Jo Stephanie Y, Domowicz Miriam S, Henry Judith G, Schwartz Nancy B
Department of Radiology University of Pennsylvania Philadelphia PA USA.
Department of Radiology University of Chicago Chicago IL USA.
JBMR Plus. 2019 Dec 17;4(2):e10254. doi: 10.1002/jbm4.10254. eCollection 2020 Feb.
Osteoarthritis and osteoporosis are widely prevalent and have far-reaching public health implications. There is increasing evidence that epigenetics, in particular, histone 3 lysine 79 methyltransferase , plays an important role in the cartilage and bone biology. In this study, we evaluated the role of in the articular cartilage, growth plate, and trabecular bone utilizing conditional KO mouse models. We generated chondrocyte-specific constitutive and inducible conditional KO mouse lines using - and systems. Prenatal deletion of in mouse chondrocytes led to perinatal mortality, accelerated ossification, and dysregulation of expression. Postnatal deletion of in mouse chondrocytes resulted in trabecular bone loss decreased extracellular matrix production, and disruption of the growth plate. In addition, pharmacological inhibition of DOT1L in a progeria mouse model partially rescued the abnormal osseous phenotype. In conclusion, is important in maintaining the growth plate, extracellular matrix production, and trabecular bone. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
骨关节炎和骨质疏松症广泛流行，对公众健康有着深远影响。越来越多的证据表明，表观遗传学，尤其是组蛋白3赖氨酸79甲基转移酶，在软骨和骨生物学中起着重要作用。在本研究中，我们利用条件性基因敲除小鼠模型评估了其在关节软骨、生长板和小梁骨中的作用。我们使用CRISPR/Cas9和Cre/LoxP系统构建了软骨细胞特异性组成型和诱导型条件性基因敲除小鼠品系。在小鼠软骨细胞中进行产前基因敲除导致围产期死亡、骨化加速和基因表达失调。在小鼠软骨细胞中进行产后基因敲除导致小梁骨丢失、细胞外基质产生减少以及生长板破坏。此外，在早衰小鼠模型中对DOT1L进行药物抑制可部分挽救异常的骨表型。总之，DOT1L在维持生长板、细胞外基质产生和小梁骨方面很重要。© 2019作者。由Wiley Periodicals, Inc.代表美国骨与矿物质研究学会出版。
