Enzymatic cross-linking of collagens in organ fibrosis – resolution and assessment

Pehrsson, Martin; Mortensen, Joachim Høg; Manon‐Jensen, Tina; Bay‐Jensen, Anne‐Christine; Karsdal, Morten A.; Davies, Michael J.

doi:10.1080/14737159.2021.1962711

Cited by 27 publications

(32 citation statements)

References 196 publications

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“…Enzyme-generated crosslinks are critical to the formation of many three-dimensional structures as these provide strength and rigidity, if biologically required. Examples include crosslinks formed within the extracellular matrix (ECM) of most, if not all, tissues, such as those formed between matrix proteins, and particularly collagens by the copper-containing lysyl oxidase (LOX) and LOX-like (LOXL) enzymes (reviewed in [ 11 ]). LOX oxidizes specific lysine (Lys) and hydroxylysine residues to carbonyls that undergo subsequent reactions to crosslink collagens (e.g., types I and III) and elastin [ 11 , 12 , 13 , 14 ].…”

Section: Enzymatic Protein Crosslinkingmentioning

confidence: 99%

“…Examples include crosslinks formed within the extracellular matrix (ECM) of most, if not all, tissues, such as those formed between matrix proteins, and particularly collagens by the copper-containing lysyl oxidase (LOX) and LOX-like (LOXL) enzymes (reviewed in [ 11 ]). LOX oxidizes specific lysine (Lys) and hydroxylysine residues to carbonyls that undergo subsequent reactions to crosslink collagens (e.g., types I and III) and elastin [ 11 , 12 , 13 , 14 ]. In contrast, the LOXL family of enzymes acts on collagen type IV and drives the assembly of basement membranes [ 11 , 15 ].…”

Section: Enzymatic Protein Crosslinkingmentioning

confidence: 99%

“…LOX oxidizes specific lysine (Lys) and hydroxylysine residues to carbonyls that undergo subsequent reactions to crosslink collagens (e.g., types I and III) and elastin [ 11 , 12 , 13 , 14 ]. In contrast, the LOXL family of enzymes acts on collagen type IV and drives the assembly of basement membranes [ 11 , 15 ]. Other enzymes also contribute to collagen crosslinking in the ECM with peroxidasin, a member of the heme peroxidase superfamily, mediating the formation of highly specific methionine (Met) to Lys crosslinks within the NC1 domains on collagen via generation of the oxidant hypobromous acid (HOBr).…”

Section: Enzymatic Protein Crosslinkingmentioning

confidence: 99%

“…In the case of the Cu 2+ -dependent LOX/LOXL reactions and collagen crosslinking, the initial Schiff base adducts can undergo multiple further condensation reactions that allow several chains to be linked together via a single site [ 11 ]. Thus, there is abundant evidence for lysyl pyrrole, hydroxylysyl pyrrole, lysyl pyridinoline and hydroxylysyl pyridinoline species involving three or four collagen chains [ 169 ].…”

Section: Types Of Crosslinks Detected Within and Between Proteins And Peptidesmentioning

confidence: 99%

“…The mechanism of formation of these species involves the initial formation of a two-chain crosslink and then further condensation with a Lys/hydroxy-Lys on third and fourth chains. These species are critical to the correct assembly of collagen-containing extracellular matrices in tissues [ 11 ].…”

Section: Types Of Crosslinks Detected Within and Between Proteins And Peptidesmentioning

confidence: 99%

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Oxidative Crosslinking of Peptides and Proteins: Mechanisms of Formation, Detection, Characterization and Quantification

et al. 2021

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Covalent crosslinks within or between proteins play a key role in determining the structure and function of proteins. Some of these are formed intentionally by either enzymatic or molecular reactions and are critical to normal physiological function. Others are generated as a consequence of exposure to oxidants (radicals, excited states or two-electron species) and other endogenous or external stimuli, or as a result of the actions of a number of enzymes (e.g., oxidases and peroxidases). Increasing evidence indicates that the accumulation of unwanted crosslinks, as is seen in ageing and multiple pathologies, has adverse effects on biological function. In this article, we review the spectrum of crosslinks, both reducible and non-reducible, currently known to be formed on proteins; the mechanisms of their formation; and experimental approaches to the detection, identification and characterization of these species.

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Section: Enzymatic Protein Crosslinkingmentioning

confidence: 99%

Section: Enzymatic Protein Crosslinkingmentioning

confidence: 99%

Section: Enzymatic Protein Crosslinkingmentioning

confidence: 99%

Section: Types Of Crosslinks Detected Within and Between Proteins And Peptidesmentioning

confidence: 99%

Section: Types Of Crosslinks Detected Within and Between Proteins And Peptidesmentioning

confidence: 99%

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Oxidative Crosslinking of Peptides and Proteins: Mechanisms of Formation, Detection, Characterization and Quantification

et al. 2021

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Regulating Lymphatic Vasculature in Fibrosis: Understanding the Biology to Improve the Modeling

Ruliffson

Whittington

2023

Advanced Biology

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Fibrosis occurs in many chronic diseases with lymphatic vascular insufficiency (e.g., kidney disease, tumors, and lymphedema). New lymphatic capillary growth can be triggered by fibrosis‐related tissue stiffening and soluble factors, but questions remain for how related biomechanical, biophysical, and biochemical cues affect lymphatic vascular growth and function. The current preclinical standard for studying lymphatics is animal modeling, but in vitro and in vivo outcomes often do not align. In vitro models can also be limited in their ability to separate vascular growth and function as individual outcomes, and fibrosis is not traditionally included in model design. Tissue engineering provides an opportunity to address in vitro limitations and mimic microenvironmental features that impact lymphatic vasculature. This review discusses fibrosis‐related lymphatic vascular growth and function in disease and the current state of in vitro lymphatic vascular models while highlighting relevant knowledge gaps. Additional insights into the future of in vitro lymphatic vascular models demonstrate how prioritizing fibrosis alongside lymphatics will help capture the complexity and dynamics of lymphatics in disease. Overall, this review aims to emphasize that an advanced understanding of lymphatics within a fibrotic disease—enabled through more accurate preclinical modeling—will significantly impact therapeutic development toward restoring lymphatic vessel growth and function in patients.

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Deciphering UVA/Riboflavin Collagen Crosslinking: A Pathway to Improve Biomedical Materials

Fan,

Jung,

Herrmann

et al. 2024

Adv Funct Materials

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Collagen crosslinking employing ultraviolet A rays and riboflavin (UVA/R) has emerged as a pivotal technique in clinical therapies, especially in ophthalmology since the 1990s. Despite its clinical adoption, the lack of clarity of the detailed mechanism and the imperative for a refined manufacturing process necessitates further investigation. This study advances the understanding of UVA/R crosslinked collagen, concentrating on identifying the primary crosslinking sites using seven synthetic peptides and exploring the pathways of riboflavin‐mediated crosslinking. The results demonstrate that tyrosine residues are key crosslinking sites, and riboflavin plays a dual role as both a catalyst and a competitive inhibitor in the crosslinking process. Furthermore, the UVA/R crosslinked collagen matrix exhibits a more harmonious balance between stability and degradability compared with chemically crosslinked collagen matrices, coupled with superior mechanical properties and augmented biocompatibility. In vivo experiments further validate its excellent biocompatibility, reduced tissue inflammation, and promotion of tissue regeneration. The research provides crucial insights into collagen crosslinking mechanisms, paving the way for the development of sophisticated collagen‐based biomaterials tailored for biomedical applications.

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Enzymatic cross-linking of collagens in organ fibrosis – resolution and assessment

Cited by 27 publications

References 196 publications

Oxidative Crosslinking of Peptides and Proteins: Mechanisms of Formation, Detection, Characterization and Quantification

Oxidative Crosslinking of Peptides and Proteins: Mechanisms of Formation, Detection, Characterization and Quantification

Regulating Lymphatic Vasculature in Fibrosis: Understanding the Biology to Improve the Modeling

Deciphering UVA/Riboflavin Collagen Crosslinking: A Pathway to Improve Biomedical Materials

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