AMPK downregulates ALK2 via increasing the interaction between Smurf1 and Smad6, leading to inhibition of osteogenic differentiation.
AMPK downregulates ALK2 via increasing the interaction between Smurf1 and Smad6, leading to inhibition of osteogenic differentiation.
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AMPK 通过增加 Smurf1 和 Smad6 之间的相互作用来下调 ALK2，从而抑制成骨分化。
DOI：
10.1016/j.bbamcr.2017.08.009
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发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
Luo Z
中科院分区：
文献类型：
--
作者：
Lin H;Ying Y;Wang YY;Wang G;Jiang SS;Huang D;Luo L;Chen YG;Gerstenfeld LC;Luo Z
激活素A受体I或激活素受体样激酶2属于I型转化生长因子-β家族，在骨发育中起重要作用。在罕见的常染色体遗传病纤维发育不良骨化性进行性变(FOP)中，95%的人存在含有R206到H突变的ALK2激活突变，该疾病导致肌肉中异位骨形成的发生。本研究评估了AMP活化蛋白激酶(AMPK)激活对ALK2R206H介导的FOP患者成纤维细胞信号转导的影响。突变的ALK2的活性被药理上的AMPK激动剂二甲双胍和阿司匹林抑制，而它们的作用被AMPK的显性负性突变体阻断，并被AMPK的结构性活性突变体模仿。此外，AMPK的激活上调了Smad6和SMurf1的表达，从而增强了它们之间的相互作用，导致其对ALK2的蛋白体依赖的降解。相反，Smad6或SMurf1的敲除可以阻止二甲双胍诱导的ALK2的减少。为了评估AMPK对ALK2活性的生物学相关性，我们在iPS细胞内诱导FOP成纤维细胞，发现二甲双胍抑制了它们的体外成骨分化。我们的研究为FOP的潜在治疗方法提供了新的见解，因为几种AMPK激动剂(例如二甲双胍、黄连素和阿司匹林等)。已经在临床上用于治疗糖尿病和代谢综合征。
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.
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