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
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
Externí odkaz: