Gα13 negatively controls osteoclastogenesis through inhibition of the Akt-GSK3β-NFATc1 signalling pathway

Mengrui Wu, Wei Chen (), Yun Lu, Guochun Zhu, Liang Hao and Yi-Ping Li ()
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Mengrui Wu: University of Alabama at Birmingham
Wei Chen: University of Alabama at Birmingham
Yun Lu: University of Alabama at Birmingham
Guochun Zhu: University of Alabama at Birmingham
Liang Hao: University of Alabama at Birmingham
Yi-Ping Li: University of Alabama at Birmingham

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Many positive signalling pathways of osteoclastogenesis have been characterized, but negative signalling pathways are less well studied. Here we show by microarray and RNAi that guanine nucleotide-binding protein subunit α13 (Gα13) is a negative regulator of osteoclastogenesis. Osteoclast-lineage-specific Gna13 conditional knockout mice have a severe osteoporosis phenotype. Gna13-deficiency triggers a drastic increase in both osteoclast number and activity (hyper-activation), mechanistically through decreased RhoA activity and enhanced Akt/GSK3β/NFATc1 signalling. Consistently, Akt inhibition or RhoA activation rescues hyper-activation of Gna13-deficient osteoclasts, and RhoA inhibition mimics the osteoclast hyperactivation resulting from Gna13-deficiency. Notably, Gα13 gain-of-function inhibits Akt activation and osteoclastogenesis, and protects mice from pathological bone loss in disease models. Collectively, we reveal that Gα13 is a master endogenous negative switch for osteoclastogenesis through regulation of the RhoA/Akt/GSK3β/NFATc1 signalling pathway, and that manipulating Gα13 activity might be a therapeutic strategy for bone diseases.

Date: 2017
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DOI: 10.1038/ncomms13700

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