MiR-137-mediated Negative Relationship Between LGR4 and RANKL Modulated Osteogenic Differentiation of Human Adipose-derived Mesenchymal Stem Cells

Overview

Journal Genet Mol Biol

Specialty Genetics

Date 2022 Sep 19

PMID 36121915

Authors

Cong Fan

Yulong Li

Affiliations

Soon will be listed here.

Abstract

MicroRNA-137 (miR-137) has recently emerged as an osteogenic regulator in several cell lines. This study aimed to identify the function of miR-137 on the crosstalk between leucine rich repeat containing G protein-coupled receptor 4 (LGR4) and receptor activator of nuclear factor-κB ligand (RANKL), thus unveiling the critical role of LGR4-RANKL interplay in the osteogenic differentiation of human adipose-derived mesenchymal stem cells (hASCs). By examining the osteogenic capacity and possible downstream genes expression with miR-137 overexpression/knockdown, we found that miR-137 downregulated LGR4 while upregulating RANKL. According to the results of dual-luciferase reporter assay, LGR4 was validated as a direct target of miR-137. Surprisingly, a negative relationship between LGR4 and RANKL was confirmed by the knockdown of these two genes. Furthermore, RANKL inhibitor could alleviate or reverse the inhibitory effects on osteogenesis generated by LGR4 knockdown. Collectively, this study indicated that miR-137-induced a negative crosstalk between LGR4 and RANKL that could contribute to the osteogenic regulation of hASCs and provide more systematic and in-depth understanding of epigenetic modulation by miR-137.

References

Ranganathan K, Sivasankar V . MicroRNAs - Biology and clinical applications. J Oral Maxillofac Pathol. 2014; 18(2):229-34. PMC: 4196292. DOI: 10.4103/0973-029X.140762. View

Boyle W, Simonet W, Lacey D . Osteoclast differentiation and activation. Nature. 2003; 423(6937):337-42. DOI: 10.1038/nature01658. View

Fan C, Jia L, Zheng Y, Jin C, Liu Y, Liu H . MiR-34a Promotes Osteogenic Differentiation of Human Adipose-Derived Stem Cells via the RBP2/NOTCH1/CYCLIN D1 Coregulatory Network. Stem Cell Reports. 2016; 7(2):236-48. PMC: 4982986. DOI: 10.1016/j.stemcr.2016.06.010. View

Kong L, Zuo R, Wang M, Wang W, Xu J, Chai Y . Silencing MicroRNA-137-3p, which Targets RUNX2 and CXCL12 Prevents Steroid-induced Osteonecrosis of the Femoral Head by Facilitating Osteogenesis and Angiogenesis. Int J Biol Sci. 2020; 16(4):655-670. PMC: 6990928. DOI: 10.7150/ijbs.38713. View

Elango J, Rahman S, Henrotin Y, Mate Sanchez de Val J, Bao B, Wang S . Parathyroid Hormone-Related Protein (PTHrP) Accelerates Soluble RANKL Signals for Downregulation of Osteogenesis of Bone Mesenchymal Stem Cells. J Clin Med. 2019; 8(6). PMC: 6616973. DOI: 10.3390/jcm8060836. View

Zheng D, Wang B, Zhu X, Hu J, Sun J, Xuan J . LncRNA OIP5-AS1 inhibits osteoblast differentiation of valve interstitial cells via miR-137/TWIST11 axis. Biochem Biophys Res Commun. 2019; 511(4):826-832. DOI: 10.1016/j.bbrc.2019.02.109. View

Silber J, Lim D, Petritsch C, Persson A, Maunakea A, Yu M . miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 2008; 6:14. PMC: 2443372. DOI: 10.1186/1741-7015-6-14. View

Chen X, Wang Z, Duan N, Zhu G, Schwarz E, Xie C . Osteoblast-osteoclast interactions. Connect Tissue Res. 2017; 59(2):99-107. PMC: 5612831. DOI: 10.1080/03008207.2017.1290085. View

Renema N, Navet B, Heymann M, Lezot F, Heymann D . RANK-RANKL signalling in cancer. Biosci Rep. 2016; 36(4). PMC: 4974605. DOI: 10.1042/BSR20160150. View

10.

Luo J, Yang Z, Ma Y, Yue Z, Lin H, Qu G . LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption. Nat Med. 2016; 22(5):539-46. DOI: 10.1038/nm.4076. View

11.

Li D, Shan W, Fang Y, Wang P, Li J . miR-137 acts as a tumor suppressor via inhibiting CXCL12 in human glioblastoma. Oncotarget. 2017; 8(60):101262-101270. PMC: 5731872. DOI: 10.18632/oncotarget.20589. View

12.

Carrillo-Lopez N, Martinez-Arias L, Alonso-Montes C, Martin-Carro B, Martin-Virgala J, Ruiz-Ortega M . The receptor activator of nuclear factor κΒ ligand receptor leucine-rich repeat-containing G-protein-coupled receptor 4 contributes to parathyroid hormone-induced vascular calcification. Nephrol Dial Transplant. 2020; 36(4):618-631. DOI: 10.1093/ndt/gfaa290. View

13.

Jiang K, Ren C, Nair V . MicroRNA-137 represses Klf4 and Tbx3 during differentiation of mouse embryonic stem cells. Stem Cell Res. 2013; 11(3):1299-313. DOI: 10.1016/j.scr.2013.09.001. View

14.

Liu X, Chen L, Tian X, Zhang T . MiR-137 and its target TGFA modulate cell growth and tumorigenesis of non-small cell lung cancer. Eur Rev Med Pharmacol Sci. 2017; 21(3):511-517. View

15.

Liu X, Xu X . MicroRNA-137 dysregulation predisposes to osteoporotic fracture by impeding ALP activity and expression via suppression of leucine-rich repeat-containing G-protein-coupled receptor 4 expression. Int J Mol Med. 2018; 42(2):1026-1033. DOI: 10.3892/ijmm.2018.3690. View

16.

Chen X, Zhi X, Wang J, Su J . RANKL signaling in bone marrow mesenchymal stem cells negatively regulates osteoblastic bone formation. Bone Res. 2018; 6:34. PMC: 6255918. DOI: 10.1038/s41413-018-0035-6. View

17.

Dinescu S, Dobranici A, Tecucianu R, Selaru A, Balahura R, Ignat S . Exosomes as Part of the Human Adipose-Derived Stem Cells Secretome- Opening New Perspectives for Cell-Free Regenerative Applications. Adv Exp Med Biol. 2020; 1312:139-163. DOI: 10.1007/5584_2020_588. View

18.

Sun P, Jia K, Zheng C, Zhu X, Li J, He L . Loss of Lgr4 inhibits differentiation, migration and apoptosis, and promotes proliferation in bone mesenchymal stem cells. J Cell Physiol. 2018; 234(7):10855-10867. DOI: 10.1002/jcp.27927. View

19.

Yu Y, Yao P, Wang Z, Xie W . Down-regulation of FTX promotes the differentiation of osteoclasts in osteoporosis through the Notch1 signaling pathway by targeting miR-137. BMC Musculoskelet Disord. 2020; 21(1):456. PMC: 7359489. DOI: 10.1186/s12891-020-03458-0. View

20.

Zhang M, Zhang P, Liu Y, Lv L, Zhang X, Liu H . RSPO3-LGR4 Regulates Osteogenic Differentiation Of Human Adipose-Derived Stem Cells Via ERK/FGF Signalling. Sci Rep. 2017; 7:42841. PMC: 5318871. DOI: 10.1038/srep42841. View