Metformin attenuates trauma-induced heterotopic ossification via inhibition of Bone Morphogenetic Protein signalling.
Metformin attenuates trauma-induced heterotopic ossification via inhibition of Bone Morphogenetic Protein signalling.
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二甲双胍通过抑制骨形态发生蛋白信号传导来减轻创伤引起的异位骨化。
DOI：
10.1111/jcmm.16076
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发表时间：
2020-12
影响因子：
5.3
通讯作者：
Luo Z
中科院分区：
文献类型：
--
作者：
Lin H;Shi F;Jiang S;Wang Y;Zou J;Ying Y;Huang D;Luo L;Yan X;Luo Z
AMP活化蛋白激酶（AMPK）是能量稳态的细胞内传感器，在能量应激下被激活，在能量过剩时被抑制。AMPK激活导致抑制消耗ATP的合成代谢过程。成骨分化是一个高度需要ATP的过程，在此过程中AMPK被抑制。骨形态发生蛋白（BMPs）信号通路在成骨分化中起着重要作用。本研究检查了二甲双胍对BMP信号传导、成骨分化和创伤诱导的异位骨化的抑制作用。我们的研究结果表明，二甲双胍抑制成骨细胞MC 3 T3-E1中BMP 6诱导的Smad 1/5磷酸化，同时上调Smad 6，这种作用可通过敲低Smad 6而减弱。此外，我们发现二甲双胍抑制ALP活性和矿化的细胞，这是由显性负突变的AMPK和模仿其组成型活性突变体减弱的事件。最后，二甲双胍给药可预防小鼠创伤诱导的异位骨化。二甲双胍处理后，AMPK活性、Smad 6和Smurf 1表达增强，同时ALK 2表达减少。总的来说，我们的研究表明二甲双胍通过激活AMPK和随后上调Smad 6来预防异位骨化。因此，二甲双胍可能是一种潜在的治疗外伤性异位骨化的药物。
AMP‐activated protein kinase (AMPK) is an intracellular sensor of energy homoeostasis that is activated under energy stress and suppressed in energy surplus. AMPK activation leads to inhibition of anabolic processes that consume ATP. Osteogenic differentiation is a process that highly demands ATP during which AMPK is inhibited. The bone morphogenetic proteins (BMPs) signalling pathway plays an essential role in osteogenic differentiation. The present study examines the inhibitory effect of metformin on BMP signalling, osteogenic differentiation and trauma‐induced heterotopic ossification. Our results showed that metformin inhibited Smad1/5 phosphorylation induced by BMP6 in osteoblast MC3T3‐E1 cells, concurrent with up‐regulation of Smad6, and this effect was attenuated by knockdown of Smad6. Furthermore, we found that metformin suppressed ALP activity and mineralization of the cells, an event that was attenuated by the dominant negative mutant of AMPK and mimicked by its constitutively active mutant. Finally, administration of metformin prevented the trauma‐induced heterotopic ossification in mice. In conjuncture, AMPK activity and Smad6 and Smurf1 expression were enhanced by metformin treatment in the muscle of injured area, concurrently with the reduction of ALK2. Collectively, our study suggests that metformin prevents heterotopic ossification via activation of AMPK and subsequent up‐regulation of Smad6. Therefore, metformin could be a potential therapeutic drug for heterotopic ossification induced by traumatic injury.
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影响因子：
4.6
作者：
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通讯作者：
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影响因子：
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