Inactivation of Glycogen Synthase Kinase-3β Is Required for Osteoclast Differentiation

• Published in: The Journal of biological chemistry 2011-11, Vol.286 (45), p.39043-39050
• Main Authors: Jang, Hyun Duk, Shin, Ji Hye, Park, Doo Ri, Hong, Jin Hee, Yoon, Kwiyeom, Ko, Ryeojin, Ko, Chang-Yong, Kim, Han-Sung, Jeong, Daewon, Kim, Nacksung, Lee, Soo Young
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus - drug effects; Active Transport, Cell Nucleus - physiology; Amino Acid Substitution; Animals; Biological Clocks - drug effects; Biological Clocks - physiology; Bone; Bone Marrow Cells - cytology; Bone Marrow Cells - enzymology; Bone Remodeling - drug effects; Bone Remodeling - physiology; Calcium - metabolism; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cell Nucleus - enzymology; Cell Nucleus - genetics; Cells, Cultured; Differentiation; Enzyme Activation - drug effects; Enzyme Activation - physiology; Enzyme Inhibitors - pharmacology; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Glycogen Synthase Kinase-3; Mice; Mice, Transgenic; Mutation, Missense; NFAT Transcription Factor; NFATC Transcription Factors - genetics; NFATC Transcription Factors - metabolism; Osteoclasts; Osteoclasts - cytology; Osteoclasts - enzymology; RANK Ligand - genetics; RANK Ligand - metabolism; RNA, Small Interfering - genetics; Signal Transduction; Signal Transduction - drug effects; Signal Transduction - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.256768

Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase originally identified as a regulator of glycogen deposition. Although the role of GSK-3β in osteoblasts is well characterized as a negative regulator of β-catenin, its effect on osteoclast formation remains largely unidentified. Here, we show that the GSK-3β inactivation upon receptor activator of NF-κB ligand (RANKL) stimulation is crucial for osteoclast differentiation. Regulation of GSK-3β activity in bone marrow macrophages by retroviral expression of the constitutively active GSK-3β (GSK3β-S9A) mutant inhibits RANKL-induced osteoclastogenesis, whereas expression of the catalytically inactive GSK-3β (GSK3β-K85R) or small interfering RNA (siRNA)-mediated GSK-3β silencing enhances osteoclast formation. Pharmacological inhibition of GSK-3β further confirmed the negative role of GSK-3β in osteoclast formation. We also show that overexpression of the GSK3β-S9A mutant in bone marrow macrophages inhibits RANKL-mediated NFATc1 induction and Ca2+ oscillations. Remarkably, transgenic mice expressing the GSK3β-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-3β in the regulation of bone remodeling through modulation of NFATc1 in RANKL signaling. Background: Bone homeostasis is maintained by balancing the activities of bone-resorbing osteoclasts and bone-forming osteoblasts. Results: GSK-3β is inactivated by receptor activator of NF-κB ligand stimulation via serine phosphorylation during osteoclastogenesis. Conclusion: GSK-3β is crucial for receptor activator of NF-κB ligand-mediated signaling as a negative regulator of osteoclast differentiation. Significance: GSK-3β acts as a novel negative regulator of osteoclast biology.