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

Abstract

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 disease fibrodysplasiaossificansprogressiva (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 patient was assessed in the present study. The activity of the mutated ALK2 was suppressed by pharmacological AMPK activators such as metformin and aspirin, while their actions were blocked 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 in its 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 clinical use for the treatment of diabetes and metabolic syndromes.

Dopamine receptor antagonists induce differentiation of PC‐3 human prostate cancer cell‐derived cancer stem cell‐like cells

“…Since the purpose of the present study was to elucidate how thioridazine and fluphenazine induced differentiation of CSC‐like cells instead of observing cell death or anti‐angiogenesis, we included AMPK and c‐Met in the list of candidate cellular target molecules regulated by thioridazine and fluphenazine together with Akt and mTOR (Figure ). This because AMPK and c‐Met could stimulate cell differentiation when they are activated or inhibited . Among these four cellular molecules, AMPK appeared to be the target molecule for inducing differentiation of C5A cells since its phosphorylation was inhibited dose‐dependently by thioridazine and fluphenazine, but not by promazine.…”

Dual Roles of the AMP-Activated Protein Kinase Pathway in Angiogenesis

“…Consistently, the serum levels of TGF-β1 in patients with type 2 diabetes receiving metformin are lower than those taking other glucose lowering medicine. Interestingly, the inhibitory effect of AMPK on TGF-β signaling is not just limited to Alk5/Smad2/3 paradigm, but also extends to BMP/ALK1/2/Smad1/5 signaling [82,133]. We have recently found that metformin inhibits ALK1-mediated tube formation and angiogenesis in matrigel plug assay [133].…”

Metformin enhances osteogenic differentiation of stem cells from human exfoliated deciduous teeth through AMPK pathway

“…AMPK inhibitor compound C abolished the metformin-induced osteogenic differentiation of SHEDs. Our data and abundant literature evidence indicate osteogenic effects of metformin, but Jeyabalan and colleagues reported no effects of metformin on osteogenesis in vivo[40,41]. It is likely that the seed cells used in some studies did not have sufficient osteogenic potential or that the animal models were not close enough to the clinical situation of bone regeneration.…”