IRX5调控炎性微环境下BMSCs成脂/成骨分化的作用机制研究

老化会造成口腔颌面部骨组织代谢障碍，是影响口腔疾病防治效果的不利因素。老化打破BMSCs成脂/成骨分化平衡，导致成骨细胞减少、脂肪细胞增多，骨髓中进行性地积累大量的脂肪。BMSCs定向分化依赖于其所处的微环境，因此，老化机体中低度、持续的无菌性炎症可能是BMSCs定向分化紊乱的驱动因素。我们推测，老化导致IL6上调，激活STAT3通路，p-STAT3识别IRX5启动子特定位点，通过招募DNMT1及HDAC1，促进IRX5启动子甲基化和去乙酰化，诱导IRX5表达下调，进而抑制IRX5靶基因OPN的表达，导致BMSCs成骨分化减弱，成脂分化增强。通过本研究，我们拟寻求炎症刺激与BMSCs定向分化的基因纽带，籍此为了解老化导致的骨代谢异常提供新的理论指导，也为BMSCs应用于骨组织工程提供新的思路。

Aging leads to functional decline of oral and maxillofacial bone, which is a detrimental factor for prevention and treatment of oral diseases. BMSCs tend to differentiate into adipocytes rather than osteoblasts with aging, which leads to progressive marrow fat accumulation. Altered differentiation capability of BMSCs is linked to aging-related chronic, low-grade sterile inflammation. We hypothesize that aging activates IL6-STAT3 signaling pathway, and then p-STAT3 directly targets the specific binding site on IRX5 putative promoter sequence and epigenetically silences IRX5 expression via recruiting DNMT1 and HDAC1. Subsequently, IRX5 regulates the switch between adipogenic and osteogenic differentiation via targeting OPN expression. We expect to seek the genetic link between inflammatory signals and adipo/osteogenic differentiation of BMSCs. This study will provide us theoretical basis to understand the mechanism of age-related abnormal bone metabolism and apply BMSCs to bone tissue engineering.