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

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.

SUBMITTER: Wang Y

PROVIDER: S-EPMC10973419 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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

Wang Yaobin Y Chen Yi Y Xiao Hefang H Liu Zhongcheng Z Liu Xuening X Feng Zhiwei Z Sheng Xiaoyun X Peng Bo B Ren Xiaojun X Xu Lihu L Teng Fei F Yi Zhi Z Niu YongKang Y Xiang Dejian D Xia Yayi Y Geng Bin B

Cell death discovery 20240327 1

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 th ...[more]

PMID: 38538596

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Project description:This study explored the impact of N6-methyladenosine (m6A) modification on the regulation of long noncoding RNA (lncRNA) and atherosclerosis progression. An atherosclerosis cell model was established by treating human aortic endothelial cells (HAECs) with oxidized low-density lipoprotein. Additionally, an atherosclerotic animal model was developed using ApoE-/- C57BL/6 male mice fed a high-fat diet. Both models were employed to assess the expression changes of proteins associated with m6A modification. First, the effect of m6A modification writer protein methyltransferase-like 3 (METTL3) knockdown on changes in the level of pyroptosis in HAECs was investigated, and bioinformatic analysis confirmed that lncRNA H19 (H19) was the potential target of m6A modification. RNA-binding protein immunoprecipitation assays were subsequently performed to explore the interaction between H19 and the m6A writer protein METTL3, as well as the reader protein recombinant insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). Finally, the effect of H19 expression on pyroptosis levels in HAECs was evaluated. In the aortas of atherosclerosis mice, overall m6A levels were significantly elevated compared with controls (p < .05), with METTL3 and METTL14 mRNA and protein levels notably increased (p < .05). Similarly, ox-LDL-treated HAECs showed a significant rise in m6A levels, along with increased METTL3 and METTL14 expression (p < .05). METTL3 knockdown in HAECs led to decreased pyroptosis, as evidenced by reduced lactate dehydrogenase release and lower levels of IL-1β, IL-18, and IL-6 (p < .05). Overexpression of H19 reversed these effects, indicating METTL3's role in promoting atherosclerosis by stabilizing H19 through m6A modification. H19 was the primary target lncRNA molecule of METTL3-mediated m6A modification in the pathogenesis of atherosclerosis. METTL3-mediated m6A modification regulated H19 expression, thereby aggravating atherosclerosis by activating pyroptosis.

Dataset Information

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

Publications

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

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