Center of Genomics and Bioinformatics, Tulane University, New Orleans, LA, 70112, USA.
Department of Cell and Molecular Biology, Tulane University, New Orleans, LA, 70118, USA.
Calcif Tissue Int. 2019 Aug;105(2):183-192. doi: 10.1007/s00223-019-00555-8. Epub 2019 May 9.
Osteoporosis is a prevalent bone metabolic disease characterized by bone fragility. As a key pathophysiological mechanism, the disease is caused by excessive bone resorption (by osteoclasts) over bone formation (by osteoblasts). Peripheral blood monocytes (PBMs) is a major systemic cell model for bone metabolism by serving as progenitors of osteoclasts and producing cytokines important for osteoclastogenesis. Protein-coding genes for osteoporosis have been widely studied by mRNA analyses of PBMs in high versus low hip bone mineral density (BMD) subjects. However, long noncoding RNAs (lncRNAs), which account for a large proportion of human transcriptome, have seldom been studied.
In this study, microarray analyses of monocytes were performed using Affymetrix exon 1.0 ST arrays in 73 Caucasian females (age: 47-56). LncRNA profile was generated by re-annotating exon array for lncRNAs detection, which yielded 12,007 lncRNAs mapped to the human genome.
575 lncRNAs were differentially expressed between the two groups. In the high BMD subjects, 309 lncRNAs were upregulated and 266 lncRNAs were downregulated (nominally significant, raw p-value < 0.05). To investigate the relationship between mRNAs and lncRNAs, we used two approaches to predict the target genes of lncRNAs and found that 26 candidate lncRNAs might regulate mRNA expression. The majority of these lncRNAs were further validated to be potentially correlated with BMD by GWAS analysis.
Overall, our findings for the first time reported the lncRNAs profiles for osteoporosis and suggested the potential regulatory mechanism of lncRNAs on protein-coding genes in bone metabolism.
骨质疏松症是一种常见的骨骼代谢疾病，其特征是骨骼脆弱。作为一个关键的病理生理机制，这种疾病是由于骨吸收（由破骨细胞）超过骨形成（由成骨细胞）引起的。外周血单核细胞（PBMs）是骨骼代谢的主要全身细胞模型，可作为破骨细胞的前体，并产生对破骨细胞生成重要的细胞因子。通过对高髋骨密度（BMD）和低髋骨密度受试者的 PBMs 的 mRNA 分析，广泛研究了骨质疏松症的蛋白质编码基因。然而，长非编码 RNA（lncRNAs），占人类转录组的很大一部分，很少被研究。
在这项研究中，使用 Affymetrix exon 1.0 ST 微阵列对 73 名高加索女性（年龄：47-56 岁）的单核细胞进行了微阵列分析。通过重新注释外显子阵列来检测 lncRNAs，生成 lncRNA 图谱，该图谱生成了 12007 个映射到人类基因组的 lncRNAs。
两组之间有 575 个 lncRNAs 表达差异。在高 BMD 受试者中，309 个 lncRNAs 上调，266 个 lncRNAs 下调（名义上显著，原始 p 值<0.05）。为了研究 mRNAs 和 lncRNAs 之间的关系，我们使用两种方法预测 lncRNAs 的靶基因，发现 26 个候选 lncRNAs 可能调节 mRNA 表达。这些 lncRNAs 的大部分进一步通过 GWAS 分析验证为与 BMD 相关。
总的来说，我们的研究结果首次报道了骨质疏松症的 lncRNAs 图谱，并提出了 lncRNAs 对骨骼代谢中蛋白质编码基因的潜在调控机制。
