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 () and Shunwu Fan ()
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Ziang Xie: Zhejiang University School of Medicine
Lei Hou: Shanghai Jiaotong University School of Medicine
Shuying Shen: Zhejiang University School of Medicine
Yizheng Wu: Zhejiang University School of Medicine
Jian Wang: Tongde Hospital of Zhejiang Province
Zhiwei Jie: Zhejiang University School of Medicine
Xiangde Zhao: Zhejiang University School of Medicine
Xiang Li: Zhejiang University School of Medicine
Xuyang Zhang: Zhejiang University School of Medicine
Junxin Chen: Zhejiang University School of Medicine
Wenbin Xu: Zhejiang University School of Medicine
Lei Ning: Zhejiang University School of Medicine
Qingliang Ma: Zhejiang University School of Medicine
Shiyu Wang: Zhejiang University School of Medicine
Haoming Wang: Zhejiang University School of Medicine
Putao Yuan: Zhejiang University School of Medicine
Xiangqian Fang: Zhejiang University School of Medicine
An Qin: Shanghai Jiaotong University School of Medicine
Shunwu Fan: Zhejiang University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-021-27629-2

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