Tumor necrosis factor-α suppresses adipogenic and osteogenic differentiation of human periodontal ligament stem cell by inhibiting miR-21/Spry1 functional axis
Tumor necrosis factor-α suppresses adipogenic and osteogenic differentiation of human periodontal ligament stem cell by inhibiting miR-21/Spry1 functional axis
复制标题
肿瘤坏死因子-α通过抑制miR-21/Spry1功能轴抑制人牙周膜干细胞的成脂和成骨分化
作者：
杨楠
牙周炎是一种慢性感染性疾病，会导致牙周组织的进行性破坏。人牙周膜干细胞(PDLSCs)是修复牙周病破坏组织的最有潜力的细胞。来源于fl炎症微环境的PDLSCs表现出减弱的ff分化潜能，但其机制尚不清楚。MicroRNAs(MiRNAs)是一类新发现的转录后调节因子，在调节细胞ff分化中起着关键作用。最近的研究表明，在fl中，炎性细胞因子可以调节miRNA，并在fl炎症性疾病中起到一定作用。肿瘤坏死因子-α是一种强有力的细胞分化负性调节因子。肿瘤坏死因子-α水平的升高与牙周病的严重程度有关。在这里，我们发现肿瘤坏死因子-α抑制了PDLSCs的成脂和成骨分化。在此基础上，我们推测肿瘤坏死因子-α可能通过调节ff信号通路参与PDLSC的分化。此外，我们还证实了在PDLSCs成脂和成骨分化受损的情况下，肿瘤坏死因子-α抑制了miR-21的表达。上调miR-21可通过抑制其靶基因Spry1，部分挽救肿瘤坏死因子-α损伤的成脂和成骨作用，提示miR-21/Spry1功能轴在ff炎症微环境下PDLSC的重建中起关键作用。在成脂和成骨过程中，肿瘤坏死因子-αfi显著上调Spry1的表达，而miR-21的过表达则显著降低Spry1的表达，提示miR-21在调节肿瘤坏死因子-α与Spry1之间的联系中起重要作用。我们的fi发现了一种分子机制，即肿瘤坏死因子-α通过抑制miR-21/Spry1功能轴来抑制PDLSCs的成脂和成骨分化。这项研究可能为针对牙周炎和其他fl炎症性疾病的新治疗策略提供分子基础。
Periodontitis is a chronic infectious disease that leads to progressive destruction of periodontal tissue. Human periodontal ligament stem cells (PDLSCs) are the most favorable candidate for the reconstruction of tissues destroyed by periodontal diseases. PDLSCs derived from inflammatory microenvironment show attenuated differentiation potential, however the mechanism is still unclear. MicroRNAs (miRNAs) are a newly discovered class of posttranscriptional regulators, and they play key roles in regulating cell differentiation. Recent studies have demonstrated that inflammatory cytokines could regulate miRNAs and contribute to some inflammatory diseases. Tumor necrosis factor (TNF-α) is a potent negative regulator of cell differentiation. Elevated levels of TNF-α were confirmed to be associated with the severity of periodontal disease. Here, we found TNF-α inhibited the adipogenic and osteogenic differentiation of PDLSCs. Based on this, we hypothesized that TNF-α could participate in PDLSC differentiation by regulating miRNA signal pathway. Moreover, we demonstrated that the expression of miR-21 was suppressed by TNF-α in impaired adipogenic and osteogenic differentiation of PDLSCs. Upregulating miR-21 can partly rescue TNF-α-impaired adipogenesis and osteogenesis by repressing its target gene Spry1, suggested that miR-21/Spry1 functional axis plays critical role in PDLSC differentiation under inflammatory microenvironment. During adipogenesis and osteogenesis, TNF-α significantly increased Spry1 levels and overexpression of miR-21 dramatically decreased Spry1 levels in the presence of TNF-α, indicated important roles of miR-21 in modulating link between TNF-α and Spry1. Our findings introduce a molecular mechanism in which TNF-α suppresses adipogenic and osteogenic differentiation of PDLSCs by inhibiting miR-21/Spry1 functional axis. This study may indicate a molecular basis for novel therapeutic strategies against periodontitis and other inflammatory diseases.