Year: 2018
Type: article
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.
Source: JCI Insight
Institutions: University of Kentucky, Rockefeller University
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,100
Funders: National Institutes of Health, National Heart, Lung, and Blood Institute, NIH Office of the Director, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences, National Center for Advancing Translational Sciences
Awards: G1011331351, G1190357211, G1212788799, Endocrine disruptor mediated activation of PXR causes dyslipidemia and atherosclerosis, G247544770, A novel mechanism for ART-associated dyslipidemia and atherosclerosis, G25137101, Center of Research on Obesity and Cardiovascular Diseases, Role of IKKβ in obesity and atherosclerosis, G5554384332, Mechanisms of atherogenic effects of bisphenol A, G6909792334, G748068828, Kentucky Center for Clinical and Translational Science, Kentucky Center for Clinical and Translational Science
OpenAlex ID: W2785201825