title: Gα13 negatively controls osteoclastogenesis through inhibition of the Akt-GSK3β-NFATc1 signalling pathway.
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.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, SHEL 810, 1825 University Boulevard, Birmingham, Alabama 35294-2182, USA.
authors.forename: Mengrui
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, SHEL 810, 1825 University Boulevard, Birmingham, Alabama 35294-2182, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, SHEL 810, 1825 University Boulevard, Birmingham, Alabama 35294-2182, USA.
authors.forename: Yun
authors.identifier: 0000-0002-4785-3401
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, SHEL 810, 1825 University Boulevard, Birmingham, Alabama 35294-2182, USA.
authors.forename: Guochun
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, SHEL 810, 1825 University Boulevard, Birmingham, Alabama 35294-2182, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Hao
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, SHEL 810, 1825 University Boulevard, Birmingham, Alabama 35294-2182, USA.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Li
mesh_terms: D036002:ADP Ribose Transferases; D000818:Animals; D015519:Bone Density; D001905:Botulinum Toxins; D005260:Female; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D020868:Gene Silencing; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008074:Lipoproteins / Q000633:toxicity; D016173:Macrophage Colony-Stimulating Factor; D008297:Male; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D010052:Ovariectomy; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D053245:RANK Ligand; D015398:Signal Transduction / Q000502:physiology
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D008074:Lipoproteins; C548887:MK 2206; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D016173:Macrophage Colony-Stimulating Factor; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D001905:Botulinum Toxins; D044365:GTP-Binding Protein alpha Subunits, G12-G13