title: NF-κB inhibits osteogenic differentiation of mesenchymal stem cells by promoting β-catenin degradation.
abstract: Mesenchymal stem cell (MSC)-based transplantation is a promising therapeutic approach for bone regeneration and repair. In the realm of therapeutic bone regeneration, the defect or injured tissues are frequently inflamed with an abnormal expression of inflammatory mediators. Growing evidence suggests that proinflammatory cytokines inhibit osteogenic differentiation and bone formation. Thus, for successful MSC-mediated repair, it is important to overcome the inflammation-mediated inhibition of tissue regeneration. In this study, using genetic and chemical approaches, we found that proinflammatory cytokines TNF and IL-17 stimulated IκB kinase (IKK)-NF-κB and impaired osteogenic differentiation of MSCs. In contrast, the inhibition of IKK-NF-κB significantly enhanced MSC-mediated bone formation. Mechanistically, we found that IKK-NF-κB activation promoted β-catenin ubiquitination and degradation through induction of Smurf1 and Smurf2. To translate our basic findings to potential clinic applications, we showed that the IKK small molecule inhibitor, IKKVI, enhanced osteogenic differentiation of MSCs. More importantly, the delivery of IKKVI promoted MSC-mediated craniofacial bone regeneration and repair in vivo. Considering the well established role of NF-κB in inflammation and infection, our results suggest that targeting IKK-NF-κB may have dual benefits in enhancing bone regeneration and repair and inhibiting inflammation, and this concept may also have applicability in many other tissue regeneration situations.
authors.affiliation: Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Chang
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Lee
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wu
authors.forename: Kang
authors.initials: K
authors.lastname: Ting
authors.forename: Janette N
authors.initials: JN
authors.lastname: Zara
authors.forename: Chia
authors.initials: C
authors.lastname: Soo
authors.forename: Khalid
authors.initials: K
authors.lastname: Al Hezaimi
authors.forename: Weiping
authors.initials: W
authors.lastname: Zou
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Chen
authors.forename: David J
authors.initials: DJ
authors.lastname: Mooney
authors.forename: Cun-Yu
authors.initials: CY
authors.lastname: Wang
mesh_terms: D000818:Animals; D000880:Anthraquinones; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D020381:Interleukin-17 / Q000494:pharmacology; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000880:Anthraquinones; D020381:Interleukin-17; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; C010078:alizarin; C492381:Smurf1 protein, mouse; C533325:Smurf2 protein, mouse; D044767:Ubiquitin-Protein Ligases; D051550:I-kappa B Kinase
keywords: Wnt; adult stem cells; osteoimmunology