Lysophosphatidic acid-activated Cl− current activity in human systemic sclerosis skin fibroblasts

• Published in: Rheumatology (Oxford, England) England), 2010-12, Vol.49 (12), p.2290-2297
• Main Authors: Yin, Zhaohong, Carbone, Laura D., Gotoh, Mari, Postlethwaite, Arnold, Bolen, Alyssa L., Tigyi, Gabor J., Murakami-Murofushi, Kimiko, Watsky, Mitchell A.
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Adult; Analysis of Variance; Basic Science; Biological and medical sciences; Case-Control Studies; Cells, Cultured; Chlorides - metabolism; Cl− channel; Diseases of the osteoarticular system; Female; Fibroblast; Fibroblasts - metabolism; Humans; Lysophosphatidic acid; Lysophospholipids - metabolism; Male; Medical sciences; Middle Aged; Muscle, Smooth - metabolism; Myofibroblast; Myofibroblasts - metabolism; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Scleroderma, Systemic - metabolism; Skin - metabolism; α-Smooth muscle actin
• ISSN: 1462-0324; 1462-0332
• DOI: 10.1093/rheumatology/keq260

Objectives. SSc (scleroderma) is an often fatal disease characterized by widespread tissue fibrosis. Fibroblasts play a key role in SSc-associated fibrosis. This study was designed to determine: (i) whether fibroblasts isolated from skin of patients with SSc have increased lysophosphatidic acid-activated Cl− current (IClLPA) activity vs healthy controls; (ii) whether myofibroblast differentiation is involved in SSc skin fibrosis; and (iii) whether SSc fibroblasts have different proliferation rates vs controls. Methods. Skin biopsies were taken from involved and uninvolved skin of SSc patients and controls. Whole-cell perforated patch-clamping was used to measure IClLPA activity in fibroblasts isolated and cultured from these biopsies. Western blotting was used to measure α-smooth muscle actin (α-SMA). Proliferation was measured using a colorimetric assay. Results. Fibroblasts cultured from SSc skin show significantly increased IClLPA activity following LPA exposure compared with control skin fibroblasts. α-SMA protein was significantly increased in cultured SSc skin fibroblasts vs controls. No significant differences in proliferation rates were found. Conclusions. Elevated IClLPA activity is a hallmark of SSc skin fibroblasts. Blocking IClLPA activation may be a new therapeutic approach for treating SSc-associated fibrosis.