Inhibition of ERK 1/2 kinases prevents tendon matrix breakdown

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

doi:10.1038/s41598-021-85331-1

Abstract

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.

Highlights

Tendon extracellular matrix (ECM) mechanical unloading results in tissue degradation and breakdown, with niche-dependent cellular stress directing proteolytic degradation of tendon
We show that the extracellular-signal regulated kinase (ERK) pathway drives tendon matrix degradation in mechanically unloaded tissue in a culture niche-dependent manner
We found that ERK 1/2 are highly phosphorylated in degrading tendon fascicles, and that ERK 1/2 activity is required for tendon deterioration

Summary

Introduction

Tendon extracellular matrix (ECM) mechanical unloading results in tissue degradation and breakdown, with niche-dependent cellular stress directing proteolytic degradation of tendon. Tendon explants lose their mechanical properties under load-deprived conditions due to proteolytic matrix degradation involving different proteases, such as matrix metalloproteases (MMP)[12,14,15,16,17,18]. We experimentally validated ERK 1/2 predictions using Western Blot analysis and found that the ERK kinases 1/2 are phosphorylated under standard culture conditions but not under reduced culture conditions nor in native, uncultured fascicles (fresh tissue) (Fig. 1D).

Results

Conclusion