Abstract
Inflammation can influence multipotency and self-renewal of mesenchymal stem cells (MSCs), resulting in their awakened bone-regeneration ability. Human periodontal ligament tissue-derived MSCs (PDLSCs) have been isolated, and their differentiation potential was found to be defective due to β-catenin signaling indirectly regulated by inflammatory microenvironments. Nuclear factor-κB (NF-κB) is well studied in inflammation by many different groups. The role of NF-κB needs to be studied in PDLSCs, although genetic evidences have recently shown that NF-κB inhibits osteoblastic bone formation in mice. However, the mechanism as to how inflammation leads to the modulation of β-catenin and NF-κB signaling remains unclear. In this study, we investigated β-catenin and NF-κB signaling through regulation of glycogen synthase kinase 3β activity (GSK-3β, which modulates β-catenin and NF-κB signaling) using a specific inhibitor LiCl and a phosphatidylinositol 3-kinase (PI3K) inhibitor LY 294002. We identified that NF-κB signaling might be more important for the regulation of osteogenesis in PDLSCs from periodontitis compared with β-catenin. BAY 11-7082 (an inhibitor of NF-κB) could inhibit phosphorylation of p65 and partly rescue the differentiation potential of PDLSCs in inflammation. Our data indicate that NF-κB has a central role in regulating osteogenic differentiation of PDLSCs in inflammatory microenvironments. Given the molecular mechanisms of NF-κB in osteogenic differentiation governed by inflammation, it can be said that NF-κB helps in improving stem cell-mediated inflammatory bone disease therapy.
Highlights
Nuclear factor-kB (NF-kB) is a transcription factor thought to have an important role in the onset of inflammation
WNT signaling is implicated in regulating osteogenic differentiation of P-Periodontal ligament stem cells (PDLSCs)
Considering that Glycogen synthase kinase 3b (GSK-3b) is a key modulator in the WNT pathway, we want to assess the role of GSK-3b after using a specific inhibitor LiCl
Summary
Nuclear factor-kB (NF-kB) is a transcription factor thought to have an important role in the onset of inflammation. Activation of NF-kB signaling induces transcription of proinflammatory genes by nuclear translocation of a transcription factor complex.[10,11] The connection between NF-kB and osteoblasts stems from initial observations that inflammation, and in particular TNF-a, inhibits bone formation.[12,13,14] it remains to be understood whether inflammatory cytokines in periodontitis could activate NF-kB signaling leading to impaired differentiation of PDLSCs. Glycogen synthase kinase 3b (GSK-3b) is known to modulate cell apoptosis and differentiation through multiple intracellular signaling pathways. In addition to b-catenin, the targets of GSK-3 that have been implicated in the regulation of cell proliferation and differentiation include several transcription factors of NF-kB signaling.[15,16,17,18,19] Recently, some studies have found that GSK 3b could modulate both NF-kB and b-catenin activity through. We rescued the osteogenic potency of PDLSCs from periodontitis using BAY 11-7082 (inhibitor of NF-kB), which could upregulate b-catenin expression only in PDLSCs from periodontitis patients (P-PDLSCs)
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