Mettl3-mediated MA RNA Methylation Regulates the Fate of Bone Marrow Mesenchymal Stem Cells and Osteoporosis

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Nov 16

PMID 30429466

Citations 206

Authors

Yunshu Wu

Liang Xie

Mengyuan Wang

Qiuchan Xiong

Yuchen Guo

Yu Liang

Jing Li

Rui Sheng

Peng Deng

Yuan Wang

Rixin Zheng

Yizhou Jiang

Ling Ye

Qianming Chen

Xuedong Zhou

Shuibin Lin

Quan Yuan

Affiliations

Soon will be listed here.

Abstract

N-methyladenosine (mA) is the most abundant epigenetic modification in eukaryotic mRNAs and is essential for multiple RNA processing events during mammalian development and disease control. Here we show that conditional knockout of the mA methyltransferase Mettl3 in bone marrow mesenchymal stem cells (MSCs) induces pathological features of osteoporosis in mice. Mettl3 loss-of-function results in impaired bone formation, incompetent osteogenic differentiation potential and increased marrow adiposity. Moreover, Mettl3 overexpression in MSCs protects the mice from estrogen deficiency-induced osteoporosis. Mechanistically, we identify PTH (parathyroid hormone)/Pth1r (parathyroid hormone receptor-1) signaling axis as an important downstream pathway for mA regulation in MSCs. Knockout of Mettl3 reduces the translation efficiency of MSCs lineage allocator Pth1r, and disrupts the PTH-induced osteogenic and adipogenic responses in vivo. Our results demonstrate the pathological outcomes of mA mis-regulation in MSCs and unveil novel epitranscriptomic mechanism in skeletal health and diseases.

Citing Articles

Methyltransferase-Like 3-Mediated N-Methyladenosine Modification on RNAs: A Novel Perspective for the Pathogenesis and Treatment of Bone Diseases.

Xiao D, Zhang D, Qu Y, Su X J Cell Mol Med. 2025; 29(5):e70483.

PMID: 40052548 PMC: 11886889. DOI: 10.1111/jcmm.70483.

An epitranscriptomic program maintains skeletal stem cell quiescence via a METTL3-FEM1B-GLI1 axis.

Wang J, Liu W, Zhang T, Cui M, Gao K, Lu P EMBO J. 2025; .

PMID: 40016417 DOI: 10.1038/s44318-025-00399-z.

Landscape analysis of m6A modification reveals the dysfunction of bone metabolism in osteoporosis mice.

Zheng L, Lan C, Gao X, Zhu A, Chen Y, Lin J Heliyon. 2025; 11(3):e42123.

PMID: 39991256 PMC: 11847259. DOI: 10.1016/j.heliyon.2025.e42123.

A novel PTH1R mutation causes primary failure of eruption via the cAMP-PI3K/AKT pathway.

Lu K, Qian Y, Gong J, Li Z, Yu M, Wang H Prog Orthod. 2025; 26(1):7.

PMID: 39988614 PMC: 11847765. DOI: 10.1186/s40510-025-00555-5.

Silencing YTHDF2 Induces Apoptosis of Neuroblastoma Cells In a Cell Line-Dependent Manner via Regulating the Expression of DLK1.

Hua Z, Gong B, Li Z Mol Neurobiol. 2025; .

PMID: 39979690 DOI: 10.1007/s12035-025-04759-y.

References

Juppner H, Abou-Samra A, Freeman M, Kong X, Schipani E, Richards J . A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science. 1991; 254(5034):1024-6. DOI: 10.1126/science.1658941. View

Wang X, Zhao B, Roundtree I, Lu Z, Han D, Ma H . N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency. Cell. 2015; 161(6):1388-99. PMC: 4825696. DOI: 10.1016/j.cell.2015.05.014. View

Batista P, Molinie B, Wang J, Qu K, Zhang J, Li L . m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell. 2014; 15(6):707-19. PMC: 4278749. DOI: 10.1016/j.stem.2014.09.019. View

Abou-Samra A, Juppner H, Force T, Freeman M, Kong X, Schipani E . Expression cloning of a common receptor for parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells: a single receptor stimulates intracellular accumulation of both cAMP and inositol trisphosphates and increases.... Proc Natl Acad Sci U S A. 1992; 89(7):2732-6. PMC: 48736. DOI: 10.1073/pnas.89.7.2732. View

Fan Y, Bi R, Densmore M, Sato T, Kobayashi T, Yuan Q . Parathyroid hormone 1 receptor is essential to induce FGF23 production and maintain systemic mineral ion homeostasis. FASEB J. 2015; 30(1):428-40. PMC: 4684518. DOI: 10.1096/fj.15-278184. View

Shi H, Wang X, Lu Z, Zhao B, Ma H, Hsu P . YTHDF3 facilitates translation and decay of N-methyladenosine-modified RNA. Cell Res. 2017; 27(3):315-328. PMC: 5339834. DOI: 10.1038/cr.2017.15. View

Fan Y, Hanai J, Le P, Bi R, Maridas D, Demambro V . Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate. Cell Metab. 2017; 25(3):661-672. PMC: 5342925. DOI: 10.1016/j.cmet.2017.01.001. View

Yoon K, Ringeling F, Vissers C, Jacob F, Pokrass M, Jimenez-Cyrus D . Temporal Control of Mammalian Cortical Neurogenesis by mA Methylation. Cell. 2017; 171(4):877-889.e17. PMC: 5679435. DOI: 10.1016/j.cell.2017.09.003. View

Hsu P, Zhu Y, Ma H, Guo Y, Shi X, Liu Y . Ythdc2 is an N-methyladenosine binding protein that regulates mammalian spermatogenesis. Cell Res. 2017; 27(9):1115-1127. PMC: 5587856. DOI: 10.1038/cr.2017.99. View

10.

Zheng G, Dahl J, Niu Y, Fedorcsak P, Huang C, Li C . ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2012; 49(1):18-29. PMC: 3646334. DOI: 10.1016/j.molcel.2012.10.015. View

11.

Silva B, Bilezikian J . Parathyroid hormone: anabolic and catabolic actions on the skeleton. Curr Opin Pharmacol. 2015; 22:41-50. PMC: 5407089. DOI: 10.1016/j.coph.2015.03.005. View

12.

Wang Y, Li Y, Yue M, Wang J, Kumar S, Wechsler-Reya R . N-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications. Nat Neurosci. 2018; 21(2):195-206. PMC: 6317335. DOI: 10.1038/s41593-017-0057-1. View

13.

Ono W, Sakagami N, Nishimori S, Ono N, Kronenberg H . Parathyroid hormone receptor signalling in osterix-expressing mesenchymal progenitors is essential for tooth root formation. Nat Commun. 2016; 7:11277. PMC: 4832076. DOI: 10.1038/ncomms11277. View

14.

Silva B, Costa A, Cusano N, Kousteni S, Bilezikian J . Catabolic and anabolic actions of parathyroid hormone on the skeleton. J Endocrinol Invest. 2011; 34(10):801-10. PMC: 4315330. DOI: 10.3275/7925. View

15.

Wang X, Lu Z, Gomez A, Hon G, Yue Y, Han D . N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2013; 505(7481):117-20. PMC: 3877715. DOI: 10.1038/nature12730. View

16.

Rosen C, Bouxsein M . Mechanisms of disease: is osteoporosis the obesity of bone?. Nat Clin Pract Rheumatol. 2006; 2(1):35-43. DOI: 10.1038/ncprheum0070. View

17.

Scheller E, Rosen C . What's the matter with MAT? Marrow adipose tissue, metabolism, and skeletal health. Ann N Y Acad Sci. 2014; 1311:14-30. PMC: 4049420. DOI: 10.1111/nyas.12327. View

18.

Liu W, Zhou L, Zhou C, Zhang S, Jing J, Xie L . GDF11 decreases bone mass by stimulating osteoclastogenesis and inhibiting osteoblast differentiation. Nat Commun. 2016; 7:12794. PMC: 5036163. DOI: 10.1038/ncomms12794. View

19.

Wang X, Feng J, Xue Y, Guan Z, Zhang D, Liu Z . Structural basis of N(6)-adenosine methylation by the METTL3-METTL14 complex. Nature. 2016; 534(7608):575-8. DOI: 10.1038/nature18298. View

20.

Yue Y, Liu J, He C . RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation. Genes Dev. 2015; 29(13):1343-55. PMC: 4511210. DOI: 10.1101/gad.262766.115. View