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ALX1-transcribed LncRNA AC132217.4 promotes osteogenesis and bone healing via IGF-AKT signaling in mesenchymal stem cells

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Abstract

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.

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Data available statement

RNA-seq data of hBMSCs during osteogenesis are deposited in the NCBI Gene Expression Omnibus and are accessible through GEO Series accession number GSE114117 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi). All other data generated or analysed during this study are included in this published article [and its supplementary information files].

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Acknowledgements

This study was supported by grants from National Natural Science Foundation of China (31900513, 81900806, 32070814), Application Program for Chinese Manned Space Station (YYWT-0901-EXP-06), and Qianjiang Talent Program of Zhejiang Province (QJD1902024).

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Authors and Affiliations

  1. Department of Cell and Developmental Biology, College of Life Sciences, Zhejiang University, Hangzhou, China

    Cui Zhang, Shali Wu, Luyang Yu, Jinfu Wang & Mengrui Wu

  2. Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Cui Zhang

  3. Department of Orthopedics, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Erman Chen

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Conceptualization, MW, JW and CZ; methodology, MW, JW and CZ; investigation, CZ, SW, EC; resources, MW and CZ writing—original draft, MW, SW and CZ; writing—review and editing, MW and CZ; funding acquisition, MW YL and CZ; supervision, MW and JW.

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Zhang, C., Wu, S., Chen, E. et al. ALX1-transcribed LncRNA AC132217.4 promotes osteogenesis and bone healing via IGF-AKT signaling in mesenchymal stem cells. Cell. Mol. Life Sci. 79, 328 (2022). https://doi.org/10.1007/s00018-022-04338-7

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