Nat10-mediated N4-acetylcytidine modification enhances Nfatc1 translation to exacerbate osteoclastogenesis in postmenopausal osteoporosis
成果类型：
Article
署名作者：
Mo, Xiaoyi; Meng, Keyu; Xu, Bohan; Li, Zehui; Lan, Shanwei; Ren, Zhengda; Xiang, Xin; Zou, Peiqian; Chen, Zesen; Lai, Zhongming; Ao, Xiang; Liu, Zhongyuan; Shang, Wanjing; Dai, Bingyang; Luo, Li; Xu, Jiajia; Wang, Zhizhang; Zhang, Zhongmin
署名单位：
Southern Medical University - China; Southern Medical University - China; Southern Medical University - China; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); Hong Kong Polytechnic University; Hong Kong Polytechnic University; Sun Yat Sen University
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-15288
DOI：
10.1073/pnas.2423991122
发表日期：
2025-04-07
关键词：
摘要：
Increased differentiation or activity of osteoclasts is the key pathogenic factor of postmenois a novel posttranscriptional mRNA modification related to many diseases. However, its impact on regulating osteoclast activation in PMOP remains uncertain. Here, we initially observed that Nat10- mediated ac4C positively correlates with osteoclast differentiation of monocytes and low bone mass in PMOP. The specific knockout of Nat10 in monocytes and remodelin, a Nat10 inhibitor, alleviates ovariectomized (OVX)- induced bone loss by downregulating osteoclast differentiation. Mechanistically, epitranscriptomic analyses reveal that the nuclear factor of activated T cells cytoplasmic 1 (Nfatc1) is the key downstream target of ac4C modification during osteoclast differentiation. Subsequently, translatomic results demonstrate that Nat10- mediated ac4C enhances the translation efficiency (TE) of Nfatc1, thereby inducing Nfatc1 expression and consequent osteoclast maturation. Cumulatively, these findings reveal the promotive role of Nat10 in osteoclast differentiation and PMOP from a novel field of RNA modifications and suggest that Nat10 can be a target of epigenetic therapy for preventing bone loss in PMOP.