title: Biphasic and dosage-dependent regulation of osteoclastogenesis by β-catenin.
abstract: Wnt/β-catenin signaling is a critical regulator of skeletal physiology. However, previous studies have mainly focused on its roles in osteoblasts, while its specific function in osteoclasts is unknown. This is a clinically important question because neutralizing antibodies against Wnt antagonists are promising new drugs for bone diseases. Here, we show that in osteoclastogenesis, β-catenin is induced during the macrophage colony-stimulating factor (M-CSF)-mediated quiescence-to-proliferation switch but suppressed during the RANKL-mediated proliferation-to-differentiation switch. Genetically, β-catenin deletion blocks osteoclast precursor proliferation, while β-catenin constitutive activation sustains proliferation but prevents osteoclast differentiation, both causing osteopetrosis. In contrast, β-catenin heterozygosity enhances osteoclast differentiation, causing osteoporosis. Biochemically, Wnt activation attenuates whereas Wnt inhibition stimulates osteoclastogenesis. Mechanistically, β-catenin activation increases GATA2/Evi1 expression but abolishes RANKL-induced c-Jun phosphorylation. Therefore, β-catenin exerts a pivotal biphasic and dosage-dependent regulation of osteoclastogenesis. Importantly, these findings suggest that Wnt activation is a more effective treatment for skeletal fragility than previously recognized that confers dual anabolic and anti-catabolic benefits.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Daniel
authors.initials: D
authors.lastname: Zeve
authors.forename: Jae Myoung
authors.initials: JM
authors.lastname: Suh
authors.forename: Xueqian
authors.initials: X
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Du
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Zerwekh
authors.forename: Paul C
authors.initials: PC
authors.lastname: Dechow
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Graff
authors.forename: Yihong
authors.initials: Y
authors.lastname: Wan
mesh_terms: D000818:Animals; D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D000074008:MDS1 and EVI1 Complex Locus Protein; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000166:cytology*; D010022:Osteopetrosis / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000097:blood; D011519:Proto-Oncogenes / Q000235:genetics; D053245:RANK Ligand / Q000494:pharmacology / Q000502:physiology; D011859:Radiography; D013977:Tibia / Q000033:anatomy & histology / Q000000981:diagnostic imaging; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C495267:CTNNB1 protein, mouse; D024042:Collagen Type I; D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D000074008:MDS1 and EVI1 Complex Locus Protein; C499305:Mecom protein, mouse; D047495:PPAR gamma; D010446:Peptide Fragments; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D014157:Transcription Factors; D051176:beta Catenin; D016173:Macrophage Colony-Stimulating Factor; D048031:JNK Mitogen-Activated Protein Kinases; D056657:Cathepsin K