TY - JOUR
T1 - Biphasic and dosage-dependent regulation of osteoclastogenesis by β-catenin
AU - Wei, W.
AU - Zeve, Daniel
AU - Suh, Jae Myoung
AU - Wang, Xueqian
AU - Du, Yang
AU - Zerwekh, Joseph E.
AU - Dechow, Paul C.
AU - Graff, Jonathan M.
AU - Wan, Yihong
PY - 2011/12
Y1 - 2011/12
N2 - 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.
AB - 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.
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U2 - 10.1128/MCB.05980-11
DO - 10.1128/MCB.05980-11
M3 - Article
C2 - 21876000
AN - SCOPUS:83255192191
SN - 0270-7306
VL - 31
SP - 4706
EP - 4719
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 23
ER -