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

W Wei, D Zeve, JM Suh, X Wang, Y Du… - … and cellular biology, 2011 - Taylor & Francis
W Wei, D Zeve, JM Suh, X Wang, Y Du, JE Zerwekh, PC Dechow, JM Graff, Y Wan
Molecular and cellular biology, 2011Taylor & Francis
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 …
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.
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