NF-κB 激活通过增加 TAZ 的表达来刺激人脂肪来源间充质干细胞的成骨分化。
NF-kappaB activation stimulates osteogenic differentiation of mesenchymal stem cells derived from human adipose tissue by increasing TAZ expression.
机构信息
Department of Physiology, School of Medicine, Pusan National University, Yangsan, Korea.
出版信息
J Cell Physiol. 2010 Apr;223(1):168-77. doi: 10.1002/jcp.22024.
Tumor necrosis factor-alpha (TNF-alpha) is a skeletal catabolic agent that stimulates osteoclastogenesis and inhibits osteoblast function. Although TNF-alpha inhibits the mineralization of osteoblasts, the effect of TNF-alpha on mesenchymal stem cells (MSC) is not clear. In this study, we determined the effect of TNF-alpha on osteogenic differentiation of stromal cells derived from human adipose tissue (hADSC) and the role of NF-kappaB activation on TNF-alpha activity. TNF-alpha treatment dose-dependently increased osteogenic differentiation over the first 3 days of treatment. TNF-alpha activated ERK and increased NF-kappaB promoter activity. PDTC, an NF-kappaB inhibitor, blocked the osteogenic differentiation induced by TNF-alpha and TLR-ligands, but U102, an ERK inhibitor, did not. Overexpression of miR-146a induced the inhibition of IRAK1 expression and inhibited basal and TNF-alpha- and TLR ligand-induced osteogenic differentiation. TNF-alpha and TLR ligands increased the expression of transcriptional coactivator with PDZ-binding motif (TAZ), which was inhibited by the addition of PDTC. A ChIP assay showed that p65 was bound to the TAZ promoter. TNF-alpha also increased osteogenic differentiation of human gastroepiploic artery smooth muscle cells. Our data indicate that TNF-alpha enhances osteogenic differentiation of hADSC via the activation of NF-kappaB and a subsequent increase of TAZ expression.
肿瘤坏死因子-α（TNF-α）是一种骨骼分解代谢剂，可刺激破骨细胞生成并抑制成骨细胞功能。尽管 TNF-α 抑制成骨细胞的矿化，但 TNF-α 对间充质干细胞（MSC）的影响尚不清楚。在这项研究中，我们确定了 TNF-α对人脂肪组织（hADSC）来源基质细胞成骨分化的影响，以及 NF-κB 激活对 TNF-α活性的作用。TNF-α 处理在治疗的前 3 天呈剂量依赖性地增加成骨分化。TNF-α 激活 ERK 并增加 NF-κB 启动子活性。NF-κB 抑制剂 PDTC 阻断了 TNF-α 和 TLR 配体诱导的成骨分化，但 ERK 抑制剂 U102 则没有。miR-146a 的过表达诱导 IRAK1 表达的抑制，并抑制基础和成骨分化以及 TNF-α 和 TLR 配体诱导的成骨分化。TNF-α 和 TLR 配体增加了具有 PDZ 结合基序的转录共激活因子（TAZ）的表达，而 PDTC 的添加则抑制了其表达。ChIP 测定表明 p65 与 TAZ 启动子结合。TNF-α 还增强了人胃网膜动脉平滑肌细胞的成骨分化。我们的数据表明，TNF-α 通过激活 NF-κB 和随后增加 TAZ 的表达来增强 hADSC 的成骨分化。
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