AMPK通过调控Smurf1的SUMO化抑制创伤性异位骨化的研究

Heterotopic ossification (HO) is the pathologic formation of ectopic bone in soft tissues. Traumatic heterotopic ossification usually occurs following severe trauma and burns. It always causes chronic pain and joint movement disorder. Currently, there are no effective or specific therapies for HO. Bone morphogenetic protein (BMP) signaling pathway plays a critical role in HO. Our preliminary data showed that AMPK inhibits BMP signaling and its associated osteogenic differentiation,but the underlying mechanism remains unclear.Our latest findings suggest that AMPK regulates SUMOylation of Smurf1,a negative regulator of BMP signaling pathway. Therefore, we hypothesize that AMPK promotes SUMOylation of Smurf1, leading to inhibition of osteogenic differentiation and HO. To this end, we will further to study the effect of AMPK on SUMOylation of Smurf1, then to elucidate the mechanism of Smurf1 SUMOylation in inhibition of BMP signaling and osteogenic differentiation by AMPK.Using the mouse model of HO, to study the effects of AMPK activators on the SUMOylation of Smurf1 in vivo and traumatic HO in mice. Altogether, this study will shed light on the regulatory role of Smurf1 in BMP signaling pathway, it will also provide us important insight by developing clinical application of AMPK activators such as metformin and berberine into prevention and treatment HO.

异位骨化是指软组织中形成异常的骨组织，以创伤性异位骨化较为常见，多发生于严重的创伤和损伤之后，目前尚无特异性的防治手段。BMP信号通路在异位骨化进展中发挥着至关重要的作用。我们的前期工作发现AMPK抑制BMP信号转导和成骨分化。此外，我们的研究还发现AMPK上调BMP信号通路负调控因子Smurf1的Sumo化，抑制BMP信号转导。因此，我们推测AMPK可通过调控Smurf1的Sumo化抑制成骨分化和异位骨化。本研究旨在探讨AMPK对Smurf1的Sumo化作用和机制，解析Smurf1的Sumo化在AMPK对BMP信号通路和成骨分化中的作用。通过小鼠异位骨化模型，研究AMPK激活剂对Smurf1的Sumo化的影响及其对创伤性异位骨化的作用。本研究不仅从新视角阐明Smurf1对BMP信号通路的调节，也将推动AMPK激活剂二甲双胍在防治异位骨化的临床应用。

异位骨化是指在软组织中病理形成异常的骨组织。一般发生在严重创伤如大面积烧伤和肌肉损伤的患者中，是临床上严重的并发症。目前没有有效的预防、治疗方法。一个有效的、理想的防治异位骨化策略是调控异位骨形成过程的关键信号通路；另一个有创新性的方法是探索现有临床上治疗其他疾病药物，重新发现其治疗效果来满足临床需求。BMP信号通路在异位骨化进展中发挥着重大作用，阻断BMP信号通路传导被认为是预防和治疗异位骨化重要的策略。我们前期发现AMPK激活可下调BMP信号转导从而抑制成骨分化，但其分子机制尚不清楚。因而深入研究AMPK调控BMP信号通路的作用机制并进一步探索AMPK激活剂二甲双胍对异位骨化的抑制作用。我们首先发现Smurf1发生Sumo化修饰，二甲双胍激活AMPK上调E3连接酶PIAS3的表达以及促进AMPK与PIAS3的相互作用，从而上调Smurf1的Sumo化修饰；进一步发现AMPK与Smurf1的Sumo化修饰在成骨分化的进程中减弱，而BMP信号通路激活，共同促进成骨分化的发展，而AMPK激活抑制成骨分化的进展；最后研究发现创伤性异位骨化进程中AMPK活性减弱；二甲双胍通过激活AMPK，抑制BMP信号通路，进而阻遏创伤性异位骨化的进展。综上所述，AMPK通过调控PIAS3上调Smurf1的Sumo化，抑制BMP信号通路，从而阻遏成骨分化和异位骨化。我们的研究结果不仅有助于阐明AMPK对BMP信号通路调节的新机理，也将推动AMPK激活剂二甲双胍和黄连素用于预防、治疗异位骨化的临床应用。