The transcription factor Fra‐2 regulates the production of extracellular matrix in systemic sclerosis

Abstract

Objective. Fra-2 belongs to the activator protein 1 family of transcription factors. Mice transgenic for Fra-2 develop a systemic fibrotic disease with vascular manifestations similar to those of systemic sclerosis (SSc). The aim of the present study was to investigate whether Fra-2 plays a role in the pathogenesis of SSc and to identify the molecular mechanisms by which Fra-2 induces fibrosis.Methods. Dermal thickness and the number of myofibroblasts were determined in skin sections from Fra-2-transgenic and wild-type mice. The expression of Fra-2 in SSc patients and in animal models of SSc was analyzed by real-time polymerase chain reaction and immunohistochemistry. Fra-2, transforming growth factor ␤ (TGF␤), and ERK signaling in SSc fibroblasts were inhibited using small interfering RNA, neutralizing antibodies, and small-molecule inhibitors.Results. Fra-2-transgenic mice developed a skin fibrosis with increases in dermal thickness and increased myofibroblast differentiation starting at age 12 weeks. The expression of Fra-2 was up-regulated in SSc patients and in different mouse models of SSc. Stimulation with TGF␤ and platelet-derived growth factor (PDGF) significantly increased the expression of Fra-2 in SSc fibroblasts and induced DNA binding of Fra-2 in an ERK-dependent manner. Knockdown of Fra-2 potently reduced the stimulatory effects of TGF␤ and PDGF and decreased the release of collagen from SSc fibroblasts.Conclusion. We demonstrate that Fra-2 is overexpressed in SSc and acts as a novel downstream mediator of the profibrotic effects of TGF␤ and PDGF. Since transgenic overexpression of Fra-2 causes not only fibrosis but also vascular disease, Fra-2 might be an interesting novel candidate for molecular-targeted therapies for SSc.

LOXL4 Is Induced by Transforming Growth Factor β1 through Smad and JunB/Fra2 and Contributes to Vascular Matrix Remodeling

“…Based on these observations and our own results in vascular endothelial cells, it can be hypothesized that Fra2 mediates a specific TGF-␤1-dependent, ECM-specific genetic program in the vasculature, which can eventually contribute to the development of fibrosis. Experiments in dermal fibroblasts from scleroderma patients have also shown that the inhibition of the ERK pathway impairs Fra2-dependent collagen production (36). In fact, ERK has been largely implicated in the activation of fibrotic responses, both in the skin and in the cardiovascular system, and in agreement with our results, this kinase is phosphorylated and activated upon stimulation with TGF-␤1 (54)(55)(56).…”

“…Fra2 has recently evolved as an extremely interesting factor in the context of vascular ECM remodeling and fibrosis (33)(34)(35)(36). In order to confirm the implication of Fra2 in the upregulation of LOXL4 expression, we performed gain-and loss-of-function experiments.…”

“…Strong expression of Fra2 was detected in lung samples from patients with idiopathic pulmonary fibrosis (33). Additionally, Fra2 was found to be overexpressed in the dermis of patients with scleroderma, where it has been proposed to play a role in the induction of ECM proteins upon TGF-␤1 stimulation (34,36). Transgenic mice overexpressing Fra2 develop extensive fibrosis in several organs, with the pulmonary tissue being particularly affected, which is initiated as a severe vasculopathy characterized by vascular remodeling and obliteration of pulmonary arteries (35).…”

Animal Models of Systemic Sclerosis

“…AP-1 is a heterodimer composed of protein subunits belonging to the family of Fos (c-Fos, Fra-1, Fra-2, FosB) and Jun family (c-Jun, JunB, JunD), which regulate cell proliferation, inflammation, and wound healing via binding of AP-1 to the promoters of target genes [52]. Recent studies have reported a significant role of two members of the AP-1 family, Fra-2, and c-Jun on production of TGF-β and on its autocrine signaling in SSc fibroblasts [53,54]. Overexpression of Fra-2 was also reported in patients with SSc, specifically in myofibroblasts, endothelial cells, and smooth muscle cells, suggesting a potential importance of Fra-2 in the pathogenesis of SSc [54,55].…”

The Main Results of Cooperation Between the V.A. Nasonova Research Institute of Rheumatology and Research Centers of Europe Within the Eustar (Eular Scleroderma Trials and Research Group) in Systemic Sclerosis

“…«Модуляция продукции дермального коллагена путем воздействия на аденозиновые А2А-рецепторы» (2010) [16].…”