RT Journal Article
SR Electronic
T1 Tendon response to matrix unloading is determined by the patho-physiological niche
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 620534
DO 10.1101/620534
A1 Stefania L. Wunderli
A1 Ulrich Blache
A1 Agnese Beretta Piccoli
A1 Barbara Niederöst
A1 Claude N. Holenstein
A1 Fabian Passini
A1 Unai Silván
A1 Louise Bundgaard
A1 Ulrich auf dem Keller
A1 Jess G. Snedeker
YR 2019
UL http://biorxiv.org/content/early/2019/04/30/620534.abstract
AB Aberrant matrix turnover with elevated matrix proteolysis is a hallmark of tendon pathology. While tendon disease mechanisms remain obscure, mechanical cues are central regulators. Unloading of tendon explants in standard culture conditions provokes rapid cell-mediated tissue breakdown. Here we show that biological response to tissue unloading depends on the mimicked physiological context. Our experiments reveal that explanted tendon tissues remain functionally stable in a simulated avascular niche of low temperature and oxygen, regardless of the presence of serum. This hyperthermic and hyperoxic niche-dependent catabolic switch was shown by whole transcriptome analysis (RNA-seq) to be a strong pathological driver of an immune-modulatory phenotype, with a stress response to reactive oxygen species (ROS) and associated activation of catabolic extracellular matrix proteolysis that involved lysosomal activation and transcription of a range of proteolytic enzymes. Secretomic and degradomic analysis through terminal amine isotopic labeling of substrates (TAILS) confirmed that proteolytic activity in unloaded tissues was strongly niche dependent. Through targeted pharmacological inhibition we isolated ROS mediated oxidative stress as a major checkpoint for matrix proteolysis. We conclude from these data that the tendon stromal compartment responds to traumatic mechanical unloading in a manner that is highly dependent on the extrinsic niche, with oxidative stress response gating the proteolytic breakdown of the functional collagen backbone.