期刊
RHEUMATOLOGY
卷 51, 期 12, 页码 2146-2154出版社
OXFORD UNIV PRESS
DOI: 10.1093/rheumatology/kes234
关键词
adhesion; integrin; ROS; CCN2; FAK; alpha-SMA; collagen
类别
资金
- Canadian Institute of Heath Research (CIHR)
- Scleroderma Society of Ontario
- Scleroderma Society
- Arthritis Research Foundation
- CIHR Strategic Training Initiative in Health Research/Joint Motion Program
- Canadian Scleroderma Research Group
Objective. Fibrotic diseases such as SSc (systemic sclerosis, scleroderma) are characterized by the abnormal presence of the myofibroblast, a specialized type of fibroblast that overexpresses the highly contractile protein alpha-smooth muscle actin. Myofibroblasts display excessive adhesive properties and hence exert a potent mechanical force. We aim to identify the precise contribution of adhesive signalling, which requires integrin-mediated activation of focal adhesion kinase (FAK)/src, to fibrogenic gene expression in normal and fibrotic SSc fibroblasts. Methods. We subject either FAK wild-type and knockout fibroblasts or normal and SSc fibroblasts treated with FAK/src inhibitors to real-time polymerase chain, western blot, cell migration and collagen gel contraction analyses. Results. FAK operates downstream of both integrin beta 1 and reactive oxygen species (ROS) to promote the expression of genes involved in matrix production and remodelling, including CCN2, alpha-smooth muscle actin and type I collagen. Blocking either FAK/src with PP2 or ROS with N-acetyl cysteine alleviates the elevated contractile and migratory capability of lesional SSc dermal fibroblasts. Conclusions. Excessive adhesive signalling is intimately involved with the fibrotic phenotype of lesional SSc fibroblasts; blocking adhesive signalling or ROS generation may be beneficial in controlling the fibrosis observed in SSc.
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