IRF2-mediated upregulation of lncRNA HHAS1 facilitates the osteogenic differentiation of bone marrow-derived mesenchymal stem cells by acting as a competing endogenous RNA.
IRF2-mediated upregulation of lncRNA HHAS1 facilitates the osteogenic differentiation of bone marrow-derived mesenchymal stem cells by acting as a competing endogenous RNA.
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IRF2介导的lncRNA HHAS1作为竞争性内源RNA促进骨髓间充质干细胞的成骨分化
DOI：
10.1002/ctm2.429
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发表时间：
2021-06
影响因子：
10.6
通讯作者：
Shen H
中科院分区：
文献类型：
--
作者：
Ye G;Wang P;Xie Z;Li J;Zheng G;Liu W;Cao Q;Li M;Cen S;Li Z;Yu W;Wu Y;Shen H
间充质干细胞（Mesenchymal stem cells，MSCs）是成骨细胞的主要来源。长链非编码RNA（longnoncodingRNA，lncRNA）是一类表达量很高的RNA，缺乏蛋白质编码能力，在细胞生物学活动中起着广泛的调节作用。然而，lncRNA在MSC成骨中的调控网络需要进一步研究。使用QRT-PCR、蛋白质印迹、免疫荧光和免疫组织化学测定来确定相关基因的水平。通过茜素红S（ARS）染色、碱性磷酸酶活性测定、苏木精和伊红染色或micro-CT评价成骨分化能力。采用RNA荧光原位杂交（FISH）和RNAscope检测HHAS 1在细胞和骨组织中的表达。进行微阵列测定以鉴定差异表达的microRNA。RNA免疫沉淀和RNA pull-down用于探索相关蛋白质和核酸之间的相互作用。lncRNA HHAS 1的水平在骨髓来源的MSC（BMSC）成骨过程中增加，并与成骨基因的水平和ARS强度呈正相关。HHAS 1定位于细胞质和细胞核，在人骨组织中表达。HHAS 1通过下调miR-204 - 5 p表达和提高RUNX家族转录因子2（RUNX 2）水平促进BMSC成骨分化。此外，干扰素调节因子2（IRF 2）在BMSC成骨分化过程中增加，并与HHAS 1的启动子相互作用，导致HHAS 1的转录激活。此外，IRF 2和HHAS 1有助于改善体内骨缺损修复。我们的研究鉴定了一种新的lncRNA HHAS 1，它促进BMSC成骨分化，并提出了IRF 2/HHAS 1/miR-204 - 5 p/RUNX 2轴在BMSC成骨调控中的作用。这些发现有助于阐明BMSC成骨的调控网络，并为临床应用提供潜在的靶点。 图形亮点1.在成骨诱导条件下，IRF 2的水平增加，并促进lncRNA HHAS 1的转录。2. HHAS 1通过充当ceRNA吸收miR-204 - 5 p，从而保护RUNX 2 mRNA免受翻译抑制并促进BMSC成骨。3.调节IRF 2或HHAS 1可以调节BMSC成骨分化，帮助改善骨缺损损伤。
Mesenchymal stem cells (MSCs) are the major source of osteoblasts. Long noncoding RNAs (lncRNAs) are abundantly expressed RNAs that lack protein‐coding potential and play an extensive regulatory role in cellular biological activities. However, the regulatory network of lncRNAs in MSC osteogenesis needs further investigation. QRT‐PCR, western blot, immunofluorescence, and immunohistochemistry assays were used to determine the levels of relevant genes. The osteogenic differentiation capability was evaluated by using Alizarin Red S (ARS) staining, alkaline phosphatase activity assays, hematoxylin & eosin staining or micro‐CT. RNA fluorescence in situ hybridization (FISH) and RNAscope were used to detect HHAS1 expression in cells and bone tissue. A microarray assay was performed to identify differentially expressed microRNAs. RNA immunoprecipitation and RNA pull‐down were used to explore the interactions between related proteins and nucleic acids. The level of lncRNA HHAS1 increased during bone marrow‐derived MSC (BMSC) osteogenesis and was positively related to the levels of osteogenic genes and ARS intensity. HHAS1 was located in both the cytoplasm and the nucleus and was expressed in human bone tissue. HHAS1 facilitated BMSC osteogenic differentiation by downregulating miR‐204‐5p expression and enhancing the level of RUNX family transcription factor 2 (RUNX2). In addition, interferon regulatory factor 2 (IRF2) was increased during BMSC osteogenic differentiation and interacted with the promoter of HHAS1, which resulted in the transcriptional activation of HHAS1. Furthermore, IRF2 and HHAS1 helped improve bone defect repair in vivo. Our study identified a novel lncRNA, HHAS1, that facilitates BMSC osteogenic differentiation and proposed a role for the IRF2/HHAS1/miR‐204‐5p/RUNX2 axis in BMSC osteogenesis regulation. These findings help elucidate the regulatory network of BMSC osteogenesis and provide potential targets for clinical application. Graphical Highlights 1. Under the condition of osteogenic induction, the level of IRF2 is increased and promotes the transcription of lncRNA HHAS1. 2. HHAS1 sponges miR‐204‐5p by acting as a ceRNA, thereby protecting RUNX2 mRNA from translation inhibition and facilitating BMSC osteogenesis. 3. Modulating IRF2 or HHAS1 can regulate BMSC osteogenic differentiation and help improve bone defect impair.
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