Abstract
Fibrosing diseases are causes of morbidity and mortality around the world, and they are characterized by excessive extracellular matrix (ECM) accumulation. The bHLH transcription factor scleraxis (SCX) regulates the synthesis of ECM proteins in heart fibrosis. SCX expression was evaluated in lung fibroblasts and tissue derived from fibrotic disease patients and healthy controls. We also measured SCX in sera from 57 healthy controls, and 56 Idiopathic Pulmonary Fibrosis (IPF), 40 Hypersensitivity Pneumonitis (HP), and 100 Systemic Sclerosis (SSc) patients. We report high SCX expression in fibroblasts and tissue from IPF patients versus controls. High SCX-serum levels were observed in IPF (0.663 ± 0.559 ng/mL, p < 0.01) and SSc (0.611 ± 0.296 ng/mL, p < 0.001), versus controls (0.351 ± 0.207 ng/mL) and HP (0.323 ± 0.323 ng/mL). Serum levels of the SCX heterodimerization partner, TCF3, did not associate with fibrotic illness. IPF patients with severely affected respiratory capacities and late-stage SSc patients presenting anti-topoisomerase I antibodies and interstitial lung disease showed the highest SCX-serum levels. SCX gain-of-function induced the expression of alpha-smooth muscle actin (α-SMA/ACTA2) in fibroblasts when co-overexpressed with TCF3. As late and severe stages of the fibrotic processes correlated with high circulating SCX, we postulate it as a candidate biomarker of fibrosis and a potential therapeutic target.
Highlights
The excessive accumulation of extracellular matrix (ECM) components, such as collagen and fibronectin, in and around inflamed or damaged tissue defines fibrosis
We show that SCX expression was elevated in primary cell cultures and lung biopsies from patients with Idiopathic Pulmonary Fibrosis (IPF) in comparison to controls
When the Hypersensitivity pneumonitis (HP) population was compared to the control group, it did not show any difference in SCX concentrations; it was statistically different from the SCX values in Systemic Sclerosis (SSc) and IPF groups (Figure 4)
Summary
The excessive accumulation of extracellular matrix (ECM) components, such as collagen and fibronectin, in and around inflamed or damaged tissue defines fibrosis. No statistical differences were discovered when the SCX concentration of HP patients was further categorized by clinical data (Figure S4) These results revealed higher SCX serum concentrations in patients with fibrotic diseases (IPF and SSc) versus healthy subjects. When the HP population was compared to the control group, it did not show any difference in SCX concentrations; it was statistically different from the SCX values in SSc and IPF patients was further categorized by clinical data (Figure S4) SCX could be a therapeutic target, due to its confirmed involvement in the activation of fibrosing gene expression, together with the observed higher expression in cells, tissue, and serum derived from patients affected by severe fibrotic diseases.
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