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IKKβ is a β-catenin kinase that regulates mesenchymal stem cell differentiation
Yipeng Sui, … , Philip A. Kern, Changcheng Zhou
Yipeng Sui, … , Philip A. Kern, Changcheng Zhou
Published January 25, 2018
Citation Information: JCI Insight. 2018;3(2):e96660. https://doi.org/10.1172/jci.insight.96660.
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Research Article Cell biology Stem cells

IKKβ is a β-catenin kinase that regulates mesenchymal stem cell differentiation

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Abstract

Mesenchymal stem cells (MSCs) can give rise to both adipocytes and osteoblasts, but the molecular mechanisms underlying MSC fate determination remain poorly understood. IκB kinase β (IKKβ), a central coordinator of inflammation and immune responses through activation of NF-κB, has been implicated as a critical molecular link between obesity and metabolic disorders. Here, we show that IKKβ can reciprocally regulate adipocyte and osteoblast differentiation of murine and human MSCs through an NF-κB–independent mechanism. IKKβ is a β-catenin kinase that phosphorylates the conserved degron motif of β-catenin to prime it for β-TrCP–mediated ubiquitination and degradation, thereby increasing adipogenesis and inhibiting osteogenesis in MSCs. Animal studies demonstrated that deficiency of IKKβ in BM mesenchymal stromal cells increased bone mass and decreased BM adipocyte formation in adult mice. In humans, IKKβ expression in adipose tissue was also positively associated with increased adiposity and elevated β-catenin phosphorylation. These findings suggest IKKβ as a key molecular switch that regulates MSC fate, and they provide potentially novel mechanistic insights into the understanding of the cross-regulation between the evolutionarily conserved IKKβ and Wnt/β-catenin signaling pathways. The IKKβ-Wnt axis we uncovered may also have important implications for development, homeostasis, and disease pathogenesis.

Authors

Yipeng Sui, Zun Liu, Se-Hyung Park, Sean E. Thatcher, Beibei Zhu, Joseph P. Fernandez, Henrik Molina, Philip A. Kern, Changcheng Zhou

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Figure 1

Deficiency or inhibition of IKKβ reduces adipogenesis but increases osteogenesis of murine MSCs.

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Deficiency or inhibition of IKKβ reduces adipogenesis but increases oste...
(A) Immunoblotting for IKKβ proteins in control or CRISPR/Cas9-mediated IKKβ-deficient C3H/10T1/2 cells. (B) Oil Red O staining of control and IKKβ-deficient MSCs induced by an adipogenic cocktail. Scale bar: 100 μm. (C) qPCR analysis of mRNA levels of adipogenic genes and adipocyte markers (n = 3). (D) Alkaline phosphatase (ALP) staining of control and IKKβ-deficient C3H/10T1/2 cells induced by an osteogenic cocktail. Scale bar: 100 μm. (E) qPCR analysis of mRNA levels of osteogenic genes and osteoblast markers (n = 3). (F–I) C3H/10T1/2 cells were treated with vehicle control or 5 μM IKKβ inhibitor BMS-345541 and were induced by differentiation media. Oil Red O staining (F) and qPCR analysis (G) of vehicle or BMS-345541–treated C3H/10T1/2 cells induced by an adipogenic cocktail (n = 3). ALP staining (H) and qPCR analysis (I) of vehicle or BMS-345541–treated C3H/10T1/2 cells induced by an osteogenic cocktail (n = 3). Scale bar: 100 μm. Error bars represent ± SEM. Significance was determined by Student’s t test (C, E, G, and I). *P < 0.05; **P < 0.01, ***P < 0.001.

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