ALX1-transcribed LncRNA AC132217.4 promotes osteogenesis and bone healing via IGF-AKT signaling in mesenchymal stem cells
ALX1-transcribed LncRNA AC132217.4 promotes osteogenesis and bone healing via IGF-AKT signaling in mesenchymal stem cells
复制标题
ALX1转录的LncRNA AC132217.4通过间充质干细胞中的IGF-AKT信号促进成骨和骨愈合
DOI：
10.1007/s00018-022-04338-7
复制
发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Mengrui Wu
中科院分区：
文献类型：
--
作者：
Cui Zhang;Shali Wu;Erman Chen;Luyang Yu;Jinfu Wang;Mengrui Wu
骨髓间充质干细胞（BMSCs）的成骨潜能对骨形成和再生至关重要。在特定人群中，骨折愈合的非愈合/延迟愈合率仍然很高，这意味着迫切需要发现促进骨生成和骨再生的新靶点。长链非编码（lnc） rna是多种生理过程的新兴调控因子，包括成骨。基于RNA测序数据的差异表达分析，我们发现胰岛素生长因子2 （IGF2）的3' utr重叠lncRNA AC132217.4在BMSCs成骨分化过程中被高度诱导。随后，功能获得和功能丧失实验均证明AC132217.4促进BMSCs的成骨细胞发育。分子机制方面，我们发现AC132217.4与IGF2 mRNA结合，调控其表达和下游AKT激活，控制成骨细胞成熟和功能。此外，我们还发现了两个剪接因子，剪接成分35 KDa （SC35）和异质核核糖核蛋白A1 (HNRNPA1)，它们在转录后水平上调控AC132217.4的生物发生。我们还发现了一个转录因子ALX1，它在转录水平上调节AC132217.7的表达，从而促进成骨。重要的是，体内过表达AC132217.4从本质上促进了小鼠胫骨钻孔模型的骨愈合过程。我们的研究表明，lncRNA AC132217.4是一种新的BMSC成骨合成代谢调节因子，可能是促进骨再生的合理治疗靶点。
The osteogenic potential of bone marrow mesenchymal stem cells (BMSCs) is critical for bone formation and regeneration. A high non-/delayed-union rate of fracture healing still occurs in specific populations, implying an urgent need to discover novel targets for promoting osteogenesis and bone regeneration. Long non-coding (lnc)RNAs are emerging regulators of multiple physiological processes, including osteogenesis. Based on differential expression analysis of RNA sequencing data, we found that lncRNA AC132217.4, a 3'UTR-overlapping lncRNA of insulin growth factor 2 (IGF2), was highly induced during osteogenic differentiation of BMSCs. Afterward, both gain-of-function and loss-of-function experiments proved that AC132217.4 promotes osteoblast development from BMSCs. As for its molecular mechanism, we found that AC132217.4 binds with IGF2 mRNA to regulate its expression and downstream AKT activation to control osteoblast maturation and function. Furthermore, we identified two splicing factors, splicing component 35 KDa (SC35) and heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), which regulate the biogenesis of AC132217.4 at the post-transcriptional level. We also identified a transcription factor, ALX1, which regulates AC132217.7 expression at the transcriptional level to promote osteogenesis. Importantly, in-vivo over-expression of AC132217.4 essentially promotes the bone healing process in a murine tibial drill-hole model. Our study demonstrates that lncRNA AC132217.4 is a novel anabolic regulator of BMSC osteogenesis and could be a plausible therapeutic target for improving bone regeneration.