Biphasic and dosage-dependent regulation of osteoclastogenesis by β-catenin

W. Wei, Daniel Zeve, Jae Myoung Suh, Xueqian Wang, Yang Du, Joseph E. Zerwekh, Paul C. Dechow, Jonathan M. Graff, Yihong Wan

Research output: Contribution to journalArticle

111 Scopus citations

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 colonystimulating factor (M-CSF)-mediated quiescence-to-proliferation switch but suppressed during the RANKLmediated 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 RANKLinduced 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.

Original languageEnglish (US)
Pages (from-to)4706-4719
Number of pages14
JournalMolecular and cellular biology
Volume31
Issue number23
DOIs
StatePublished - Dec 1 2011

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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