AMPK downregulates ALK2 via increasing the interaction between Smurf1 and Smad6, leading to inhibition of in vitro osteogenic differentiation

Publication date: Available online 25 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Author(s): Hui Lin, Ying Ying, Yuan-Yuan Wang, Gang Wang, Shan-Shan Jiang, Deiang Huang, Lingyu Luo, Ye-Guang Chen, Louis C. Gerstenfeld, Zhijun Luo
Activin A receptor type I or activin receptor-like kinase 2 (ACVRI/ALK2) belongs to type I TGF-β family and plays an important role in bone development. Activating mutations of ALK2 containing the R206 to H mutation, are present in 95% in the rare autosomal genetic diseasefibrodysplasiaossificansprogressiva (FOP), which leads to the development of ectopic bone formation in muscle.The effect of AMP-activated protein kinase (AMPK)activation on ALK2R206H-mediated signaling in fibroblast obtained from a FOP patientwasassessed in the present study. The activity of the mutated ALK2 was suppressed bypharmacological AMPK activators such as metformin and aspirin,while their actions wereblocked by the dominant negative mutant of AMPK and mimicked by the constitutively active mutant of AMPK. Furthermore, activation of AMPK upregulated Smad6 and Smurf1 and thereby enhanced their interactions, resulting inits proteosome-dependent degradation of ALK2. In contrast, knockdown of Smad6 or Smurf1 prevented metformin-induced reduction of ALK2. To evaluate the biological relevance of AMPK action on ALK2 activity,we induced FOP fibroblasts within iPS cells and found that their osteogenic differentiation in vitro was inhibited by metformin. Our studies provide novel insight into potential approaches to treatment of FOP,since several AMPK activators (e.g. metformin,berberine,and aspirin, etc.) are already in clinicaluse for the treatment of diabetes and metabolic syndromes.



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