ALX1-transcribed LncRNA AC132217.4 Promotes Osteogenesis and Bone Healing Via IGF-AKT Signaling in Mesenchymal Stem Cells

Overview

Journal Cell Mol Life Sci

Publisher Springer

Specialty Biology

Date 2022 May 31

PMID 35639207

Authors

Cui Zhang

Shali Wu

Erman Chen

Luyang Yu

Jinfu Wang

Mengrui Wu

Affiliations

Soon will be listed here.

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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References

Wu M, Chen G, Li Y . TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 2016; 4:16009. PMC: 4985055. DOI: 10.1038/boneres.2016.9. View

Kang H, Sung J, Jung H, Woo K, Hong S, Roh S . Insulin-like growth factor 2 promotes osteogenic cell differentiation in the parthenogenetic murine embryonic stem cells. Tissue Eng Part A. 2011; 18(3-4):331-41. DOI: 10.1089/ten.TEA.2011.0074. View

Zhu G, Zhang T, Chen M, Yao K, Huang X, Zhang B . Bone physiological microenvironment and healing mechanism: Basis for future bone-tissue engineering scaffolds. Bioact Mater. 2021; 6(11):4110-4140. PMC: 8091181. DOI: 10.1016/j.bioactmat.2021.03.043. View

Koh A, Niikura T, Lee S, Oe K, Koga T, Dogaki Y . Differential gene expression and immunolocalization of insulin-like growth factors and insulin-like growth factor binding proteins between experimental nonunions and standard healing fractures. J Orthop Res. 2011; 29(12):1820-6. DOI: 10.1002/jor.21457. View

Zhang X, Xing H, Qi F, Liu H, Gao L, Wang X . Local delivery of insulin/IGF-1 for bone regeneration: carriers, strategies, and effects. Nanotheranostics. 2020; 4(4):242-255. PMC: 7484631. DOI: 10.7150/ntno.46408. View

Caplan A, Bruder S . Mesenchymal stem cells: building blocks for molecular medicine in the 21st century. Trends Mol Med. 2001; 7(6):259-64. DOI: 10.1016/s1471-4914(01)02016-0. View

Jia Q, Jiang W, Ni L . Down-regulated non-coding RNA (lncRNA-ANCR) promotes osteogenic differentiation of periodontal ligament stem cells. Arch Oral Biol. 2014; 60(2):234-41. DOI: 10.1016/j.archoralbio.2014.10.007. View

Yang L, Li Y, Gong R, Gao M, Feng C, Liu T . The Long Non-coding RNA-ORLNC1 Regulates Bone Mass by Directing Mesenchymal Stem Cell Fate. Mol Ther. 2019; 27(2):394-410. PMC: 6369452. DOI: 10.1016/j.ymthe.2018.11.019. View

Pini J, Kueper J, Hu Y, Kawasaki K, Yeung P, Tsimbal C . ALX1-related frontonasal dysplasia results from defective neural crest cell development and migration. EMBO Mol Med. 2020; 12(10):e12013. PMC: 7539331. DOI: 10.15252/emmm.202012013. View

10.

Jiao H, Xiao E, Graves D . Diabetes and Its Effect on Bone and Fracture Healing. Curr Osteoporos Rep. 2015; 13(5):327-35. PMC: 4692363. DOI: 10.1007/s11914-015-0286-8. View

11.

Zhang C, Hong F, Wang C, Li L, Chen J, Liu F . TRIB3 inhibits proliferation and promotes osteogenesis in hBMSCs by regulating the ERK1/2 signaling pathway. Sci Rep. 2017; 7(1):10342. PMC: 5583332. DOI: 10.1038/s41598-017-10601-w. View

12.

Fatica A, Bozzoni I . Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet. 2013; 15(1):7-21. DOI: 10.1038/nrg3606. View

13.

Uz E, Alanay Y, Aktas D, Vargel I, Gucer S, Tuncbilek G . Disruption of ALX1 causes extreme microphthalmia and severe facial clefting: expanding the spectrum of autosomal-recessive ALX-related frontonasal dysplasia. Am J Hum Genet. 2010; 86(5):789-96. PMC: 2869009. DOI: 10.1016/j.ajhg.2010.04.002. View

14.

Ulitsky I, Bartel D . lincRNAs: genomics, evolution, and mechanisms. Cell. 2013; 154(1):26-46. PMC: 3924787. DOI: 10.1016/j.cell.2013.06.020. View

15.

Gu H, Li Z, Lv X, Zhao A, Zhu M, Zhang Y . LncRNA KCNQ1OT1 delayed fracture healing through the Wnt/β-catenin pathway. Eur Rev Med Pharmacol Sci. 2019; 23(11):4575-4583. DOI: 10.26355/eurrev_201906_18034. View

16.

Kline A, Gruen G, Pape H, Tarkin I, Irrgang J, Wukich D . Early complications following the operative treatment of pilon fractures with and without diabetes. Foot Ankle Int. 2009; 30(11):1042-7. DOI: 10.3113/FAI.2009.1042. View

17.

Quinn J, Chang H . Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet. 2015; 17(1):47-62. DOI: 10.1038/nrg.2015.10. View

18.

Yakar S, Werner H, Rosen C . Insulin-like growth factors: actions on the skeleton. J Mol Endocrinol. 2018; 61(1):T115-T137. PMC: 5966339. DOI: 10.1530/JME-17-0298. View

19.

Locatelli V, Bianchi V . Effect of GH/IGF-1 on Bone Metabolism and Osteoporsosis. Int J Endocrinol. 2014; 2014:235060. PMC: 4132406. DOI: 10.1155/2014/235060. View

20.

Chen E, Zhang W, Ye C, Gao X, Jiang L, Zhao T . Knockdown of SIRT7 enhances the osteogenic differentiation of human bone marrow mesenchymal stem cells partly via activation of the Wnt/β-catenin signaling pathway. Cell Death Dis. 2017; 8(9):e3042. PMC: 5636975. DOI: 10.1038/cddis.2017.429. View