Mechanical strain promotes skin fibrosis through LRG-1 induction mediated by ELK1 and ERK signalling

Ya Gao,Qingfeng Li,Yifan Zhang,Jia Zhou,Zhibo Xie,Chia-Kang Ho,Jing Wang

doi:10.1038/s42003-019-0600-6

Abstract

Biomechanical force and pathological angiogenesis are dominant features in fibro-proliferative disorders. Understanding the role and regulation of the mechanical microenvironment in which pathological angiogenesis occurs is an important challenge when investigating numerous angiogenesis-related diseases. In skin fibrosis, dermal fibroblasts and vascular endothelial cells are integral to hypertrophic scar formation. However, few studies have been conducted to closely investigate their relationship. Here we show, that leucine-rich-alpha-2-glycoprotein 1 (LRG-1) a regulator of pathological angiogenesis, links biomechanical force to angiogenesis in skin fibrosis. We discover that LRG-1 is overexpressed in hypertrophic scar tissues, and that depletion of Lrg-1 in mouse skin causes mild neovascularization and skin fibrosis formation in a hypertrophic scarring model. Inhibition of FAK or ERK attenuates LRG-1 expression through the ELK1 transcription factor, which binds to the LRG-1 promoter region after transcription initiation by mechanical force. Using LRG-1 to uncouple mechanical force from angiogenesis may prove clinically successful in treating fibro-proliferative disorders.

Highlights

Hypertrophic scarring (HS) is a skin fibrotic disorder that occurs following extensive cutaneous injury with excessive fibrosis, characterized by aberrant fibroblast function[1], abundant collagen deposits[2], and superfluously formed microvessels[3]
To understand the mechanism by which ERK regulates leucinerich-alpha-2-glycoprotein 1 (LRG-1) expression, we examined transcription factors (TFs) regulated by the ERK pathway, and we used PROMO and JASPAR to perform an online prediction of TF binding ability in the LRG-1 promoter region (Fig. 8a, Supplementary Table 1); NFκB1 and ELK1 were the TFs of interest
We discovered that LRG-1 plays a key role in the progression of skin fibrosis as well as a new mechanism linking biomechanical force and pathological angiogenesis

Summary

Introduction

Hypertrophic scarring (HS) is a skin fibrotic disorder that occurs following extensive cutaneous injury with excessive fibrosis, characterized by aberrant fibroblast function[1], abundant collagen deposits[2], and superfluously formed microvessels[3]. An earlier study reported that FAK links mechanical force to skin fibrosis via an inflammatory signaling pathway[11]. It can activate downstream pro-fibrotic targets to transmit mechanical force and boost collagen production[19]. It is well-known that pathological angiogenesis is indispensable in hypertrophic scar formation[3]. By manipulating LRG-1 expression, we may find a promising therapeutic treatment for HS and provide a new strategy for the treatment of diseases that involve biomechanical force and pathological angiogenesis, such as organ fibrosis and cancer

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