Scraping fibrosis: expressway to the core of fibrosis

Abstract

Animal experiments using single organs as models of fibrosis spur therapeutic development toward promising targets, but testing of these therapies in human fibrosis yielded disappointing results and limited efficacy. Finding core pathways relevant in different organs that can become fibrotic will uncover molecules that will prove useful as therapeutic targets in many species, including humans. In ‘Bench to Bedside’, Scott Friedman, Wajahat Mehal and John Iredale discuss this new paradigm in fibrosis research and its potential as a new drug development approach. In ‘Bedside to Bench’, Alison Eddy peruses how the protein encoded by UMOD, a gene linked to variable risk for chronic kidney disease and hypertension in humans, may have a role in fibrosis and kidney disease. Uncovering the normal function of UMOD and its gene variants will shed light on the pathogenesis of chronic kidney disease and aid in the discovery of new targets for kidney fibrosis and hypertension.

Figure 1

Organ specialization predated mammalian speciation and provides a practical approach to uncover core and regulatory pathways as antifibrotic targets. Integrating the concept of core and regulatory pathways into an evolutionary timeline will help to establish a rationale for comparing data among different organs, showing common ancestors at successive points of evolution. At an early evolutionary point, A, an organism did not have major organs—heart, lungs and liver—but then major organs developed, B, followed by the evolution of a common ancestor into all vertebrates, including fish, birds and mammals (C–F). A strict criterion for a core fibrotic pathway would be the contribution of a molecule within a fibrosis pathway in multiple organs, rather than to fibrosis of the same organ in single or different mammals.