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PKC? positively regulates RANKL-induced osteoclastogenesis by inactivating GSK-3?.


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-?B ligand (RANKL) signaling has remained elusive. We now demonstrate that PKC? acts as a positive regulator which inactivates glycogen synthase kinase-3? (GSK-3?) and promotes NFATc1 induction during RANKL-induced osteoclastogenesis. Among PKCs, PKC? expression is increased by RANKL. Pharmacological inhibition of PKC? decreased the formation of osteoclasts which was caused by the inhibition of NFATc1 induction. Importantly, the phosphorylation of GSK-3? was decreased by PKC? inhibition. Likewise, down-regulation of PKC? by RNA interference suppressed osteoclast differentiation, NFATc1 induction, and GSK-3? phosphorylation. The administration of PKC inhibitor to the RANKL-injected mouse calvaria efficiently protected RANKL-induced bone destruction. Thus, the PKC? pathway, leading to GSK-3? inactivation and NFATc1 induction, has a key role in the differentiation of osteoclasts. Our results also provide a further rationale for PKC?'s therapeutic targeting to treat inflammation-related bone diseases.

SUBMITTER: Shin J 

PROVIDER: S-EPMC4213766 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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PKCβ positively regulates RANKL-induced osteoclastogenesis by inactivating GSK-3β.

Shin Jihye J   Jang Hyunduk H   Lin Jingjing J   Lee Soo Young SY  

Molecules and cells 20140926 10


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-κB ligand (RANKL) signaling has remained elusive. We now demonstrate that PKCβ acts as a positive regulator which inactivates glycogen synthase kinase-3β (GSK-3β) and promotes NFATc1 induction during RANKL-induced osteoclastogenesis. Among PKCs, PKCβ expression is increased by RANKL. Pharmac  ...[more]

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