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Inhibition of CRY2 by STAT3/miRNA-7-5p Promotes Osteoblast Differentiation through Upregulation of CLOCK/BMAL1/P300 Expression
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2019-12-24 , DOI: 10.1016/j.omtn.2019.12.020 Zhenghui Tang 1 , Tianyuan Xu 2 , Yinghua Li 3 , Wenchao Fei 2 , Gong Yang 4 , Yang Hong 3
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2019-12-24 , DOI: 10.1016/j.omtn.2019.12.020 Zhenghui Tang 1 , Tianyuan Xu 2 , Yinghua Li 3 , Wenchao Fei 2 , Gong Yang 4 , Yang Hong 3
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Accumulating evidence indicates that cryptochrome circadian regulatory (CRY) proteins have emerged as crucial regulators of osteogenic differentiation. However, the associated mechanisms are quite elusive. In this study, we show that knockdown of CRY2 downregulated the expression of runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), osteocalcin (OCN), and osteopontin (OPN) to facilitate osteoblast differentiation. Further study identified that CRY2 was directly targeted by microRNA (miR)-7-5p, which was highly induced during osteoblast differentiation. The expression of Runx2, ALP, collagen type I alpha 1 (Col1a1), and OCN was upregulated by overexpression of miR-7-5p and induction of osteoblast differentiation. Moreover, signal transducer and activator of transcription 3 (STAT3) transcriptionally activated miR-7-5p to significantly enhance the expression of above osteogenic marker genes and mineral formation. However, overexpression of CRY2 abolished the osteogenic differentiation induced by miR-7-5p overexpression. Silencing of CRY2 unraveled the binding of CRY2 with the circadian locomotor output cycles kaput (CLOCK)/brain and muscle ARNT-like 1 (BMAL1) complex to release CLOCK/BMAL1, which facilitated the binding of CLOCK/BMAL1 to the promoter region of the P300 E-box to stimulate the transcription of P300. P300 subsequently promoted the acetylation of histone 3 and the formation of a transcriptional complex with Runx2 to enhance osteogenesis. Taken together, our study revealed that CRY2 is repressed by STAT3/miR-7-5p to promote osteogenic differentiation through CLOCK/BMAL1/P300 signaling. The involved molecules may be potentially targeted for treatment of osteoporosis.
中文翻译：
STAT3/miRNA-7-5p 抑制 CRY2 通过上调 CLOCK/BMAL1/P300 表达促进成骨细胞分化
越来越多的证据表明，隐花色素昼夜节律调节（CRY）蛋白已成为成骨分化的关键调节因子。然而，相关机制却相当难以捉摸。在这项研究中，我们发现敲除CRY2可下调runt相关转录因子2（Runx2）、碱性磷酸酶（ALP）、骨钙素（OCN）和骨桥蛋白（OPN）的表达，从而促进成骨细胞分化。进一步的研究发现，CRY2 是 microRNA (miR)-7-5p 的直接靶向，在成骨细胞分化过程中被高度诱导。 Runx2、ALP、I 型胶原蛋白 α1 (Col1a1) 和 OCN 的表达通过 miR-7-5p 的过表达和成骨细胞分化的诱导而上调。此外，信号转导和转录激活因子3（STAT3）转录激活miR-7-5p，显着增强上述成骨标志基因的表达和矿物质形成。然而，CRY2 的过表达消除了 miR-7-5p 过表达诱导的成骨分化。 CRY2 的沉默揭示了 CRY2 与昼夜节律运动输出周期 kaput (CLOCK)/脑和肌肉 ARNT 样 1 (BMAL1) 复合物的结合，从而释放 CLOCK/BMAL1，这促进了 CLOCK/BMAL1 与 CLOCK/BMAL1 的启动子区域的结合。 P300 E-box 刺激 P300 的转录。 P300 随后促进组蛋白 3 的乙酰化并与 Runx2 形成转录复合物以增强成骨。综上所述，我们的研究表明，CRY2 被 STAT3/miR-7-5p 抑制，通过 CLOCK/BMAL1/P300 信号传导促进成骨分化。所涉及的分子可能成为治疗骨质疏松症的潜在靶点。
更新日期：2019-12-24
中文翻译：
STAT3/miRNA-7-5p 抑制 CRY2 通过上调 CLOCK/BMAL1/P300 表达促进成骨细胞分化
越来越多的证据表明，隐花色素昼夜节律调节（CRY）蛋白已成为成骨分化的关键调节因子。然而，相关机制却相当难以捉摸。在这项研究中，我们发现敲除CRY2可下调runt相关转录因子2（Runx2）、碱性磷酸酶（ALP）、骨钙素（OCN）和骨桥蛋白（OPN）的表达，从而促进成骨细胞分化。进一步的研究发现，CRY2 是 microRNA (miR)-7-5p 的直接靶向，在成骨细胞分化过程中被高度诱导。 Runx2、ALP、I 型胶原蛋白 α1 (Col1a1) 和 OCN 的表达通过 miR-7-5p 的过表达和成骨细胞分化的诱导而上调。此外，信号转导和转录激活因子3（STAT3）转录激活miR-7-5p，显着增强上述成骨标志基因的表达和矿物质形成。然而，CRY2 的过表达消除了 miR-7-5p 过表达诱导的成骨分化。 CRY2 的沉默揭示了 CRY2 与昼夜节律运动输出周期 kaput (CLOCK)/脑和肌肉 ARNT 样 1 (BMAL1) 复合物的结合，从而释放 CLOCK/BMAL1，这促进了 CLOCK/BMAL1 与 CLOCK/BMAL1 的启动子区域的结合。 P300 E-box 刺激 P300 的转录。 P300 随后促进组蛋白 3 的乙酰化并与 Runx2 形成转录复合物以增强成骨。综上所述，我们的研究表明，CRY2 被 STAT3/miR-7-5p 抑制，通过 CLOCK/BMAL1/P300 信号传导促进成骨分化。所涉及的分子可能成为治疗骨质疏松症的潜在靶点。
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