Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China.
Nat Commun. 2022 Jan 10;13(1):50. doi: 10.1038/s41467-021-27629-2.
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.
机械力对于骨骼的发育和重塑至关重要。在这里，我们报告称，机械力通过调节成骨细胞中水解酶二甲基精氨酸二甲氨基水解酶 1（Ddah1）的表达来调节代谢物不对称二甲基精氨酸（ADMA）的产生。Ddah1 的-394 4Ndel/ins 多态性和较高的血清 ADMA 浓度与骨密度呈负相关。Ddah1 的全局或成骨细胞特异性缺失导致 ADMA 水平升高但骨形成减少。进一步的分子研究揭示，机械刺激增强了 TAZ/SMAD4 诱导的 Ddah1 转录。成骨细胞系细胞中 Ddah1 的缺失不能对机械刺激相关的骨形成作出反应。总之，该研究表明机械力能够下调 ADMA 以增强骨形成。
