Zimmerman Sarah M, Dimori Milena, Heard-Lipsmeyer Melissa E, Morello Roy
Department of Physiology and Biophysics University of Arkansas for Medical Sciences Little Rock AR USA.
Department of Orthopaedic Surgery University of Arkansas for Medical Sciences Little Rock AR USA.
JBMR Plus. 2019 Feb 11;3(7):e10171. doi: 10.1002/jbm4.10171. eCollection 2019 Jul.
Osteocytes are long-lived, highly interconnected, terminally differentiated osteoblasts that reside within mineralized bone matrix. They constitute about 95% of adult bone cells and play important functions including in the regulation of bone remodeling, phosphate homeostasis, and mechanical stimuli sensing and response. However, the role of osteocytes in the pathogenesis of congenital diseases of abnormal bone matrix is poorly understood. This study characterized in vivo transcriptional changes in osteocytes from KO and mouse models of osteogenesis imperfecta (OI) compared with wild-type (WT) control mice. To do this, RNA was extracted from osteocyte-enriched cortical femurs and tibias, sequenced and subsequently analyzed to identify differentially expressed transcripts. These models were chosen because they mimic two types of OI with different genetic mutations that result in distinct type I collagen defects. A large number of transcripts were dysregulated in either model of OI, but 281 of them were similarly up- or downregulated in both compared with WT controls. Conversely, very few transcripts were differentially expressed between the KO and mice, indicating that distinct alterations in type I collagen can lead to shared pathogenic processes and similar phenotypic outcomes. Bioinformatics analyses identified several critical hubs of dysregulation that were enriched in annotation terms such as development and differentiation, ECM and collagen fibril organization, cell adhesion, signaling, regulatory processes, pattern binding, chemotaxis, and cell projections. The data further indicated alterations in important signaling pathways such as WNT and TGF-β but also highlighted new candidate genes to pursue in future studies. Overall, our study suggested that the osteocyte transcriptome is broadly dysregulated in OI with potential long-term consequences at the cellular level, which deserve further investigations. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
骨细胞是寿命长、高度相互连接的终末分化成骨细胞，位于矿化的骨基质中。它们约占成年骨细胞的95%，发挥着重要功能，包括调节骨重塑、磷酸盐稳态以及机械刺激感知和反应。然而，骨细胞在异常骨基质先天性疾病发病机制中的作用尚不清楚。本研究对与野生型（WT）对照小鼠相比，来自成骨不全（OI）的基因敲除（KO）和小鼠模型的骨细胞进行了体内转录变化特征分析。为此，从富含骨细胞的股骨和胫骨皮质中提取RNA，进行测序并随后分析以鉴定差异表达的转录本。选择这些模型是因为它们模拟了两种具有不同基因突变的OI类型，这些基因突变导致不同的I型胶原缺陷。在OI的任一模型中，大量转录本表达失调，但与WT对照相比，其中281个在两者中同样上调或下调。相反，KO和小鼠之间很少有转录本差异表达，表明I型胶原的不同改变可导致共同的致病过程和相似的表型结果。生物信息学分析确定了几个关键的失调枢纽，这些枢纽在发育和分化、细胞外基质和胶原纤维组织、细胞粘附、信号传导、调节过程、模式结合、趋化性和细胞突起等注释术语中富集。数据进一步表明重要信号通路如WNT和TGF-β发生了改变，但也突出了未来研究中值得探索的新候选基因。总体而言，我们的研究表明，在OI中骨细胞转录组广泛失调，在细胞水平上可能产生长期后果，值得进一步研究。© 2019作者。由Wiley Periodicals, Inc.代表美国骨与矿物质研究学会出版。
