of phosphatidylinositol‐3 kinase, blocks osteoclastic bone resorptionFEBS Letters, 1995
- Phenytoin: Mechanisms of its anticonvulsant actionAnnals of Neurology, 1986