S.7.1 Ultrasonographic hand features in systemic sclerosis and correlates with clinical, biological and radiographic findings

Abstract

increased synthesis of extracellular matrix components is a major hallmark of SSc. Focal adhesion kinase (FAK), an essential component in the extracellular matrix-mediated adhesive signalling, was found to be hyperactivated in lesional scleroderma fibroblasts, and therefore this kinase has been hypothesized to be a key mediator of this disease. The present study was undertaken to investigate the role of FAK signalling in SSc and to evaluate the therapeutic potential of FAK inhibition for the treatment of lung fibrosis. FAK activity and expression is up-regulated in lungs of mice subjected to non-infectious injury and in human idiopathic pulmonary fibrosis (IPF) or scleroderma (SSc) patients as investigated by immunohistochemistry (IHC). Genetic or pharmacological targeting of FAK abrogates fibrogenesis in the bleomycin-induced lung fibrosis model as quantitated by IHC and collagen content. In vitro, FAK activation is required for endothelin-1induced myofibroblast differentiation, extracellular matrix (ECM) production and contractility as tested by western blot, real-time PCR and gel contraction assay. These results implicate FAK as a central mediator of fibrogenesis, and highlight this kinase as a potential therapeutic target in fibrotic diseases. These findings might have direct translational implications because different inhibitors of FAK are available and have yielded promising results in cancer trials.