Emch Michael J, Wicik Zofia, Aspros Kirsten G M, Vukajlovic Tanja, Pitel Kevin S, Narum Anders K, Weivoda Megan M, Tang Xiaojia, Kalari Krishna R, Turner Russell T, Iwaniec Urszula T, Monroe David G, Subramaniam Malayannan, Hawse John R
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
Department of Neurochemistry, Institute of Psychiatry and Neurology, Sobieskiego 9 Street, 02-957 Warsaw, Poland.
Mol Ther Nucleic Acids. 2023 Jun 3;33:28-41. doi: 10.1016/j.omtn.2023.05.026. eCollection 2023 Sep 12.
Estrogen signaling is critical for the development and maintenance of healthy bone, and age-related decline in estrogen levels contributes to the development of post-menopausal osteoporosis. Most bones consist of a dense cortical shell and an internal mesh-like network of trabecular bone that respond differently to internal and external cues such as hormonal signaling. To date, no study has assessed the transcriptomic differences that occur specifically in cortical and trabecular bone compartments in response to hormonal changes. To investigate this, we employed a mouse model of post-menopausal osteoporosis (ovariectomy, OVX) and estrogen replacement therapy (ERT). mRNA and miR sequencing revealed distinct transcriptomic profiles between cortical and trabecular bone in the setting of OVX and ERT. Seven miRs were identified as likely contributors to the observed estrogen-mediated mRNA expression changes. Of these, four miRs were prioritized for further study and decreased predicted target gene expression in bone cells, enhanced the expression of osteoblast differentiation markers, and altered the mineralization capacity of primary osteoblasts. As such, candidate miRs and miR mimics may have therapeutic relevance for bone loss resulting from estrogen depletion without the unwanted side effects of hormone replacement therapy and therefore represent novel therapeutic approaches to combat diseases of bone loss.
雌激素信号传导对于健康骨骼的发育和维持至关重要，雌激素水平随年龄增长而下降会导致绝经后骨质疏松症的发生。大多数骨骼由致密的皮质壳和内部网状小梁骨网络组成，它们对激素信号等内部和外部信号的反应不同。迄今为止，尚无研究评估因激素变化而在皮质骨和小梁骨区域中特异性发生的转录组差异。为了研究这一点，我们采用了绝经后骨质疏松症的小鼠模型（卵巢切除术，OVX）和雌激素替代疗法（ERT）。mRNA和miR测序揭示了在OVX和ERT情况下皮质骨和小梁骨之间不同的转录组概况。七种miR被确定可能是观察到的雌激素介导的mRNA表达变化的促成因素。其中，四种miR被优先进行进一步研究，它们降低了骨细胞中预测的靶基因表达，增强了成骨细胞分化标志物的表达，并改变了原代成骨细胞的矿化能力。因此，候选miR和miR模拟物可能对雌激素缺乏导致的骨质流失具有治疗相关性，而没有激素替代疗法的不良副作用，因此代表了对抗骨质流失疾病的新型治疗方法。
