Biphasic and Dosage-Dependent Regulation of Osteoclastogenesis by beta-Catenin

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Wnt/beta-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, beta-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, beta-catenin deletion blocks osteoclast precursor proliferation, while beta-catenin constitutive activation sustains proliferation but prevents osteoclast differentiation, both causing osteopetrosis. In contrast, beta-catenin heterozygosity enhances osteoclast differentiation, causing osteoporosis. Biochemically, Wnt activation attenuates whereas Wnt inhibition stimulates osteoclastogenesis. Mechanistically, beta-catenin activation increases GATA2/Evi1 expression but abolishes RANKL-induced c-Jun phosphorylation. Therefore, beta-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.
Publisher
AMER SOC MICROBIOLOGY
Issue Date
2011-12
Language
English
Article Type
Article
Keywords

ACTIVATED RECEPTOR-GAMMA; INCREASES BONE-FORMATION; STEM-CELLS; OSTEOPROTEGERIN LIGAND; SCLEROSTIN ANTIBODY; MULTIPLE-MYELOMA; C-JUN; WNT; DIFFERENTIATION; MICE

Citation

MOLECULAR AND CELLULAR BIOLOGY, v.31, no.23, pp.4706 - 4719

ISSN
0270-7306
DOI
10.1128/MCB.05980-11
URI
http://hdl.handle.net/10203/198272
Appears in Collection
MSE-Journal Papers(저널논문)
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