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METTL3-mediated m6A modification increases Hspa1a stability to inhibit osteoblast aging

Authors :
Yaobin Wang
Yi Chen
Hefang Xiao
Zhongcheng Liu
Xuening Liu
Zhiwei Feng
Xiaoyun Sheng
Bo Peng
Xiaojun Ren
Lihu Xu
Fei Teng
Zhi Yi
YongKang Niu
Dejian Xiang
Yayi Xia
Bin Geng
Source :
Cell Death Discovery, Vol 10, Iss 1, Pp 1-12 (2024)
Publication Year :
2024
Publisher :
Nature Publishing Group, 2024.

Abstract

Abstract Senile osteoporosis is mainly caused by osteoblasts attenuation, which results in reduced bone mass and disrupted bone remodeling. Numerous studies have focused on the regulatory role of m6A modification in osteoporosis; however, most of the studies have investigated the differentiation of bone marrow mesenchymal stem cells (BMSCs), while the direct regulatory mechanism of m6A on osteoblasts remains unknown. This study revealed that the progression of senile osteoporosis is closely related to the downregulation of m6A modification and methyltransferase-like 3 (METTL3). Overexpression of METTL3 inhibits osteoblast aging. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) revealed that METTL3 upregulates the stability of Hspa1a mRNA, thereby inhibiting osteoblast aging. Moreover, the results demonstrated that METTL3 enhances the stability of Hspa1a mRNA via m6A modification to regulate osteoblast aging. Notably, YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) participates in stabilizing Hspa1a mRNA in the METTL3-mediated m6A modification process, rather than the well-known degradation function. Mechanistically, METTL3 increases the stability of Hspa1a mRNA in a YTHDF2-dependent manner to inhibit osteoblast aging. Our results confirmed the significant role of METTL3 in osteoblast aging and suggested that METTL3 could be a potential therapeutic target for senile osteoporosis.

Details

Language :
English
ISSN :
20587716
Volume :
10
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Cell Death Discovery
Publication Type :
Academic Journal
Accession number :
edsdoj.b411b91c495466d973db801ba5d3b53
Document Type :
article
Full Text :
https://doi.org/10.1038/s41420-024-01925-4