Effects of Age and Estrogen on Skeletal Gene Expression in Humans as Assessed by RNA Sequencing.
Effects of Age and Estrogen on Skeletal Gene Expression in Humans as Assessed by RNA Sequencing.
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DOI：
10.1371/journal.pone.0138347
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Khosla S
中科院分区：
文献类型：
--
作者：
Farr JN;Roforth MM;Fujita K;Nicks KM;Cunningham JM;Atkinson EJ;Therneau TM;McCready LK;Peterson JM;Drake MT;Monroe DG;Khosla S
精确描述随着衰老和雌激素(E)治疗而改变的特定基因和途径可能会导致新的骨骼生物标志物和新型骨疗法的发展。然而，先前的人类骨骼研究仅限于检查预先指定的基因和途径。另一方面，高通量RNA测序（RNAseq）提供了一种无偏倚的方法来检查整个转录组。在这里，我们提出了从髂骨针活检中获得的人类骨骼样本的RNAseq分析，以首次在体内对可能随着人类衰老和E治疗而改变的骨骼中的所有基因和途径进行了研究。健康妇女58例，其中年轻妇女19例（平均年龄±SD， 30.3±5.4岁），老年妇女19例（73.1±6.6岁），老年妇女20例（70.5±5.2岁），接受3周E治疗。使用普遍接受的标准（错误发现率[q] < 0.10），衰老总共改变了678个基因和12条通路，其中包括一个已知调节骨代谢的子集（如Notch）。有趣的是，作为Wnt/β-catenin信号通路的经典下游靶点，LEF1转录因子在老年女性和年轻女性的骨骼中显著下调；与此一致的是，在老年女性和年轻女性中，LEF1结合位点在差异表达基因的启动子区域显著富集，这表明衰老与骨骼中Wnt信号的改变有关。此外，在E治疗改变的21个独特的骨基因中，INHBB（编码抑制素，β B多肽）的表达随着年龄的增长而下降（下降了0.6倍），在E治疗后恢复到年轻成人的水平。总之，我们的数据表明，衰老改变了骨骼转录组的很大一部分，而E疗法似乎有显著的影响，尽管影响范围较小。这些数据为鉴定与年龄相关的骨质流失相关的新型生物标志物提供了宝贵的资源，也突出了可能靶向治疗骨质疏松症的潜在途径。ClinicalTrials.gov NCT02349113
Precise delineation of the specific genes and pathways altered with aging and estrogen (E) therapy may lead to new skeletal biomarkers and the development of novel bone therapeutics. Previous human bone studies, however, have been limited by only examining pre-specified genes and pathways. High-throughput RNA sequencing (RNAseq), on the other hand, offers an unbiased approach to examine the entire transcriptome. Here we present an RNAseq analysis of human bone samples, obtained from iliac crest needle biopsies, to yield the first in vivo interrogation of all genes and pathways that may be altered in bone with aging and E therapy in humans. 58 healthy women were studied, including 19 young women (mean age ± SD, 30.3 ± 5.4 years), 19 old women (73.1 ± 6.6 years), and 20 old women treated with 3 weeks of E therapy (70.5 ± 5.2 years). Using generally accepted criteria (false discovery rate [q] < 0.10), aging altered a total of 678 genes and 12 pathways, including a subset known to regulate bone metabolism (e.g., Notch). Interestingly, the LEF1 transcription factor, which is a classical downstream target of the Wnt/β-catenin signaling pathway, was significantly downregulated in the bones from the old versus young women; consistent with this, LEF1 binding sites were significantly enriched in the promoter regions of the differentially expressed genes in the old versus young women, suggesting that aging was associated with alterations in Wnt signaling in bone. Further, of the 21 unique genes altered in bone by E therapy, the expression of INHBB (encoding for the inhibin, beta B polypeptide), which decreased with aging (by 0.6-fold), was restored to young adult levels in response to E therapy. In conclusion, our data demonstrate that aging alters a substantial portion of the skeletal transcriptome, whereas E therapy appears to have significant, albeit less wide-ranging effects. These data provide a valuable resource for the potential identification of novel biomarkers associated with age-related bone loss and also highlight potential pathways that could be targeted to treat osteoporosis. ClinicalTrials.gov NCT02349113