HDAC表观遗传修饰NKILA在IL-1β抑制颞下颌关节滑膜间充质干细胞成软骨分化中的调控机制

Synovium-derived mesenchymal stem cells(SMSC) differentiate down to cartilage is one of the most important repair mechanisms for temporomandibular joint injury.The concentration of IL-1β in synovial fluid is significantly up-regulated when temporomandibular joint get injuried，and will inhibit the chondrogenic potential of SMSC obviously.So far,the underlining regulatory mechanisms remain unclear.In our previous study, we found that IL-1β inhibited the chondrogenic potential of SMSC through activating NFκB pathway and up-regulating IL6 secretion；In our recent preliminary study, we found HDAC inhibitors SAHA and LBH589 could inhibit IL-1β-mediated NFκB activation and IL6 secretion, and reverse the inhibition effect of chondrogenic differentiation mediated by IL-1β；Meanwhile, The most important negative feedback regulation factor of NFκB pathway,long non-coding RNA NKILA, could also be significanlty up-regulated by HDAC inhibitors. All the above results suggest that there are some HDAC subtypes (HDACs) be up-regulated after IL-1β stimulation, then enhanced deacetylation degree of transcriptional regulatory region of NKILA and inhibit the transcription factors binding, leading to inhibition of NKILA expression;The negative feedback regulation effect of NKILA was weaken and then promote NFκB pathway activation and IL6 secretion, leading to inhibition of chondrogenic potential of SMSC. In This study, we aim to clarify the exact HDACs that plays a key regulatory role in this biological process, and the transcription factors binding to the transcriptional regulatory regions of NKILA inhibited by these HDACs will also be clarified. This study will lay the theoretical foundation for the application of HDAC subtype-specific inhibitors in combination with stem cells to treat temporomandibular joint arthritis.

滑膜间充质干细胞（SMSC）成软骨分化是颞下颌关节损伤的重要修复机制之一。颞下颌关节损伤时，关节液中IL-1β明显上调并抑制SMSC成软骨分化，其机制尚未阐明。前期发现IL-1β能激活SMSC NFκB通路上调IL6分泌从而抑制其成软骨分化；HDAC抑制剂能抑制IL-1β介导的NFκB激活和IL6分泌，重塑SMSC成软骨分化潜能，同时也上调NFκB通路负反馈调控因子NKILA表达；这提示HDAC家族中很可能存在特定亚型HDACs，在IL-1β刺激时表达上调，使NKILA转录调控区乙酰化减弱，抑制转录因子结合进而下调NKILA表达，促进NFκB通路激活和IL6分泌，从而抑制SMSC成软骨分化。本研究将明确IL-1β抑制SMSC成软骨分化中起关键调控作用的HDACs，并明确HDACs抑制与NKILA转录调控区结合的转录因子，为应用HDACs抑制剂联合干细胞治疗颞下颌关节炎奠定理论基础。

滑膜间充质干细胞（SMSC）成软骨分化是颞下颌关节损伤的重要修复机制之一。颞下颌关节损伤时，关节液中IL-1β明显上调并抑制SMSC成软骨分化，其机制尚未阐明。前期发现IL-1β能激活SMSC NFκB通路上调IL6分泌从而抑制其成软骨分化；HDAC抑制剂能抑制IL-1β介导的NFκB激活和IL6分泌，重塑SMSC成软骨分化潜能，同时也上调NFκB通路负反馈调控因子NKILA表达；这提示HDAC家族中很可能存在特定亚型HDACs，在IL-1β刺激时表达上调，使NKILA转录调控区乙酰化减弱，抑制转录因子结合进而下调NKILA表达，促进NFκB通路激活和IL6分泌，从而抑制SMSC成软骨分化。本研究原计划明确IL-1β抑制SMSC成软骨分化中起关键调控作用的HDACs，并明确HDACs抑制与NKILA转录调控区结合的转录因子。本课题组已筛出与该生物学过程密切相关的HDAC家族亚型HDAC10；并进一步深入研究HDAC家族调控“IL-1β抑制SMSC成软骨分化”的机制，发现SAHA通过抑制MARK4/NFKB/L6通路激活来调控此生物学过程；通过动物实验以及体外细胞学实验发现HDAC抑制剂通过抑制NFKB/IL6/MMP13信号通路从而改善IL-1β介导的SMSC成软骨分化抑制；从“LncRNA调控颞下颌关节滑膜干细胞免疫功能的角度”来认识LncRNA调控关节病理过程的分子机制，发现敲低 LncRNA AK09462有助于抑制IL-1β诱发滑膜干细胞NFκB-IL6通路激活，从而影响SMSC成软骨分化。该成果为临床使用HDAC抑制剂联合滑膜干细胞治疗颞下颌关节炎奠定基础。

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