Nanoscale dysregulation of collagen structure-function disrupts mechano-homeostasis and mediates pulmonary fibrosis

Mark G. Jones, Orestis G. Andriotis, James J.W. Roberts, Kerry Lunn, Victoria J. Tear, Lucy Cao, Kjetil Ask, David E. Smart, Alessandra Bonfanti, Peter Johnson, Aiman Alzetani, Franco Conforti, Regan Doherty, Chester Y. Lai, Benjamin Johnson, Konstantinos N. Bourdakos, Sophie V. Fletcher, Ben G. Marshall, Sanjay Jogai, Christopher J. BreretonSerena J. Chee, Christian H. Ottensmeier, Patricia Sime, Jack Gauldie, Martin Kolb, Sumeet Mahajan, Aurelie Fabre, Atul Bhaskar, Wolfgang Jarolimek, Luca Richeldi, Katherine M.A. O’Reilly, Phillip D. Monk, Philipp J. Thurner, Donna E. Davies

Research output: Contribution to journalArticlepeer-review

Abstract

Matrix stiffening with downstream activation of mechanosensitive pathways is strongly implicated in progressive fibrosis; however, pathologic changes in extracellular matrix ECM that initiate mechano-homeostasis dysregulation are not defined in human disease. By integrated multiscale biomechanical and biological analyses of idiopathic pulmonary fibrosis lung tissue, we identify that increased tissue stiffness is a function of dysregulated post-translational collagen cross-linking rather than any collagen concentration increase whilst at the nanometre-scale collagen fibrils are structurally and functionally abnormal with increased stiffness, reduced swelling ratio, and reduced diameter. In ex vivo and animal models of lung fibrosis, dual inhibition of lysyl oxidase-like LOXL 2 and LOXL3 was sufficient to normalise collagen fibrillogenesis, reduce tissue stiffness, and improve lung function in vivo. Thus, in human fibrosis, altered collagen architecture is a key determinant of abnormal ECM structure-function, and inhibition of pyridinoline cross-linking can maintain mechano-homeostasis to limit the self-sustaining effects of ECM on progressive fibrosis.

Original languageEnglish
Article numbere36354
JournaleLife
Volume7
DOIs
Publication statusPublished - Jul 3 2018

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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