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

ABSTRACT: Glycogen synthase kinase-3? (GSK-3?) is a serine/threonine kinase originally identified as a regulator of glycogen deposition. Although the role of GSK-3? in osteoblasts is well characterized as a negative regulator of ?-catenin, its effect on osteoclast formation remains largely unidentified. Here, we show that the GSK-3? inactivation upon receptor activator of NF-?B ligand (RANKL) stimulation is crucial for osteoclast differentiation. Regulation of GSK-3? activity in bone marrow macrophages by retroviral expression of the constitutively active GSK-3? (GSK3?-S9A) mutant inhibits RANKL-induced osteoclastogenesis, whereas expression of the catalytically inactive GSK-3? (GSK3?-K85R) or small interfering RNA (siRNA)-mediated GSK-3? silencing enhances osteoclast formation. Pharmacological inhibition of GSK-3? further confirmed the negative role of GSK-3? in osteoclast formation. We also show that overexpression of the GSK3?-S9A mutant in bone marrow macrophages inhibits RANKL-mediated NFATc1 induction and Ca(2+) oscillations. Remarkably, transgenic mice expressing the GSK3?-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-3? in the regulation of bone remodeling through modulation of NFATc1 in RANKL signaling.

SUBMITTER: Jang HD

PROVIDER: S-EPMC3234729 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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

Jang Hyun Duk HD Shin Ji Hye JH Park Doo Ri DR Hong Jin Hee JH Yoon Kwiyeom K Ko Ryeojin R Ko Chang-Yong CY Kim Han-Sung HS Jeong Daewon D Kim Nacksung N Lee Soo Young SY

The Journal of biological chemistry 20110923 45

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 ...[more]

PMID: 21949120

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Project description:BackgroundChronic lung diseases such as asthma, COPD and pulmonary fibrosis are characterized by abnormal extracellular matrix (ECM) turnover. TGF-β is a key mediator stimulating ECM production by recruiting and activating lung fibroblasts and initiating their differentiation process into more active myofibroblasts. Glycogen synthase kinase-3 (GSK-3) regulates various intracellular signalling pathways; its role in TGF-β₁-induced myofibroblast differentiation is currently largely unknown.PurposeTo determine the contribution of GSK-3 signalling in TGF-β₁-induced myofibroblast differentiation.Experimental approachWe used MRC5 human lung fibroblasts and primary pulmonary fibroblasts of individuals with and without COPD. Protein and mRNA expression were determined by immunoblotting and RT-PCR analysis respectively.ResultsStimulation of MRC5 and primary human lung fibroblasts with TGF-β₁ resulted in time- and dose-dependent increases of α-sm-actin and fibronectin expression, indicative of myofibroblast differentiation. Pharmacological inhibition of GSK-3 by SB216763 dose-dependently attenuated TGF-β₁-induced expression of these myofibroblasts markers. Moreover, silencing of GSK-3 by siRNA or pharmacological inhibition by CT/CHIR99021 fully inhibited the TGF-β₁-induced expression of α-sm-actin and fibronectin. The effect of GSK-3 inhibition on α-sm-actin expression was similar in fibroblasts from individuals with and without COPD. Neither smad, NF-κB nor ERK1/2 were involved in the inhibitory actions of GSK-3 inhibition by SB126763 on myofibroblast differentiation. Rather, SB216763 increased the phosphorylation of CREB, which in its phosphorylated form acts as a functional antagonist of TGF-β/smad signalling.Conclusion and implicationWe demonstrate that GSK-3 signalling regulates TGF-β₁-induced myofibroblast differentiation by regulating CREB phosphorylation. GSK-3 may constitute a useful target for treatment of chronic lung diseases.

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

Publications

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

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