The molecular basis of circadian clock regulation of collagen homeostasis: implications for fibrosis

This presentation was given by Karl Kadler, Director of Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, UK. It was presented at the ISN’s Forefronts Symposium 2015 taking place in Shenzhen, China, on October 22-25, 2015 for which the theme was ‘Immunomodulation of Cardio-Renal Function’ during Session 9: Immunity, Fibrosis and Kidney Disease.

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Presentation Abstract: 

Fibrosis is a feature of most chronic diseases in which excess or ectopic deposition of type I collagen fibrils replaces specialised tissue, often with lethal outcomes.  Although recognized for some time to be fundamental to understanding the pathophysiology of fibrosis, the molecular mechanisms of collagen fibril formation remain unclear. This is because the large and insoluble collagen fibrils are refractory to conventional biochemical and molecular approaches.  

We have made progress in understanding how cells synthesise collagen fibrils in vivo by studying tendon.  The highly-organised 3D matrix in tendon is ideal for studying all stages and timing of collagen fibrillogenesis (Kalson et al., PNAS 2014). The principles of fibril assembly revealed in tendon are common to all collagen fibril-containing tissues and during fibrosis. Therefore the information we are obtaining from studies of tendon might be directly relevant to collagen fibril formation during kidney fibrosis. 

In my talk I will describe the use of serial block face-scanning electron microscopy (SBF-SEM) to studies of collagen fibrillogenesis in vivo (Starborg et al., Nat Protoc 2013).  I will show how this technique can be used to obtain high-resolution images of cells synthesising collagen fibrils at sites on the plasma membrane.  I will show the application of SBF-SEM in the discovery of a novel two-stage model for fibrous tissue expansion (Kalson et al., eLIFE, 2015). 

Work in my lab has also shown that tendon is a peripheral clock tissue in which the expression of 750 genes is regulated on a 24-hourly rhythm (Scientific Reports 2014).  Recent work has shown that disruption of the tendon clock leads to abnormal collagen fibril formation, resulting in fibrosis. We have identified some of the key regulatory genes. I will show unpublished data on the importance of some of the genes we have identified in the regulation of collagen fibril synthesis and turnover, and how disruption of their expression leads to fibrosis.