| First Author | Sui Y | Year | 2018 |
| Journal | JCI Insight | Volume | 3 |
| Issue | 2 | PubMed ID | 29367460 |
| Mgi Jnum | J:311054 | Mgi Id | MGI:6765203 |
| Doi | 10.1172/jci.insight.96660 | Citation | Sui Y, et al. (2018) IKKbeta is a beta-catenin kinase that regulates mesenchymal stem cell differentiation. JCI Insight 3(2) |
| abstractText | Mesenchymal stem cells (MSCs) can give rise to both adipocytes and osteoblasts, but the molecular mechanisms underlying MSC fate determination remain poorly understood. IkappaB kinase beta (IKKbeta), a central coordinator of inflammation and immune responses through activation of NF-kappaB, has been implicated as a critical molecular link between obesity and metabolic disorders. Here, we show that IKKbeta can reciprocally regulate adipocyte and osteoblast differentiation of murine and human MSCs through an NF-kappaB-independent mechanism. IKKbeta is a beta-catenin kinase that phosphorylates the conserved degron motif of beta-catenin to prime it for beta-TrCP-mediated ubiquitination and degradation, thereby increasing adipogenesis and inhibiting osteogenesis in MSCs. Animal studies demonstrated that deficiency of IKKbeta in BM mesenchymal stromal cells increased bone mass and decreased BM adipocyte formation in adult mice. In humans, IKKbeta expression in adipose tissue was also positively associated with increased adiposity and elevated beta-catenin phosphorylation. These findings suggest IKKbeta 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 IKKbeta and Wnt/beta-catenin signaling pathways. The IKKbeta-Wnt axis we uncovered may also have important implications for development, homeostasis, and disease pathogenesis. |
