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 journalArticle

8 Citations (Scopus)

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

Fingerprint

Pulmonary Fibrosis
Homeostasis
Military electronic countermeasures
Collagen
Fibrosis
Stiffness
Tissue
Lung
Protein-Lysine 6-Oxidase
Idiopathic Pulmonary Fibrosis
Extracellular Matrix
Swelling
Animals
Animal Models
Chemical activation

ASJC Scopus subject areas

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

Cite this

Jones, M. G., Andriotis, O. G., Roberts, J. J. W., Lunn, K., Tear, V. J., Cao, L., ... Davies, D. E. (2018). Nanoscale dysregulation of collagen structure-function disrupts mechano-homeostasis and mediates pulmonary fibrosis. eLife, 7, [e36354]. https://doi.org/10.7554/eLife.36354

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

In: eLife, Vol. 7, e36354, 03.07.2018.

Research output: Contribution to journalArticle

Jones, MG, Andriotis, OG, Roberts, JJW, Lunn, K, Tear, VJ, Cao, L, Ask, K, Smart, DE, Bonfanti, A, Johnson, P, Alzetani, A, Conforti, F, Doherty, R, Lai, CY, Johnson, B, Bourdakos, KN, Fletcher, SV, Marshall, BG, Jogai, S, Brereton, CJ, Chee, SJ, Ottensmeier, CH, Sime, P, Gauldie, J, Kolb, M, Mahajan, S, Fabre, A, Bhaskar, A, Jarolimek, W, Richeldi, L, O’Reilly, KMA, Monk, PD, Thurner, PJ & Davies, DE 2018, 'Nanoscale dysregulation of collagen structure-function disrupts mechano-homeostasis and mediates pulmonary fibrosis', eLife, vol. 7, e36354. https://doi.org/10.7554/eLife.36354
Jones, Mark G. ; Andriotis, Orestis G. ; Roberts, James J.W. ; Lunn, Kerry ; Tear, Victoria J. ; Cao, Lucy ; Ask, Kjetil ; Smart, David E. ; Bonfanti, Alessandra ; Johnson, Peter ; Alzetani, Aiman ; Conforti, Franco ; Doherty, Regan ; Lai, Chester Y. ; Johnson, Benjamin ; Bourdakos, Konstantinos N. ; Fletcher, Sophie V. ; Marshall, Ben G. ; Jogai, Sanjay ; Brereton, Christopher J. ; Chee, Serena J. ; Ottensmeier, Christian H. ; Sime, Patricia ; Gauldie, Jack ; Kolb, Martin ; Mahajan, Sumeet ; Fabre, Aurelie ; Bhaskar, Atul ; Jarolimek, Wolfgang ; Richeldi, Luca ; O’Reilly, Katherine M.A. ; Monk, Phillip D. ; Thurner, Philipp J. ; Davies, Donna E. / Nanoscale dysregulation of collagen structure-function disrupts mechano-homeostasis and mediates pulmonary fibrosis. In: eLife. 2018 ; Vol. 7.
@article{33a918a4c5ca432c965f70954cc49199,
title = "Nanoscale dysregulation of collagen structure-function disrupts mechano-homeostasis and mediates pulmonary fibrosis",
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.",
author = "Jones, {Mark G.} and Andriotis, {Orestis G.} and Roberts, {James J.W.} and Kerry Lunn and Tear, {Victoria J.} and Lucy Cao and Kjetil Ask and Smart, {David E.} and Alessandra Bonfanti and Peter Johnson and Aiman Alzetani and Franco Conforti and Regan Doherty and Lai, {Chester Y.} and Benjamin Johnson and Bourdakos, {Konstantinos N.} and Fletcher, {Sophie V.} and Marshall, {Ben G.} and Sanjay Jogai and Brereton, {Christopher J.} and Chee, {Serena J.} and Ottensmeier, {Christian H.} and Patricia Sime and Jack Gauldie and Martin Kolb and Sumeet Mahajan and Aurelie Fabre and Atul Bhaskar and Wolfgang Jarolimek and Luca Richeldi and O’Reilly, {Katherine M.A.} and Monk, {Phillip D.} and Thurner, {Philipp J.} and Davies, {Donna E.}",
year = "2018",
month = "7",
day = "3",
doi = "10.7554/eLife.36354",
language = "English",
volume = "7",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - Nanoscale dysregulation of collagen structure-function disrupts mechano-homeostasis and mediates pulmonary fibrosis

AU - Jones, Mark G.

AU - Andriotis, Orestis G.

AU - Roberts, James J.W.

AU - Lunn, Kerry

AU - Tear, Victoria J.

AU - Cao, Lucy

AU - Ask, Kjetil

AU - Smart, David E.

AU - Bonfanti, Alessandra

AU - Johnson, Peter

AU - Alzetani, Aiman

AU - Conforti, Franco

AU - Doherty, Regan

AU - Lai, Chester Y.

AU - Johnson, Benjamin

AU - Bourdakos, Konstantinos N.

AU - Fletcher, Sophie V.

AU - Marshall, Ben G.

AU - Jogai, Sanjay

AU - Brereton, Christopher J.

AU - Chee, Serena J.

AU - Ottensmeier, Christian H.

AU - Sime, Patricia

AU - Gauldie, Jack

AU - Kolb, Martin

AU - Mahajan, Sumeet

AU - Fabre, Aurelie

AU - Bhaskar, Atul

AU - Jarolimek, Wolfgang

AU - Richeldi, Luca

AU - O’Reilly, Katherine M.A.

AU - Monk, Phillip D.

AU - Thurner, Philipp J.

AU - Davies, Donna E.

PY - 2018/7/3

Y1 - 2018/7/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85052113445&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052113445&partnerID=8YFLogxK

U2 - 10.7554/eLife.36354

DO - 10.7554/eLife.36354

M3 - Article

C2 - 29966587

AN - SCOPUS:85052113445

VL - 7

JO - eLife

JF - eLife

SN - 2050-084X

M1 - e36354

ER -