Sui Hao, Zhang Tao
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
Sichuan Da Xue Xue Bao Yi Xue Ban. 2021 May;52(3):364-372. doi: 10.12182/20210560202.
The proliferation and multi-directional differentiation potential of mesenchymal stem cells (MSCs) enabled its wide use in the development of new therapies for bone and cartilage repair. Although preliminary work has been done to verify the gene expression profile of MSCs osteogenic and chondrogenic differentiation, it is still unclear what key factors initiate the differentiation of MSCs, resulting in its limited application in bone and cartilage tissue engineering. The epigenetic mechanism mediated by histone demethylases (lysine [K]-specific histone demethylases, KDMs) is the key link in regulating MSCs lineage differentiation. The lysine-specific histone demethylase (LSD) family containing Tower domain and the histone demethylase family containing Jumonji C (JmjC) domain regulate the expression of various osteogenic-related genes, including Runt-related transcription factor 2 ( 2), osterix ( ), osteocalcin ( ), to mediate MSCs osteogenic differentiation. The KDM2/4/6 subfamilies regulate the chondrogenic differentiation of MSCs through multiple pathways centered on SRY-related high-mobility-group-box gene 9 ( 9). In addition, nanotopology, mircoRNAs, etc. regulate the expression of a variety of osteogenic and chondrogenic transcription factors through up- and down-regulation of KDMs. In summary, the role of histone demethylase in the osteogenic and chondrogenic differentiation of mesenchymal stem cells will help us better understand the pathogenesis of bone and cartilage damage diseases, and establish the foundation of future clinical applications for bone and cartilage tissue engineering.
间充质干细胞（MSCs）的增殖能力和多向分化潜能使其在骨与软骨修复新疗法的开发中得到广泛应用。尽管已经开展了初步工作来验证MSCs成骨和成软骨分化的基因表达谱，但仍不清楚启动MSCs分化的关键因素是什么，这导致其在骨与软骨组织工程中的应用受限。由组蛋白去甲基化酶（赖氨酸[K]特异性组蛋白去甲基化酶，KDMs）介导的表观遗传机制是调节MSCs谱系分化的关键环节。含Tower结构域的赖氨酸特异性组蛋白去甲基化酶（LSD）家族和含Jumonji C（JmjC）结构域的组蛋白去甲基化酶家族调节多种成骨相关基因的表达，包括Runx相关转录因子2（Runx2）、osterix（Osx）、骨钙素（OC），以介导MSCs的成骨分化。KDM2/4/6亚家族通过以SRY相关高迁移率族盒基因9（SOX9）为中心的多条途径调节MSCs的成软骨分化。此外，纳米拓扑结构、微小RNA等通过上调和下调KDMs来调节多种成骨和成软骨转录因子的表达。综上所述，组蛋白去甲基化酶在间充质干细胞成骨和成软骨分化中的作用将有助于我们更好地理解骨与软骨损伤疾病的发病机制，并为未来骨与软骨组织工程的临床应用奠定基础。
