Osteoporosis has a profound influence on public health. First-line bisphosphonates often cause osteonecrosis of the jaw meanwhile inhibiting osteoclasts. Therefore, it is important to develop effective treatments. The results of this study showed that the increased level of NFATc1 m6A methylation caused by zoledronic acid (ZOL), with 4249A as the functional site, is highly correlated with the decreased bone resorption of osteoclasts. Upstream, METTL14 regulates osteoclast bone absorption through the methylation functional site of NFATc1. Downstream, YTHDF1 and YTHDF2 show antagonistic effects on the post-transcriptional regulation of NFATc1 after the m6A methylation level is elevated by METTL14. In this study, meRIP-Seq, luciferase reporter assays, meRIP and other methods were used to elucidate the NFATc1 regulatory mechanism of osteoclasts from the perspective of RNA methylation. In addition, EphA2 overexpression on exosomes is an effective biological method for targeted delivery of METTL14 into osteoclasts. Importantly, this study shows that METTL14 released by exosomes can increase the m6A methylation level of NFATc1 to inhibit osteoclasts, help postmenopausal osteoporosis patients preserve bone mass, and avoid triggering osteonecrosis of the jaw, thus becoming a new bioactive molecule for the treatment of osteoporosis.
基金：
This work was
supported by the National Natural Science Foundation of China (No. 82141108) to
Jiang Li, the China Postdoctoral Science Foundation funded project (No.
2020M671162) to Wei Wang and the Natural Science Foundation of Jiangsu Province
(No. BK20201350) to Ping Zhang.
第一作者机构：[1]Shanghai Jiao Tong Univ, Tongren Hosp, Sch Med, Dept Stomatol, 1111 Xianxia Rd, Shanghai 200336, Peoples R China
共同第一作者：
通讯作者：
通讯机构：[2]Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Sch Med, Dept OralPathol, 639 Zhizaoju Rd, Shanghai 200011, Peoples R China[3]Shanghai Jiao Tong Univ, Coll Stomatol, 639 Zhizaoju Rd, Shanghai 200011, Peoples R China[4]Natl Ctr Stomatol, 639 Zhizaoju Rd, Shanghai 200011, Peoples R China[5]Natl Clin Res Ctr Oral Dis, 639 Zhizaoju Rd, Shanghai 200011, Peoples R China[6]Shanghai Key Lab Stomatol, 639 Zhizaoju Rd, Shanghai 200011, Peoples R China[11]Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Sch Med, Dept Gen Dent, 639 Zhizaoju Rd, Shanghai 200011, Peoples R China
推荐引用方式(GB/T 7714)：
Yang Jin-Gang,Sun Bao,Wang Zheng,et al.Exosome-targeted delivery of METTL14 regulates NFATc1 m6A methylation levels to correct osteoclast-induced bone resorption[J].CELL DEATH & DISEASE.2023,14(11):doi:10.1038/s41419-023-06263-4.
APA：
Yang, Jin-Gang,Sun, Bao,Wang, Zheng,Li, Xing,Gao, Jia-hui...&Wang, Wei.(2023).Exosome-targeted delivery of METTL14 regulates NFATc1 m6A methylation levels to correct osteoclast-induced bone resorption.CELL DEATH & DISEASE,14,(11)
MLA：
Yang, Jin-Gang,et al."Exosome-targeted delivery of METTL14 regulates NFATc1 m6A methylation levels to correct osteoclast-induced bone resorption".CELL DEATH & DISEASE 14..11(2023)
生物学