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.

NF-κB Decoy Oligodeoxynucleotide Enhanced Osteogenesis in Mesenchymal Stem Cells Exposed to Polyethylene Particle

“…30 Previous reports suggested that TNF-a enhances osteoclastogenesis and inhibits osteogenesis at an early stage of inflammation, but induces osteogenesis at the later tissue repair stages of inflammation. 30 The role of NF-kB in osteogenesis in previous reports [31][32][33][34][35] and our current findings may be due to different time points of evaluation, different proinflammatory stimuli, and the specific osteogenic markers tested.…”

“…36 In other studies, the suppression of NF-kB promoted osteogenesis in primary bone marrow-derived MSCs and conditional NF-kB-deficient mice. 31 The suppressive effects of NF-kB on osteogenesis are mediated by direct upregulation of Smurf1/2 expression to enhance b-catenin degradation. 31 On the contrary, Cho et al demonstrated that NF-kB activated by TNF-a promoted osteogenesis through upregulation of a transcriptional coactivator with PDZ-binding motif (TAZ) in adipose-derived MSCs.…”

“…31 The suppressive effects of NF-kB on osteogenesis are mediated by direct upregulation of Smurf1/2 expression to enhance b-catenin degradation. 31 On the contrary, Cho et al demonstrated that NF-kB activated by TNF-a promoted osteogenesis through upregulation of a transcriptional coactivator with PDZ-binding motif (TAZ) in adipose-derived MSCs. 33 In our experimental model, we confirmed that the genes involved in osteogenic regulation were suppressed by NF-kB decoy ODN (Supplementary Fig.…”

Macrophage interactions with polylactic acid and chitosan scaffolds lead to improved recruitment of human mesenchymal stem/stromal cells: a comprehensive study with different immune cells

“…Importantly, it was shown in a murine model that upon biomaterial subcutaneous implantation there is first recruitment of inflammatory cells, which is then correlated with recruitment of MSC [4][5][6][7]. MSC recruitment can then lead to subsequent modulation of inflammation and is essential to promote the constructive remodelling of the tissue [8,9].…”

IL-12p40 impairs mesenchymal stem cell-mediated bone regeneration via CD4+ T cells

“…13 Meanwhile, IL-17 stimulates the nuclear factor kappa B (NF-κB) signaling pathway and impairs the differentiation of BMMSCs. 15 Therefore, defining the crosstalk between proinflammatory cytokines and BMMSCs is an important goal of the newly emerging osteoimmunology field, and such insights may also be helpful for designing improved protocols for BMMSC-mediated bone repair and regeneration.…”