TAmiRNA GmbH, Vienna, Austria.
Austrian Cluster for Tissue Regeneration, Vienna, Austria.
J Bone Miner Res. 2021 Jun;36(6):1131-1144. doi: 10.1002/jbmr.4276. Epub 2021 Mar 10.
MicroRNAs regulate bone homeostasis, and circulating microRNAs have been proposed as novel bone biomarkers. The effect of anti-osteoporotic treatment on circulating microRNAs has not been described in detail. Therefore, we performed a comprehensive analysis of microRNA serum levels in ovariectomized (OVX) and sham-operated (SHAM) rats over 12 weeks of antiresorptive or osteoanabolic treatment. Forty-two Sprague Dawley rats underwent SHAM surgery (n = 10) or ovariectomy (n = 32). After 8 weeks, OVX rats were randomized to antiresorptive treatment with zoledronate (n = 11), osteoanabolic treatment with teriparatide (n = 11), or vehicle treatment (n = 10). Serum samples were collected at weeks 8, 12, 16, and 20 after surgery. A total of 91 microRNAs were analyzed by RT-qPCR in serum samples collected at week 20. Based on the results, 29 microRNAs were selected for longitudinal analysis at all four study time points. Changes in bone mineral density and microstructure were followed up by in vivo micro-CT and ex vivo nano-CT. Ovariectomy resulted in the loss of trabecular bone, which was reversed by osteoanabolic and antiresorptive treatment. Differential expression analysis identified 11 circulating miRNAs that were significantly regulated after treatment. For example, miR-107 and miR-31-5p increased in vehicle-treated OVX animals, whereas they decreased during teriparatide treatment. Additional miRNAs were identified that showed significant correlations to bone microstructure or bone miRNA expression, including miR-203a-3p, which exhibited a significant negative correlation to vertebral and tibial trabecular bone volume fraction (%). Longitudinal analysis confirmed eight microRNAs with significant changes in serum over time that were prevented by teriparatide and zoledronate treatment (miR-34a-5p, miR-31-5p, miR-30d-3p, miR-378a-5p) or teriparatide treatment only (miR-375-3p, miR-183-5p, miR-203a-3p, miR-203b-3p). Gene target network analysis identified WNT and Notch signaling as the main signaling pathways controlled by these miRNAs. Thus, ovariectomy results in time-dependent deregulation of circulating miRNAs compared with SHAM animals. Anti-osteoporotic treatments can rescue this effect, showing that bone-related miRNAs might act as novel biomarkers for treatment monitoring. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
微小 RNA 调节骨稳态，循环微小 RNA 已被提议作为新的骨生物标志物。抗骨质疏松治疗对循环微小 RNA 的影响尚未详细描述。因此，我们对去卵巢（OVX）和假手术（SHAM）大鼠在抗吸收或成骨合成治疗 12 周期间的血清微小 RNA 水平进行了全面分析。42 只 Sprague Dawley 大鼠接受 SHAM 手术（n=10）或卵巢切除术（n=32）。8 周后，OVX 大鼠随机接受唑来膦酸（n=11）抗吸收治疗、特立帕肽（n=11）成骨合成治疗或载体治疗（n=10）。手术后第 8、12、16 和 20 周采集血清样本。在第 20 周采集的血清样本中，通过 RT-qPCR 分析了 91 个微小 RNA。基于这些结果，选择了 29 个微小 RNA 进行所有四个研究时间点的纵向分析。通过体内 micro-CT 和体外 nano-CT 对骨密度和微观结构的变化进行了跟踪。成骨合成和抗吸收治疗逆转了去卵巢引起的骨小梁丢失。差异表达分析确定了 11 个在治疗后明显受调控的循环微小 RNA。例如，miR-107 和 miR-31-5p 在接受载体治疗的 OVX 动物中增加，而在特立帕肽治疗中则减少。还鉴定了一些其他微小 RNA，它们与骨微结构或骨微小 RNA 表达显著相关，包括 miR-203a-3p，它与椎体和胫骨小梁体积分数（%）呈显著负相关。纵向分析证实了 8 个随时间在血清中发生显著变化的微小 RNA，这些变化被特立帕肽和唑来膦酸治疗（miR-34a-5p、miR-31-5p、miR-30d-3p、miR-378a-5p）或特立帕肽治疗（miR-375-3p、miR-183-5p、miR-203a-3p、miR-203b-3p）所预防。基因靶标网络分析确定 WNT 和 Notch 信号作为这些微小 RNA 调控的主要信号通路。因此，与 SHAM 动物相比，卵巢切除术导致循环微小 RNA 的时间依赖性失调。抗骨质疏松治疗可以挽救这种影响，表明骨相关微小 RNA 可能作为治疗监测的新型生物标志物。© 2021 作者。《骨与矿物研究杂志》由 Wiley 期刊出版公司代表美国骨与矿物研究协会（ASBMR）出版。
