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 language | English |
|---|---|
| Article number | e36354 |
| Journal | eLife |
| Volume | 7 |
| DOIs | |
| Publication status | Published - Jul 3 2018 |
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ASJC Scopus subject areas
- Neuroscience(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)
Cite this
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 journal › Article
}
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.
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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 -