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

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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 2011

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Catenins
Osteogenesis
Osteoclasts
Osteopetrosis
Bone Diseases
Neutralizing Antibodies
Osteoblasts
Osteoporosis
Macrophages
Phosphorylation
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Biphasic and dosage-dependent regulation of osteoclastogenesis by β-catenin. / Wei, W.; Zeve, Daniel; Suh, Jae Myoung; Wang, Xueqian; Du, Yang; Zerwekh, Joseph E.; Dechow, Paul C.; Graff, Jonathan M.; Wan, Yihong.

In: Molecular and Cellular Biology, Vol. 31, No. 23, 12.2011, p. 4706-4719.

Research output: Contribution to journalArticle

Wei, W, Zeve, D, Suh, JM, Wang, X, Du, Y, Zerwekh, JE, Dechow, PC, Graff, JM & Wan, Y 2011, 'Biphasic and dosage-dependent regulation of osteoclastogenesis by β-catenin', Molecular and Cellular Biology, vol. 31, no. 23, pp. 4706-4719. https://doi.org/10.1128/MCB.05980-11
Wei, W. ; Zeve, Daniel ; Suh, Jae Myoung ; Wang, Xueqian ; Du, Yang ; Zerwekh, Joseph E. ; Dechow, Paul C. ; Graff, Jonathan M. ; Wan, Yihong. / Biphasic and dosage-dependent regulation of osteoclastogenesis by β-catenin. In: Molecular and Cellular Biology. 2011 ; Vol. 31, No. 23. pp. 4706-4719.
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