METTL7A-mediated m6A modification of corin reverses bisphosphonates-impaired osteogenic differentiation of orofacial BMSCs  

作　　者：Yizhou Jin Xiao Han Yuejun Wang Zhipeng Fan 

机构地区：[1]Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction,Beijing Stomatological Hospital,School of Stomatology,Capital Medical University,Beijing,China [2]Beijing Laboratory of Oral Health,Capital Medical University,Beijing,China [3]Research Unit of Tooth Development and Regeneration,Chinese Academy of Medical Sciences,Beijing,China

出　　处：《International Journal of Oral Science》2024年第3期528-538,共11页国际口腔科学杂志（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(82130028 to Z.P.F.);National Key Research and Development Program(2022YFA1104401);CAMS Innovation Fund for Medical Sciences(2019-I2M-5-031 to Z.P.F.);grants from Innovation Research Team Project of Beijing Stomatological Hospital,Capital Medical University(NO.CXTD202204 to Z.P.F.).

摘　　要：Bisphosphonate-related osteonecrosis of jaw(BRONJ)is characterized by impaired osteogenic differentiation of orofacial bone marrow stromal cells(BMSCs).Corin has recently been demonstrated to act as a key regulator in bone development and orthopedic disorders.However,the role of corin in BRONJ-related BMSCs dysfunction remains unclarified.A m6A epitranscriptomic microarray study from our group shows that the CORIN gene is significantly upregulated and m6A hypermethylated during orofacial BMSCs osteogenic differentiation.Corin knockdown inhibits BMSCs osteogenic differentiation,whereas corin overexpression or soluble corin(sCorin)exerts a promotion effect.Furthermore,corin expression is negatively regulated by bisphosphonates(BPs).Corin overexpression or sCorin reverses BPs-impaired BMSCs differentiation ability.Mechanistically,we find altered expression of phos-ERK in corin knockdown/overexpression BMSCs and BMSCs under sCorin stimulation.PD98059(a selective ERK inhibitor)blocks the corin-mediated promotion effect.With regard to the high methylation level of corin during osteogenic differentiation,we apply a non-selective m6A methylase inhibitor,Cycloleucine,which also blocks the corin-mediated promotion effect.Furthermore,we demonstrate that METTL7A modulates corin m6A modification and reverses BPs-impaired BMSCs function,indicating that METTL7A regulates corin expression and thus contributes to orofacial BMSCs differentiation ability.To conclude,our study reveals that corin reverses BPs-induced BMSCs dysfunction,and METTL7A-mediated corin m6A modification underlies corin promotion of osteogenic differentiation via the ERK pathway.We hope this brings new insights into future clinical treatments for BRONJ.

关 键 词：IMPAIRED cor mediated 

分 类 号：R782[医药卫生—口腔医学]