| First Author | Jang HD | Year | 2011 |
| Journal | J Biol Chem | Volume | 286 |
| Issue | 45 | Pages | 39043-50 |
| PubMed ID | 21949120 | Mgi Jnum | J:178155 |
| Mgi Id | MGI:5297625 | Doi | 10.1074/jbc.M111.256768 |
| Citation | Jang HD, et al. (2011) Inactivation of glycogen synthase kinase-3beta is required for osteoclast differentiation. J Biol Chem 286(45):39043-50 |
| abstractText | Glycogen synthase kinase-3beta (GSK-3beta) is a serine/threonine kinase originally identified as a regulator of glycogen deposition. Although the role of GSK-3beta in osteoblasts is well characterized as a negative regulator of beta-catenin, its effect on osteoclast formation remains largely unidentified. Here, we show that the GSK-3beta inactivation upon receptor activator of NF-kappaB ligand (RANKL) stimulation is crucial for osteoclast differentiation. Regulation of GSK-3beta activity in bone marrow macrophages by retroviral expression of the constitutively active GSK-3beta (GSK3beta-S9A) mutant inhibits RANKL-induced osteoclastogenesis, whereas expression of the catalytically inactive GSK-3beta (GSK3beta-K85R) or small interfering RNA (siRNA)-mediated GSK-3beta silencing enhances osteoclast formation. Pharmacological inhibition of GSK-3beta further confirmed the negative role of GSK-3beta in osteoclast formation. We also show that overexpression of the GSK3beta-S9A mutant in bone marrow macrophages inhibits RANKL-mediated NFATc1 induction and Ca(2+) oscillations. Remarkably, transgenic mice expressing the GSK3beta-S9A mutant show an osteopetrotic phenotype due to impaired osteoclast differentiation. Further, osteoclast precursor cells from the transgenic mice show defects in expression and nuclear localization of NFATc1. These findings demonstrate a novel role for GSK-3beta in the regulation of bone remodeling through modulation of NFATc1 in RANKL signaling. |
