Department of Physiology, School of Medicine, Pusan National University, Yangsan, Korea.
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。
