机械过载牵拉刺激引导高迁移率族蛋白-1（HMGB-1）外泌诱发肌腱炎的机制研究

The incidence of tendonitis is high. It is often caused by repeated mechanical overloading and seriously affect the quality of life. The pathogenesis is not clear while there is no specific treatment. Relation between HMGB-1 and inflammation is popular in recent research, but no publication mentioned HMGB-1 with tendonitis before. Our previous experiments proved HMGB-1 existed in tendon tissue and we also observed that mechanical overloading could induce HMGB-1 released from intracellular to extracellular. In vivo experiment showed that HMGB-1 was increased in the ECM of tendon tissue from the tendonitis/tendinopathy animal model induced by mechanical overloading. So we hypothesize the tendonitis induced by mechanical overloading is mainly resulted by HMGB-1 released to extracellular. We plan to both in Vitro and in Vivo reprove the phenomenon of HMGB-1 release induced by mechanical overloading, and then verify HMGB-1 is the key factor and trigger of tendon tissue inflammation, finally explore the cellular and molecular mechanisms of how released HMGB-1 induces tendon inflammation, especially pays attention to the change of NF-κB pathway and MAPK pathway. Thus to prove our hypothesis and enhance our understanding of the pathogenesis of tendonitis, which can serve as a theoretical underpinning for developing new specific therapy of tendonitis in the further.

肌腱炎发生率高，常因反复过载牵拉刺激导致且严重影响生活质量，目前机制不明且无特效治疗。HMGB-1与炎症发生的关联目前成为研究热点，但尚无HMGB-1与肌腱炎相关研究。我们前期预实验证实肌腱组织中存在HMGB-1且发现机械过载牵拉可诱导胞内HMGB-1外泌至胞外现象，体内实验重现机械过载牵拉诱发肌腱炎模型中证实组织间HMGB-1含量升高，故提出机械过载刺激诱发肌腱炎是通过HMGB-1外泌再刺激肌腱细胞炎症反应而实现的假说。拟通过体内外确证过载牵拉诱导HMGB-1外泌现象，再体内过表达肌腱中HMGB-1含量对比组织炎症状态明确HMGB-1是调控炎症关键，再体外验证外泌HMGB-1诱发肌腱细胞炎症反应的细胞机制并通过研究NF-κB、MAPK等通路活化情况明确分子机制；最终明确“机械过载-HMGB-1外泌-肌腱炎”假说的机理，增进对肌腱炎发生机制的认识并为后续开发靶向治疗肌腱炎药物提供理论基础。

肌腱炎发生率高，常因反复过载牵拉刺激导致且严重影响生活质量，目前机制不明且无特效治疗。HMGB-1与炎症发生的关联目前成为研究热点，但尚无HMGB-1与肌腱炎相关研究。本研究旨在探索HMGB-1与肌腱炎发生发展的关系。本研究首先通体内体外试验证实了HMGB-1存在于肌腱组织及细胞中，再通过给与过量的机械牵拉刺激可见肌腱组织或细胞中的HMGB-1外泌现象。而我们又通过体内动物实验证实无论是外源性还是内源性增加肌腱组织中的HMGB-1含量均可诱使肌腱炎的发生，因此我们认为HMGB-1是调控启动肌腱炎发生的关键因子。另外细胞学实验证实HMGB-1可以导致肌腱的迁移速率增加，炎性改变和高代谢状态增加，而合成代谢减弱。另外对肌腱细胞的增殖速率无明显影响。而进一步机制研究表明以上表征的改变是因为HMGB-1通过调控MAPK和典型的NF-kB信号通路实现在肌腱细胞中激活炎症反应的发生进而实现对肌腱炎发生的调控。最后我们还综述了肌腱（干/祖）细胞与细胞外基质和机械应力之间的生物学联系，为未来进一步探索肌腱，细胞外基质以及机械应力三者之间的关系奠定知识基础。