(Circadian) control of collagen homeostasis - new tools and insights

Over 20% of the human body's total protein mass is collagen-I (hereby referred to as “collagen”), usually in the form of centimetre-long fibrils. To understand the mechanism of uncurable collagen pathologies such as fibrosis and genetic diseases like osteogenesis imperfecta, requires a detailed understanding of how cells regulate the assembly of collagen into fibrils. Fibroblasts are canonically the sole arbiters of collagen assembly, but recent evidence suggests that immune cells, particularly macrophages, directly deposit collagen. This highlights the complexity of collagen homeostasis yet to be deciphered.

We have demonstrated that in fibroblasts, the circadian clock regulates collagen homeostasis, and endocytic recycling drives collagen fibrillogenesis, a process that is enhanced in collagen pathologies. We hypothesize that the endosome determines collagen fates and developed new mass spectrometry-based proteomics technique, to investigate the intracellular proteins involved in collagen endocytic trafficking and identified non-conventional pathways. New data demonstrated crosstalk between cell types that impacts on collagen fibrillogenesis through circadian regulation. However, this dependency on circadian rhythm may not be universal, as mathematical modelling in embryonic tissues suggested a quick crystallisation event for rapid fibrillogenesis, which is supported by data from laser-capture microdissection coupled with mass spectrometry analysis. We are also developing new molecular tools to help unravel the dynamics of collagen, from molecular up to tissue level, in order to understand the fundamental biology of collagen, and to identify new therapeutic strategies for collagen pathologies.