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.
Highlights
Mechanical force is critical for the development and remodeling of bone
The -394 4N del/ins polymorphism of Ddah[1] and increased level of asymmetric dimethylarginine (ADMA) is negatively associated with bone mineral density
Given that loss-of-function polymorphism of Ddah[1] promoter was associated with increased susceptibility to metabolic syndrome (MS)[13], we asked whether ADMA level and Ddah[1] promoter polymorphism were associated with the bone mineral density (BMD) in humans
Summary
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. Global or osteoblast-specific deletion of Ddah[1] leads to increased ADMA level but reduced bone formation. Deletion of Ddah[1] in osteoblast-lineage cells fails to respond to mechanical stimulus-associated bone formation. The study reveals mechanical force is capable of down-regulating ADMA to enhance bone formation. Emerging evidences suggest that plasma ADMA levels are significantly associated with SNPs (Single Nucleotide Polymorphisms) in Ddah[1], which contributed to cardiovascular diseases and diabetes[10,11]. These SNPs of Ddah[1] are likely associated with metabolic syndrome including metabolic bone diseases[13,14]. Our initial aim was to investigate if the loss-of-function Ddah[1] promoter polymorphism is associated with osteoporosis
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