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Circulating miR-338 Cluster activities on osteoblast differentiation: Potential Diagnostic and Therapeutic Targets for Postmenopausal Osteoporosis.
Theranostics ( IF 12.4 ) Pub Date : 2019-01-01 , DOI: 10.7150/thno.34493
Chujiao Lin 1 , Shuaitong Yu 1 , Runze Jin 1 , Yao Xiao 1 , Minghui Pan 2 , Fei Pei 1 , Xiaojing Zhu 3 , Huarong Huang 3 , Zunyi Zhang 3 , Shuo Chen 4 , Huan Liu 1, 5 , Zhi Chen 1
Affiliation  

MicroRNAs (miRNAs) are the most abundant RNA species found in serum, and recently, several miRNAs have been found to be associated with osteoporosis. However, the development of such associated miRNAs into diagnostic and therapeutic targets remains unaddressed, mostly because of a lack of functional validation. Here, we identified circulating miR-338 associated with postmenopausal osteoporosis, and performed functional validation in vivo and in vitro. Methods: We collected the serum from postmenopausal osteoporosis patients (N=15) and female volunteers of the same age but with normal bone density (N=15) and examined the enrichment of miR-338 cluster. We also confirmed such enrichment using mice subjected to ovariectomy at different stages. We employed primary bone marrow stromal cells from mice and the MC-3T3 cell line along with CRISPR, RNA-seq and ChIP-qPCR to validate the biological function of secreted miR-338 cluster on osteoblastic differentiation and their upstream regulators. Moreover, we generated miR-338 knockout mice and OVX mice injected with an inhibitor against miR-338 cluster to confirm its biological function in vivo. Results: We observed a significant enrichment of miR-338 cluster in postmenopausal osteoporosis patients. Such enrichment was also prominent in serum from mice subjected to ovariectomy and was detected much earlier than bone density decreases revealed by micro-CT. We also confirmed the presence of an estrogen-dependent Runx2/Sox4/miR-338 positive feedback loop that modulated osteoblast differentiation, providing a possible explanation for our clinical findings. Moreover, deletion of the miR-338 cluster or direct intravenous injection of an miR-338 cluster inhibitor significantly prevented osteoporosis after ovariectomy. Conclusion: Circulating miR-338 cluster in the serum could serve as a promising diagnostic and therapeutic target for postmenopausal osteoporosis patients.

中文翻译:

循环的miR-338簇在成骨细胞分化方面的活性:绝经后骨质疏松症的潜在诊断和治疗目标。

MicroRNA(miRNA)是在血清中发现的最丰富的RNA种类,最近,发现一些miRNA与骨质疏松症有关。但是,这种相关的miRNA成为诊断和治疗靶标的开发仍未解决,主要是因为缺乏功能验证。在这里,我们确定了与绝经后骨质疏松症相关的循环miR-​​338,并在体内和体外进行了功能验证。方法:我们收集绝经后骨质疏松患者(N = 15)和相同年龄但骨密度正常(N = 15)的女性志愿者的血清,并检查miR-338簇的富集。我们还证实了使用在不同阶段进行卵巢切除术的小鼠进行的这种富集。我们采用了来自小鼠的原代骨髓基质细胞和MC-3T3细胞系以及CRISPR,RNA-seq和ChIP-qPCR可验证分泌的miR-338簇对成骨细胞分化的生物学功能及其上游调节剂。此外,我们生成了miR-338敲除小鼠和OVX小鼠,注射了抗miR-338簇的抑制剂以证实其在体内的生物学功能。结果:我们观察到绝经后骨质疏松症患者中miR-338簇明显富集。这种富集在接受卵巢切除术的小鼠的血清中也很明显,并且被检测到的时间远远早于微型CT显示的骨密度降低。我们还证实了存在依赖雌激素的Runx2 / Sox4 / miR-338阳性反馈环,该环调节成骨细胞的分化,为我们的临床发现提供了可能的解释。而且,删除miR-338簇或直接静脉内注射miR-338簇抑制剂可显着预防卵巢切除术后的骨质疏松。结论:血清中循环的miR-338簇可作为绝经后骨质疏松患者的有希望的诊断和治疗靶标。
更新日期:2019-01-01
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