Organ scarring, referred to as fibrosis, results from a failed wound-healing response to chronic tissue injury and is characterised by the aberrant accumulation of various extracellular matrix (ECM) components. Once established, fibrosis is recognised as a hallmark of stiffened and dysfunctional tissues, hence, various fibrosis-related diseases collectively contribute to high morbidity and mortality in developed countries. Despite this, these diseases are ineffectively treated by currently-available medications. The pro-fibrotic cytokine, transforming growth factor (TGF)-β1, has emerged as the master regulator of fibrosis progression, owing to its ability to promote various factors and processes that facilitate rapid ECM synthesis and deposition, whilst negating ECM degradation. TGF-β1 signal transduction is tightly controlled by canonical (Smad-dependent) and non-canonical (MAP kinase- and Rho-associated protein kinase-dependent) intracellular protein activity, whereas its pro-fibrotic actions can also be facilitated by the Wnt/β-catenin pathway. This review outlines the pathological sequence of events and contributing roles of TGF-β1 in the progression of fibrosis, and how the Wnt/β-catenin pathway contributes to tissue repair in acute disease settings, but to fibrosis and related tissue dysfunction in synergy with TGF-β1 in chronic diseases. It also outlines the anti-fibrotic and related signal transduction mechanisms of the hormone, relaxin, that are mediated via its negative modulation of TGF-β1 and Wnt/β-catenin signaling, but through the promotion of Wnt/β-catenin activity in acute disease settings. Collectively, this highlights that the crosstalk between TGF-β1 signal transduction and the Wnt/β-catenin cascade may provide a therapeutic target that can be exploited to broadly treat and reverse established fibrosis.
Keywords: Fibrosis; RXFP1; Relaxin; TGF-beta1; Wnt/beta-catenin.
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