transglutaminase 2 (TGM2) and Its Novel Targeted Activator in Diabetic Bone Regeneration: From Mechanism to Application

To screen and identify key molecule regulating T2DM (Type 2 diabetes mellitus)-impaired bone regeneration, cellular osteogenic potential and mitochondrial function, and to elucidate the regulatory mechanisms of this molecule. Microarray analysis was performed to compare transcriptional profiles between bone marrow mesenchymal stem cells (BMMSCs) derived from normal rats (Wistar) and T2DM rats (GK). BMMSCs were transfected with overexpression plasmids targeting candidate molecule and small interfering RNA (siRNA) was used to silence candidate gene expression, then the osteogenic differentiation potential and mitochondrial function of BMMSCs were assessed. Microarray and qRT-PCR revealed significantly elevated expression of TGM2 in BMMSCs from T2DM rats compared to those from normal rats. TGM2 silencing suppressed osteogenic differentiation and mitochondrial function of BMMSCs, and TGM2 overexpression rescued osteogenic capacity. TGM2 serves as a critical regulator of osteogenic differentiation potential and mitochondrial function in BMMSCs derived from T2DM rats本研究旨在筛选并鉴定调控2型糖尿病（Type 2 diabetes mellitus, T2DM）所致骨再生损伤、细胞成骨潜能及线粒体功能的关键分子，并阐明该分子的调控机制。本研究通过基因芯片分析，比较正常Wistar大鼠与T2DM模型GK大鼠来源的骨髓间充质干细胞（bone marrow mesenchymal stem cells, BMMSCs）的转录组表达谱。研究人员通过靶向候选分子的过表达质粒转染BMMSCs，并利用小干扰RNA（small interfering RNA, siRNA）沉默候选基因的表达，随后检测BMMSCs的成骨分化潜能与线粒体功能。基因芯片分析与实时定量聚合酶链反应（quantitative real-time polymerase chain reaction, qRT-PCR）结果显示，与正常大鼠来源的BMMSCs相比，T2DM模型大鼠来源的BMMSCs中TGM2的表达水平显著升高。沉默TGM2的表达会抑制BMMSCs的成骨分化与线粒体功能，而过表达TGM2则可恢复其成骨能力。TGM2可作为调控T2DM模型大鼠来源BMMSCs成骨分化潜能与线粒体功能的关键调控因子。