Inactivation of glycogen synthase kinase-3β is required for osteoclast differentiation

Hyun Duk Jang, Ji Hye Shin, Doo Ri Park, Jin Hee Hong, Kwiyeom Yoon, Ryeojin Ko, Chang Yong Ko, Han Sung Kim, Daewon Jeong, Nacksung Kim, Soo Young Lee

Research output: Contribution to journalArticle

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Abstract

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 Ca 2+ 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.

Original languageEnglish
Pages (from-to)39043-39050
Number of pages8
JournalJournal of Biological Chemistry
Volume286
Issue number45
DOIs
Publication statusPublished - 2011 Nov 11

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Glycogen Synthase Kinase 3
Osteoclasts
Bone
Macrophages
Transgenic Mice
Bone Marrow
Catenins
Bone Remodeling
Protein-Serine-Threonine Kinases
Osteoblasts
Glycogen
Osteogenesis
Small Interfering RNA
Modulation
Pharmacology
Ligands
Phenotype
Defects

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Jang, H. D., Shin, J. H., Park, D. R., Hong, J. H., Yoon, K., Ko, R., ... Lee, S. Y. (2011). Inactivation of glycogen synthase kinase-3β is required for osteoclast differentiation. Journal of Biological Chemistry, 286(45), 39043-39050. https://doi.org/10.1074/jbc.M111.256768
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. / Inactivation of glycogen synthase kinase-3β is required for osteoclast differentiation. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 45. pp. 39043-39050.
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Jang, HD, Shin, JH, Park, DR, Hong, JH, Yoon, K, Ko, R, Ko, CY, Kim, HS, Jeong, D, Kim, N & Lee, SY 2011, 'Inactivation of glycogen synthase kinase-3β is required for osteoclast differentiation', Journal of Biological Chemistry, vol. 286, no. 45, pp. 39043-39050. https://doi.org/10.1074/jbc.M111.256768

Inactivation of glycogen synthase kinase-3β is required for osteoclast differentiation. / 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.

In: Journal of Biological Chemistry, Vol. 286, No. 45, 11.11.2011, p. 39043-39050.

Research output: Contribution to journalArticle

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T1 - Inactivation of glycogen synthase kinase-3β is required for osteoclast differentiation

AU - Jang, Hyun Duk

AU - Shin, Ji Hye

AU - Park, Doo Ri

AU - Hong, Jin Hee

AU - Yoon, Kwiyeom

AU - Ko, Ryeojin

AU - Ko, Chang Yong

AU - Kim, Han Sung

AU - Jeong, Daewon

AU - Kim, Nacksung

AU - Lee, Soo Young

PY - 2011/11/11

Y1 - 2011/11/11

N2 - 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 Ca 2+ 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.

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