Mechanical force promotes dimethylarginine dimethylaminohydrolase 1-mediated hydrolysis of the metabolite asymmetric dimethylarginine to enhance bone formation

Ziang Xie; Lei Hou; Shuying Shen; Yizheng Wu; Jian Wang; Zhiwei Jie; Xiangde Zhao; Xiang Li; Xuyang Zhang; Junxin Chen; Wenbin Xu; Lei Ning; Qingliang Ma; Shiyu Wang; Haoming Wang; Putao Yuan; Xiangqian Fang; An Qin; Shunwu Fan

doi:10.1038/s41467-021-27629-2

Mechanical force promotes dimethylarginine dimethylaminohydrolase 1-mediated hydrolysis of the metabolite asymmetric dimethylarginine to enhance bone formation

Nat Commun. 2022 Jan 10;13(1):50. doi: 10.1038/s41467-021-27629-2.

Authors

Ziang Xie^#^{1

2}, Lei Hou^#³, Shuying Shen^#^{1

2}, Yizheng Wu^{1

2}, Jian Wang⁴, Zhiwei Jie^{1

2}, Xiangde Zhao^{1

2}, Xiang Li^{1

2}, Xuyang Zhang^{1

2}, Junxin Chen^{1

2}, Wenbin Xu^{1

2}, Lei Ning^{1

2}, Qingliang Ma^{1

2}, Shiyu Wang^{1

2}, Haoming Wang^{1

2}, Putao Yuan^{1

2}, Xiangqian Fang^{5

6}, An Qin⁷, Shunwu Fan^{8

9}

Affiliations

¹ Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China.
³ Department of Cardiology, Shanghai Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁴ Department of Orthopaedics, Tongde Hospital of Zhejiang Province, Hangzhou, China.
⁵ Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. orthofxq@zju.edu.cn.
⁶ Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China. orthofxq@zju.edu.cn.
⁷ Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. dr_qinan@163.com.
⁸ Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. shunwu_fan@zju.edu.cn.
⁹ Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China. shunwu_fan@zju.edu.cn.

^# Contributed equally.

Abstract

Mechanical force is critical for the development and remodeling of bone. Here we report that mechanical force regulates the production of the metabolite asymmetric dimethylarginine (ADMA) via regulating the hydrolytic enzyme dimethylarginine dimethylaminohydrolase 1 (Ddah1) expression in osteoblasts. The presence of -394 4 N del/ins polymorphism of Ddah1 and higher serum ADMA concentration are negatively associated with bone mineral density. Global or osteoblast-specific deletion of Ddah1 leads to increased ADMA level but reduced bone formation. Further molecular study unveils that mechanical stimulation enhances TAZ/SMAD4-induced Ddah1 transcription. Deletion of Ddah1 in osteoblast-lineage cells fails to respond to mechanical stimulus-associated bone formation. Taken together, the study reveals mechanical force is capable of down-regulating ADMA to enhance bone formation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amidohydrolases / genetics
Amidohydrolases / metabolism*
Animals
Arginine / analogs & derivatives*
Arginine / metabolism*
Bone and Bones
Female
Hydrolysis
Male
Mechanical Phenomena*
Mice
Mice, Inbred C57BL
Mice, Knockout
Osteogenesis / physiology*

Substances

N,N-dimethylarginine
Arginine
Amidohydrolases
dimethylargininase