Exploring Extracellular Matrix Crosslinking as a Therapeutic Approach to Fibrosis

Lloyd, Sarah M.; He, Yupeng

doi:10.3390/cells13050438

Cited by 4 publications

(2 citation statements)

References 103 publications

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“…Members of the copper-dependent lysyl oxidase family ( LOX1 , LOXL1 , LOXL2 , LOXL3 , and LOXL4 ) orchestrate this redox process: initially, LOX oxidatively deaminates lysine or hydroxylysine residues in collagen and elastin proteins, transforming them into allysine residues. Subsequently, two allysine residues condense in a variety of aldol dimers [ 143 ], which seems to be the major stable cross-linking bond at both ends of the type I collagen molecule in tissues that use the lysine aldehyde pathway [ 144 ]. However, it has been contested [ 145 ].…”

Section: Indirect Targetingmentioning

confidence: 99%

The Versatility of Collagen in Pharmacology: Targeting Collagen, Targeting with Collagen

Revert-Ros,

Ventura,

Prieto-Ruiz

et al. 2024

IJMS

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Collagen, a versatile family of proteins with 28 members and 44 genes, is pivotal in maintaining tissue integrity and function. It plays a crucial role in physiological processes like wound healing, hemostasis, and pathological conditions such as fibrosis and cancer. Collagen is a target in these processes. Direct methods for collagen modulation include enzymatic breakdown and molecular binding approaches. For instance, Clostridium histolyticum collagenase is effective in treating localized fibrosis. Polypeptides like collagen-binding domains offer promising avenues for tumor-specific immunotherapy and drug delivery. Indirect targeting of collagen involves regulating cellular processes essential for its synthesis and maturation, such as translation regulation and microRNA activity. Enzymes involved in collagen modification, such as prolyl-hydroxylases or lysyl-oxidases, are also indirect therapeutic targets. From another perspective, collagen is also a natural source of drugs. Enzymatic degradation of collagen generates bioactive fragments known as matrikines and matricryptins, which exhibit diverse pharmacological activities. Overall, collagen-derived peptides present significant therapeutic potential beyond tissue repair, offering various strategies for treating fibrosis, cancer, and genetic disorders. Continued research into specific collagen targeting and the application of collagen and its derivatives may lead to the development of novel treatments for a range of pathological conditions.

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Section: Indirect Targetingmentioning

confidence: 99%

The Versatility of Collagen in Pharmacology: Targeting Collagen, Targeting with Collagen

Revert-Ros,

Ventura,

Prieto-Ruiz

et al. 2024

IJMS

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“…Iso/desmosine species are reported to be exclusive to elastin cross-linking 4 . Several excellent reviews are available for further information about this class of enzymes and the resulting cross-linked species [5][6][7][8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

Assessing Heterogeneity in the N-Telopeptides of Type I Collagen by Mass Spectrometry

Darula,

McCabe,

Barrett

et al. 2024

Preprint

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Collagen cross-links created by the lysyl oxidase and lysyl hydroxylase families of enzymes are a significant contributing factor to the biomechanical strength and rigidity of tissues, which in turn influence cell signaling and ultimately cell phenotype. In the clinic, the proteolytically liberated N-terminal cross-linked peptide of collagen I (NTX) is used as a biomarker of bone and connective tissue turnover, which is altered in several disease processes. Despite the clinical utility of these collagen breakdown products, the majority of the cross-linked peptide species have not been identified in proteomic datasets. Here we evaluate several parameters for the preparation and identification of these peptides from the collagen I-rich Achilles tendon. Our refined approach involving chemical digestion for protein solubilization coupled with mass spectrometry allows for the identification of the NTX cross-links in a range of modification states. Based on the specificity of the enzymatic cross-linking reaction we utilized follow-up variable modification searches to facilitate identification with a wider range of analytical workflows. We then applied a spectral library approach to identify differences in collagen cross-links in bovine pulmonary hypertension. The presented method offers unique opportunities to understand extracellular matrix remodeling events in development, aging, wound healing, and fibrotic disease that modulate collagen architecture through lysyl-hydroxylase and lysyl-oxidase enzymes.

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Investigation of the Urinary Peptidome to Unravel Collagen Degradation in Health and Kidney Disease

Mina,

Iglesias‐Martinez,

Ley

et al. 2024

Proteomics

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Naturally occurring fragments of collagen type I alpha 1 chain (COL1A1) have been previously associated with chronic kidney disease (CKD), with some fragments showing positive and others negative associations. Using urinary peptidome data from healthy individuals (n = 1131) and CKD patients (n = 5585) this aspect was investigated in detail. Based on the hypothesis that many collagen peptides are derived not from the full, mature collagen molecule, but from (larger) collagen degradation products, relationships between COL1A1 peptides containing identical sequences were investigated, with the smaller (offspring) peptide being a possible degradation product of the larger (parent) one. The strongest correlations were found for relationships where the parent differed by a maximum of three amino acids from the offspring, indicating an exopeptidase‐regulated stepwise degradation process. Regression analysis indicated that CKD affects this degradation process. A comparison of matched CKD patients and control individuals (n = 612 each) showed that peptides at the start of the degradation process were consistently downregulated in CKD, indicating an attenuation of COL1A1 endopeptidase‐mediated degradation. However, as these peptides undergo further degradation, likely mediated by exopeptidases, this downregulation can become less significant or even reverse, leading to an upregulation of later‐stage fragments and potentially explaining the inconsistencies observed in previous studies.

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Exploring Extracellular Matrix Crosslinking as a Therapeutic Approach to Fibrosis

Cited by 4 publications

References 103 publications

The Versatility of Collagen in Pharmacology: Targeting Collagen, Targeting with Collagen

The Versatility of Collagen in Pharmacology: Targeting Collagen, Targeting with Collagen

Assessing Heterogeneity in the N-Telopeptides of Type I Collagen by Mass Spectrometry

Investigation of the Urinary Peptidome to Unravel Collagen Degradation in Health and Kidney Disease

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