Inhibition of ERK 1/2 kinases prevents tendon matrix breakdown.

Ulrich Blache, Stefania L Wunderli, Amro A Hussien, Tino Stauber, Gabriel Flückiger, Maja Bollhalder, Barbara Niederöst, Sandro F Fucentese, Jess G Snedeker

Scientific reports 2021 Mar 25

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Tendon extracellular matrix (ECM) mechanical unloading results in tissue degradation and breakdown, with niche-dependent cellular stress directing proteolytic degradation of tendon. Here, we show that the extracellular-signal regulated kinase (ERK) pathway is central in tendon degradation of load-deprived tissue explants. We show that ERK 1/2 are highly phosphorylated in mechanically unloaded tendon fascicles in a vascular niche-dependent manner. Pharmacological inhibition of ERK 1/2 abolishes the induction of ECM catabolic gene expression (MMPs) and fully prevents loss of mechanical properties. Moreover, ERK 1/2 inhibition in unloaded tendon fascicles suppresses features of pathological tissue remodeling such as collagen type 3 matrix switch and the induction of the pro-fibrotic cytokine interleukin 11. This work demonstrates ERK signaling as a central checkpoint to trigger tendon matrix degradation and remodeling using load-deprived tissue explants.

Citation

Ulrich Blache, Stefania L Wunderli, Amro A Hussien, Tino Stauber, Gabriel Flückiger, Maja Bollhalder, Barbara Niederöst, Sandro F Fucentese, Jess G Snedeker. Inhibition of ERK 1/2 kinases prevents tendon matrix breakdown. Scientific reports. 2021 Mar 25;11(1):6838