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Tendon response to matrix unloading is determined by the patho-physiological niche.
Matrix Biology ( IF 6.9 ) Pub Date : 2020-01-07 , DOI: 10.1016/j.matbio.2019.12.003
Stefania L Wunderli 1 , Ulrich Blache 1 , Agnese Beretta Piccoli 1 , Barbara Niederöst 1 , Claude N Holenstein 1 , Fabian S Passini 1 , Unai Silván 1 , Louise Bundgaard 2 , Ulrich Auf dem Keller 2 , Jess G Snedeker 1
Affiliation  

Although the molecular mechanisms behind tendon disease remain obscure, aberrant stromal matrix turnover and tissue hypervascularity are known hallmarks of advanced tendinopathy. We harness a tendon explant model to unwind complex cross-talk between the stromal and vascular tissue compartments. We identify the hypervascular tendon niche as a state-switch that gates degenerative matrix remodeling within the tissue stroma. Here pathological conditions resembling hypervascular tendon disease provoke rapid cell-mediated tissue breakdown upon mechanical unloading, in contrast to unloaded tendons that remain functionally stable in physiological low-oxygen/-temperature niches. Analyses of the stromal tissue transcriptome and secretome reveal that a stromal niche with elevated tissue oxygenation and temperature drives a ROS mediated cellular stress response that leads to adoption of an immune-modulatory phenotype within the degrading stromal tissue. Degradomic analysis further reveals a surprisingly rich set of active matrix proteases behind the progressive loss of tissue mechanics. We conclude that the tendon stromal compartment responds to aberrant mechanical unloading in a manner that is highly dependent on the vascular niche, with ROS gating a complex proteolytic breakdown of the functional collagen backbone.



中文翻译:

肌腱对基质卸载的反应由病理生理位决定。

尽管肌腱疾病的分子机制仍然不清楚,但异常的基质基质更新和组织血管增生是晚期肌腱病的标志。我们利用肌腱外植体模型消除基质和血管组织间的复杂串扰。我们将高血管肌腱位点识别为一种状态开关,它可以控制组织基质内变性基质的重塑。在这种情况下,类似于血管紧张性肌腱疾病的病理状况会在机械卸载时引起快速的细胞介导的组织破坏,这与在生理低氧/温度低位环境中保持功能稳定的卸载肌腱相反。基质组织转录组和分泌组的分析表明,组织氧合和温度升高的基质生态位驱动ROS介导的细胞应激反应,从而导致降解基质细胞内采用免疫调节表型。降解组学分析进一步揭示了在组织力学的逐步丧失背后令人惊讶地丰富的活性基质蛋白酶。我们得出的结论是,肌腱间质隔室以高度依赖血管生态位的方式对异常的机械卸载作出反应,ROS控制功能性胶原蛋白骨架的复杂蛋白水解作用。降解组学分析进一步揭示了在组织力学的逐步丧失背后令人惊讶地丰富的活性基质蛋白酶。我们得出的结论是,肌腱间质隔室以高度依赖血管生态位的方式响应异常的机械卸载,ROS控制功能性胶原蛋白骨架的复杂蛋白水解作用。降解组学分析进一步揭示了在组织力学的逐步丧失背后令人惊讶地丰富的活性基质蛋白酶。我们得出的结论是,肌腱间质隔室以高度依赖血管生态位的方式对异常的机械卸载作出反应,ROS控制了功能性胶原蛋白骨架的复杂蛋白水解作用。

更新日期:2020-01-07
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