Extracellular SPARC cooperates with TGF-β signalling to induce pro-fibrotic activation of systemic sclerosis patient dermal fibroblasts
Autor: | Kris A. Reedquist, Andrea Ottria, Wioleta Marut, Beatriz Malvar Fernandez, Timothy R D J Radstake, Samuel Garcia, Barbara Giovannone, Tiago Carvalheiro |
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Rok vydání: | 2019 |
Předmět: |
Transcriptional Activation
TGF-β dermal fibroblasts 0301 basic medicine Inflammation Transforming Growth Factor beta1 Extracellular matrix 03 medical and health sciences 0302 clinical medicine Rheumatology Fibrosis medicine Humans Osteonectin Pharmacology (medical) RNA Messenger signalling skin and connective tissue diseases Fibroblast Cells Cultured AcademicSubjects/MED00360 Skin Extracellular Matrix Proteins Scleroderma Systemic integumentary system biology business.industry fibrosis SPARC Fibroblasts Clinical Science medicine.disease Extracellular Matrix Fibronectin 030104 developmental biology medicine.anatomical_structure Case-Control Studies 030220 oncology & carcinogenesis Cancer research biology.protein medicine.symptom Signal transduction business Tyrosine kinase SSc Signal Transduction Transforming growth factor |
Zdroj: | Rheumatology (Oxford, England) |
ISSN: | 1462-0332 1462-0324 |
Popis: | Objectives SSc is an autoimmune disease characterized by inflammation, vascular injury and excessive fibrosis in multiple organs. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein that regulates processes involved in SSc pathology, such as inflammation and fibrosis. In vivo and in vitro studies have implicated SPARC in SSc, but it is unclear if the pro-fibrotic effects of SPARC on fibroblasts are a result of intracellular signalling or fibroblast interactions with extracellular SPARC hampering further development of SPARC as a potential therapeutic target. This study aimed to analyse the potential role of exogenous SPARC as a regulator of fibrosis in SSc. Methods Dermal fibroblasts from both healthy controls and SSc patients were stimulated with SPARC alone or in combination with TGF-β1, in the absence or presence of a TGF receptor 1 inhibitor. mRNA and protein expression of extracellular matrix components and other fibrosis-related mediators were measured by quantitative PCR and western blot. Results Exogenous SPARC induced mRNA and protein expression of collagen I, collagen IV, fibronectin 1, TGF-β and SPARC by dermal fibroblasts from SSc patients, but not from healthy controls. Importantly, exogenous SPARC induced the activation of the tyrosine kinase SMAD2 and pro-fibrotic gene expression induced by SPARC in SSc fibroblasts was abrogated by inhibition of TGF-β signalling. Conclusion These results indicate that exogenous SPARC is an important pro-fibrotic mediator contributing to the pathology driving SSc but in a TGF-β dependent manner. Therefore, SPARC could be a promising therapeutic target for reducing fibrosis in SSc patients, even in late states of the disease. |
Databáze: | OpenAIRE |
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