Correction: Lysyl oxidases regulate fibrillar collagen remodelling in idiopathic pulmonary fibrosis (doi: 10.1242/dmm.030114)

Tjin, Gavin; White, Eric S.; Faiz, Alen; Sicard, Delphine; Tschumperlin, Daniel J.; Mahar, Annabelle; Kable, Eleanor; Burgess, Janette K.

doi:10.1242/dmm.033191

Cited by 5 publications

(4 citation statements)

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“…In IPF, LOX gene expression did not change between healthy and IPF. However, on protein level it was reported that LOX deposition was decreased in IPF tissue (Tjin et al, 2017). Therefore, it would be appropriate to determine enzyme activity as gene and protein expression do not always correlate.…”

Section: Discussionmentioning

confidence: 99%

Substrate stiffness engineered to replicate disease conditions influence senescence and fibrotic responses in primary lung fibroblasts

Blokland

Nizamoglu²,

Habibie³

et al. 2022

Front. Pharmacol.

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In fibrosis remodelling of ECM leads to changes in composition and stiffness. Such changes can have a major impact on cell functions including proliferation, secretory profile and differentiation. Several studies have reported that fibrosis is characterised by increased senescence and accumulating evidence suggests that changes to the ECM including altered composition and increased stiffness may contribute to premature cellular senescence. This study investigated if increased stiffness could modulate markers of senescence and/or fibrosis in primary human lung fibroblasts. Using hydrogels representing stiffnesses that fall within healthy and fibrotic ranges, we cultured primary fibroblasts from non-diseased lung tissue on top of these hydrogels for up to 7 days before assessing senescence and fibrosis markers. Fibroblasts cultured on stiffer (±15 kPa) hydrogels showed higher Yes-associated protein-1 (YAP) nuclear translocation compared to soft hydrogels. When looking at senescence-associated proteins we also found higher secretion of receptor activator of nuclear factor kappa-B ligand (RANKL) but no change in transforming growth factor-β1 (TGF-β1) or connective tissue growth factor (CTGF) expression and higher decorin protein deposition on stiffer matrices. With respect to genes associated with fibrosis, fibroblasts on stiffer hydrogels compared to soft had higher expression of smooth muscle alpha (α)-2 actin (ACTA2), collagen (COL) 1A1 and fibulin-1 (Fbln1) and higher Fbln1 protein deposition after 7 days. Our results show that exposure of lung fibroblasts to fibrotic stiffness activates genes and secreted factors that are part of fibrotic responses and part of the Senescence-associated secretory phenotype (SASP). This overlap may contribute to the creation of a feedback loop whereby fibroblasts create a perpetuating cycle reinforcing progression of a fibrotic response.

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Section: Discussionmentioning

confidence: 99%

Substrate stiffness engineered to replicate disease conditions influence senescence and fibrotic responses in primary lung fibroblasts

Blokland

Nizamoglu²,

Habibie³

et al. 2022

Front. Pharmacol.

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“…As mentioned before, dosing with bleomycin at night exacerbated the collagen deposition in the lungs, which agrees with our gene and protein expression results 37 . Surprisingly, we have observed the augmented protein expression of LOX in the lung injured area when dosed at 7 p.m. compared to the 7 a.m. group, and LOX is responsible for crosslinking collagen fibers to prevent the degradation of collagens 43,44 . To measure the REV-ERBα expressions in IPF patients, we stained for REV-ERBα in pulmonary fibrotic lesion areas.…”

Section: Discussionmentioning

confidence: 58%

“…Both gene and protein expressions of lysyl oxidases were upregulated in Rev-erbα Het mice infected with IAV, but not in WT mice infected with IAV. Lysyl oxidases are known to stabilize the collagen fibers via crosslinking to prevent collagen degradation and improve tissue scarring 43,44 . Other than collagen, lysyl oxidases are also responsible for crosslinking elastin, which was further upregulated in Rev-erbα Het mice infected with IAV.…”

Section: Discussionmentioning

confidence: 99%

Circadian clock molecule REV-ERBα regulates lung fibrotic progression through collagen stabilization

et al. 2023

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Molecular clock REV-ERBα is central to regulating lung injuries, and decreased REV-ERBα abundance mediates sensitivity to pro-fibrotic insults and exacerbates fibrotic progression. In this study, we determine the role of REV-ERBα in fibrogenesis induced by bleomycin and Influenza A virus (IAV). Bleomycin exposure decreases the abundance of REV-ERBα, and mice dosed with bleomycin at night display exacerbated lung fibrogenesis. Rev-erbα agonist (SR9009) treatment prevents bleomycin induced collagen overexpression in mice. Rev-erbα global heterozygous (Rev-erbα Het) mice infected with IAV showed augmented levels of collagens and lysyl oxidases compared with WT-infected mice. Furthermore, Rev-erbα agonist (GSK4112) prevents collagen and lysyl oxidase overexpression induced by TGFβ in human lung fibroblasts, whereas the Rev-erbα antagonist exacerbates it. Overall, these results indicate that loss of REV-ERBα exacerbates the fibrotic responses by promoting collagen and lysyl oxidase expression, whereas Rev-erbα agonist prevents it. This study provides the potential of Rev-erbα agonists in the treatment of pulmonary fibrosis.

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“…[ 8 ] LOXL2 plays an indispensable role in extracellular matrix remodeling, and fibril formation, and is closely associated with tissue fibrosis, tumor invasion, and metastasis. [ 9,10 ] Elevated LOXL2 levels have been reported in many fibrotic diseases, [ 11–14 ] while reduced expression has been observed in certain diseases involving impaired copper metabolism. [ 15,16 ] Therefore, inhibition of LOXL2 is considered a promising therapeutic strategy for the treatment of these diseases.…”

Section: Introductionmentioning

confidence: 99%

Conformation Changes Associated with the Formation and Activation of Lysine Tyrosylquinone of LOXL2 Studied by Metadynamics Simulation

Wang,

Lin,

et al. 2024

Advcd Theory and Sims

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Lysyl oxidase‐like 2 (LOXL2) is a Cu2+‐dependent amine oxidase that catalyzes the oxidative deamination of lysine residues of elastin and collagen to generate aldehyde groups. In the active state of LOXL2, its conserved catalytic domain has a lysine tyrosylquinone (LTQ) cofactor and a copper ion. LTQ is post‐translationally derived from Lys653 and Tyr689 of LOXL2. In this study, well‐tempered metadynamics simulations are used to investigate the conformation modulation from the inactive state to active state and obtain the free energy landscape. Interestingly, the simulations show that LTQ precursor residues cannot get close in Zn2+−bound LOXL2, whereas the copper ion binding triggers a conformation change to form an optional structure for LTQ biosynthesis. It is found that a prominent loop, consisting of residues 654–658, hinders the formation of LTQ in Zn2+−LOXL2 by preventing Lys653 from moving into active site of LOXL2, whereas this loop is relatively flexible in Cu2+−LOXL2. After the formation of LTQ, it needs to be activated by adjusting its position to be exposed to the solvent, thus allowing it to react with its substrate proteins. The results indicate that this process involves an intermediate state and that the activation of LTQ overcomes an energy barrier of 5.9 kcal mol−1.

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Correction: Lysyl oxidases regulate fibrillar collagen remodelling in idiopathic pulmonary fibrosis (doi: 10.1242/dmm.030114)

Cited by 5 publications

References 0 publications

Substrate stiffness engineered to replicate disease conditions influence senescence and fibrotic responses in primary lung fibroblasts

Substrate stiffness engineered to replicate disease conditions influence senescence and fibrotic responses in primary lung fibroblasts

Circadian clock molecule REV-ERBα regulates lung fibrotic progression through collagen stabilization

Conformation Changes Associated with the Formation and Activation of Lysine Tyrosylquinone of LOXL2 Studied by Metadynamics Simulation

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