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Circulating miR-338 Cluster activities on osteoblast differentiation: Potential Diagnostic and Therapeutic Targets for Postmenopausal Osteoporosis.
循环 miR-338 成骨细胞分化的集群活动: 绝经后骨质疏松症的潜在诊断和治疗靶点。

摘要

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.

译文

MicroRNAs (miRNAs) 是在血清中发现的最丰富的 RNA 物种,最近,一些 miRNAs 被发现与骨质疏松症有关。然而,这种相关的 miRNAs 发展成诊断和治疗靶点仍未解决,主要是因为缺乏功能验证。在此,我们鉴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: 我们从绝经后骨质疏松症患者 (N = 15) 和同龄但骨密度正常的女性志愿者 (N = 15) 中收集血清,并检查 miR-338 簇的富集情况。我们还使用在不同阶段接受卵巢切除术的小鼠证实了这种富集。我们使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 验证分泌的 miR-338 簇对成骨细胞分化及其上游调控因子的生物学功能。此外,我们生成了 miR-338 基因敲除小鼠和 OVX 小鼠,注射了一种针对 miR-338 簇的抑制剂,以确认其在体内的生物学功能。结果: 我们在绝经后骨质疏松症患者中观察到 miR-338 簇的显著富集。这种富集在患有卵巢切除术的小鼠的血清中也很突出,并且比 micro-CT 显示的骨密度降低更早被检测到。我们还证实了雌激素依赖性 Runx2/Sox4/miR-338 正反馈回路的存在,该回路调节成骨细胞分化,为我们的临床发现提供了可能的解释。此外,删除 miR-338 簇或直接静脉注射 miR-338 簇抑制剂可显著预防卵巢切除术后的骨质疏松症。结论: 血清中循环 miR-338 簇可作为绝经后骨质疏松症患者的诊断和治疗靶点。

postmenopausal osteoporosis

妇产 骨质疏松 疾病
概述  :  

绝经后骨质疏松症早期可能没有任何症状,骨质在不知不觉中流失,直到发生骨折后才被意识到,亦被称之为“无声杀手”。目前尚无任何治疗手段可以恢复已经失去的骨量,治疗只能延缓进一步的骨破坏。由于早期没有典型的临床症状,所以常常不能引起医患足够的重视,以致许多患者只能无奈的面对从病痛到恢复的漫漫长路。简单地说,骨质疏松症是一种全身性疾病,其特点是全身性骨量减少和骨组织的微结构退行性破坏,导致骨脆性增加、骨强度降低,容易发生骨折。 骨质疏松的类型

postmenopausal   英 [pəʊst,menəʊ'pɔːzəl]  美 [,postmɛnə'pɔzəl]

释    义    adj. (妇女)绝经后的

例    句    A postmenopausal woman, by comparison, loses that amount of bone in a year.  相比之下,绝经后的妇女一年就会失去那么多的骨质。

 

osteoporosis  英 [ˌɒstiəʊpəˈrəʊsɪs]   美 [ˌɑːstioʊpəˈroʊsɪs] 

释    义    n. [外科] 骨质疏松症

例    句    And there was another discovery in the hospital. She had osteoporosis.  在医院,他们还发现,她患有骨质疏松症。

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