Egr-1: new conductor for the tissue repair orchestra directs harmony (regeneration) or cacophony (fibrosis)

Fibroblasts and myofibroblasts are the key effector cells executing physiological tissue repair leading to regeneration on the one hand, and pathological fibrogenesis leading to chronic fibrosing conditions on the other. Recent studies identify the multifunctional transcription factor early growth response-1(Egr-1) as an important mediator of fibroblast activation triggered by diverse stimuli. Egr-1 has potent stimulatory effects on fibrotic gene expression, and aberrant Egr-1 expression or function is associated with animal models of fibrosis and human fibrotic disorders, including emphysema, pulmonary fibrosis, pulmonary hypertension and systemic sclerosis. Pharmacological suppression or genetic targeting of Egr-1 blocks fibrotic responses in vitro and ameliorates experimental fibrosis in the skin and lung. In contrast, Egr-1 appears to act as a negative regulator of hepatic fibrosis in mouse models, suggesting a context-dependent role in fibrosis. The Egr-1-binding protein Nab2 is an endogenous inhibitor of Egr-1-mediated signalling and abrogates the stimulation of fibrotic responses induced by transforming growth factor-beta (TGF beta). Moreover, mice deficient in Nab2 show excessive collagen accumulation in the skin. These observations highlight a previously unsuspected fundamental physiological function for the Egr-1Nab2 signalling axis in regulating fibrogenesis, and suggest that Egr-1 may be a potential novel therapeutic target in human diseases complicated by fibrosis. This review summarizes recent advances in understanding the regulation and complex functional role of Egr-1 and its related proteins and inhibitors in pathological fibrosis.