Nat10-mediated N4-acetylcytidine modification enhances Nfatc1 translation to exacerbate osteoclastogenesis in postmenopausal osteoporosis
Abstract
Increased differentiation or activity of osteoclasts is the key pathogenic factor of postmenopausal osteoporosis (PMOP). N4‐acetylcytidine (ac4C) modification, catalyzed by Nat10, is 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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (18)
Xiaoyi Mo
Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University
Keyu Meng
Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University
Bohan Xu
Department of Pathology, Nanfang Hospital, Southern Medical University
Zehui Li
Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University
Shanwei Lan
Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University
Zhengda Ren
Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University
Xin Xiang
Institute of Materials, China Academy of Engineering Physics
Peiqian Zou
Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University
Zesen Chen
Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University
Zhongming Lai
Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University
Xiang Ao
School of Biology and Biological Engineering, South China University of Technology
Zhongyuan Liu
Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University
Wanjing Shang
Bingyang Dai
Department of Biomedical Engineering, The Hong Kong Polytechnic University
Li Luo
Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-sen University
Jiajia Xu
State Key Laboratory of Physical Chemistry of Solid Surfaces, iChEM, College of Chemistry and Chemical Engineering, Innovation Laboratory for Sciences and Technologies of Energy Materials of Fujian Province (IKKEM)
Zhizhang Wang
Department of Pathology, Nanfang Hospital, Southern Medical University
Zhongmin Zhang
Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University