CircHmbox1 Targeting miRNA-1247-5p Is Involved in the Regulation of Bone Metabolism by TNF-α in Postmenopausal Osteoporosis.
CircHmbox1 Targeting miRNA-1247-5p Is Involved in the Regulation of Bone Metabolism by TNF-α in Postmenopausal Osteoporosis.
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CircHmbox1 靶向 miRNA-1247-5p 参与绝经后骨质疏松症中 TNF-α 骨代谢的调节
DOI：
10.3389/fcell.2020.594785
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发表时间：
2020
影响因子：
5.5
通讯作者：
Guo L
中科院分区：
文献类型：
--
作者：
Liu Z;Li C;Huang P;Hu F;Jiang M;Xu X;Li B;Deng L;Ye T;Guo L
肿瘤坏死因子-α促进破骨细胞分化，促进骨吸收，抑制成骨细胞分化，抑制骨形成，在绝经后骨质疏松症的发生发展中起重要作用。最近的研究表明，环状RNA在骨质疏松症中起着重要作用。本研究的目的是探讨CircRNA是否参与了肿瘤坏死因子-α调控的破骨细胞分化和成骨细胞分化。采用定量逆转录聚合酶链式反应检测肿瘤坏死因子-α诱导破骨细胞分化过程中CircRNA-CircHmbox1和miR-1247-5p的表达。通过Western印迹、TRAP染色、碱性磷酸酶染色、茜素红S染色、Transwell和细胞转染法，证实肿瘤坏死因子-α能抑制破骨细胞低表达的胞外区Hmbox1向成骨细胞分化。生物信息学分析和荧光素酶报告揭示了Hmbox1/miR-1247-5p/B细胞淋巴瘤6(Bcl6)相互作用的机制。在本研究中，我们发现，在体内和体外，在肿瘤坏死因子-α诱导的破骨细胞形成过程中，CircRNA-CircHmbox1的水平明显降低。CircHmbox1主要通过与microRNA-1247-5p结合来抑制RANKL诱导的破骨细胞分化。肿瘤坏死因子-α抑制破骨细胞外体向成骨细胞分化，破骨细胞Hmbox1低表达。机制研究表明，microRNA-1247-5p通过靶向bcl6调控破骨细胞分化和成骨细胞分化，证实其在成骨细胞分化和破骨细胞分化中起相反作用。我们的结果提供了证据表明，以miR-1247-5p为靶点的CircHmbox1参与了肿瘤坏死因子-α对PMOP骨代谢的调节。
Tumor necrosis factor-alpha (TNF-α) promotes osteoclasts differentiation to enhance bone resorption and inhibits osteoblasts differentiation to impair bone formation, which plays a central role in the development of postmenopausal osteoporosis (PMOP). Recent studies implicated an important role of circular RNAs (circRNAs) in osteoporosis. The purpose of this study is to investigate whether circRNAs might be implicated in TNF-α-regulated osteoclasts differentiation and osteoblasts differentiation in PMOP. QRT-PCR was applied to detect expression of circRNA-circHmbox1 and miR-1247-5p in TNF-α-induced osteoclasts differentiation. Western blot, TRAP staining, alkaline phosphatase staining, alizarin red S staining, transwell and cell transfection were conducted to confirm that TNF-α inhibited osteoblasts differentiation by exosomal with low circHmbox1 expression from osteoclasts. Bioinformatics analysis and luciferase reporter revealed the mechanisms of the circHmbox1/miR-1247-5p/B cell lymphoma 6 (Bcl6) interaction. In this study, we found that the level of circRNA-circHmbox1 was obviously reduced in TNF-α-induced osteoclast formation in vivo and in vitro. CircHmbox1 could inhibit RANKL-induced osteoclasts differentiation primarily through binding to microRNA-1247-5p. TNF-α decreased osteoblasts differentiation by exosomal with low circHmbox1 expression from osteoclasts. Mechanistic studies showed that microRNA-1247-5p regulated osteoclasts differentiation and osteoblasts differentiation by targeting Bcl6, which was confirmed to play opposite roles in osteoblasts differentiation and osteoclasts differentiation. Our results provide evidence that circHmbox1-targeting miR-1247-5p is involved in the regulation of bone metabolisms by TNF-α in PMOP.