Dataset Information

Tendon tissue degradome in response to the patho-physiological niche

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Tendon

SUBMITTER: Ulrich auf dem Keller

LAB HEAD: Ulrich auf dem Keller

PROVIDER: PXD013635 | Pride | 2020-01-28

REPOSITORIES: Pride

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Publications

Tendon response to matrix unloading is determined by the patho-physiological niche.

Wunderli Stefania L SL Blache Ulrich U Beretta Piccoli Agnese A Niederöst Barbara B Holenstein Claude N CN Passini Fabian S FS Silván Unai U Bundgaard Louise L Auf dem Keller Ulrich U Snedeker Jess G JG

Matrix biology : journal of the International Society for Matrix Biology 20200107

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 provok ...[more]

PMID: 31917255

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Project description:Skeletal muscle atrophy is a consequence of many diseases, environmental insults, inactivity, age and injury. Atrophy is characterized by active degradation and removal of contractile proteins and a reduction in fiber size. Animal models have been extensively used to identify pathways leading to atrophic conditions. Here we have used genome-wide expression profiling analysis and quantitative PCR to identify the molecular changes that occur in two clinically relevant animal mouse models of muscle atrophy, hindlimb casting and Achilles tendon laceration (tenotomy). Gastrocnemius muscle samples were collected 2, 7 and 14 days after insult. The total amount of muscle loss as measured by wet weight and muscle fiber size was equivalent between models, although tenotomy resulted in a more rapid induction of muscle atrophy. Furthermore, tentomy resulted in the regulation of significantly more mRNA transcripts then casting. Analysis of the regulated genes and pathways suggest that the mechanism of atrophy is distinct between these models. The degradation following casting appears ubiquitin-proteasome-mediated while degradation following tenotomy appears lysosomal and matrix-metalloproteinase (MMP)-mediated. This data suggests that there are multiple mechanisms leading to muscle atrophy and that specific therapeutic agents may be necessary to combat the atrophy seen under different conditions. Muscle atrophy was induced through two methods; unloading induced by tendon laceration (Tenotomy) and immobilization induced by hindlimb casting (Casting). For the tenotomy, eight week old male C57/B6 mice were anesthetized by ether inhalation and subsequent intramuscular injection of ketamine-xylazine (0.1 ml/g). The right Achilles tendon just proximal to the calcaneus was severed with a sterile scalpel. The mice were allowed to recover and move freely about their cage. An additional cohort of animals was sham operated (Sham) which involved isolation and manipulation of the Achilles tendon without laceration. For the casting, the right hindlimbs of eight week old male C57Bl/6 mice were immobilized through casting. After 2, 7 or 14 days, animals were sacrificed and the left and right gastrocnemius muscles were carefully removed, flash frozen in liquid nitrogen, and stored at -80°C for further processing. The left untreated legs served as controls. A group of naïve animals that received no treatment or manipulation was included as an additional control. Each group consisted of between 5 and 10 samples for a total of 111 individual samples.

Dataset Information

Tendon tissue degradome in response to the patho-physiological niche

Publications

Tendon response to matrix unloading is determined by the patho-physiological niche.

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