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http://dx.doi.org/10.14348/molcells.2014.0220

PKCβ Positively Regulates RANKL-Induced Osteoclastogenesis by Inactivating GSK-3β  

Shin, Jihye (Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University)
Jang, Hyunduk (Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University)
Lin, Jingjing (Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University)
Lee, Soo Young (Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University)
Publication Information
Molecules and Cells / v.37, no.10, 2014 , pp. 747-752 More about this Journal
Abstract
Protein kinase C (PKC) family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. However, the role of PKC in receptor activator of NF-${\kappa}B$ ligand (RANKL) signaling has remained elusive. We now demonstrate that $PKC{\beta}$ acts as a positive regulator which inactivates glycogen synthase kinase-$3{\beta}$ (GSK-$3{\beta}$) and promotes NFATc1 induction during RANKL-induced osteoclastogenesis. Among PKCs, $PKC{\beta}$ expression is increased by RANKL. Pharmacological inhibition of $PKC{\beta}$ decreased the formation of osteoclasts which was caused by the inhibition of NFATc1 induction. Importantly, the phosphorylation of GSK-$3{\beta}$ was decreased by $PKC{\beta}$ inhibition. Likewise, down-regulation of $PKC{\beta}$ by RNA interference suppressed osteoclast differentiation, NFATc1 induction, and GSK-$3{\beta}$ phosphorylation. The administration of PKC inhibitor to the RANKL-injected mouse calvaria efficiently protected RANKL-induced bone destruction. Thus, the $PKC{\beta}$ pathway, leading to GSK-$3{\beta}$ inactivation and NFATc1 induction, has a key role in the differentiation of osteoclasts. Our results also provide a further rationale for $PKC{\beta}$'s therapeutic targeting to treat inflammation-related bone diseases.
Keywords
glycogen synthase kinase-$3{\beta}$; osteoclast differentiation; protein kinase $C{\beta}$; receptor activator of NF-${\kappa}B$ ligand;
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