https://orcid.org/0000-0002-5196-6919
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ABSTRACT
Introduction: Enzymatic cross-linking of the collagens within the extracellular matrix (ECM) catalyzed by enzymes such as lysyl oxidase (LOX) and lysyl oxidase like-enzymes 1–4 (LOXL), transglutaminase 2 (TG2), and peroxidasin (PXDN) contribute to fibrosis progression through extensive collagen cross-linking. Studies in recent years have begun elucidating the important role of collagen cross-linking in perpetuating progression of organ fibrosis independently of inflammation through an increasingly stiff and noncompliant ECM. Therefore, collagen cross-linking and the cross-linking enzymes have become new targets in anti-fibrotic therapy as well as targets of novel biomarkers to properly assess resolution of the fibrotic ECM.
Areas covered: The enzymatic actions of enzymes catalyzing collagen cross-linking and their relevance in organ fibrosis. Potential biomarkers specifically quantifying proteolytic fragments of collagen cross-linking is discussed based on Pubmed search done in November 2020 as well as the authors knowledge.
Expert opinion: Current methods for the assessment of fibrosis involve the use of invasive and/or cumbersome and expensive methods such as tissue biopsies. Thus, an unmet need exists for the development and validation of minimally invasive biomarkers of proteolytic fragments of cross-linked collagens. These biomarkers may aid in the development and proper assessment of fibrosis resolution in coming years.
Article highlights
Collagen hydroxylation and subsequent cross-linking are catalyzed by enzymes such as, LHs, LOX(L)s, TG2, and PXDN. These processes are critical for structural and mechanical tissue properties.
The LOX(L)s constitute the primary enzymes catalyzing collagen cross-linking, whereas PXDN catalyzed cross-linking is suggested to be selective towards type IV collagen cross-linking.
Prolonged and extensive enzymatic collagen cross-linking by myofibroblast during fibrosis is suggested a key driver of fibrosis progression
Growing evidence underlining the importance of pro-fibrotic collagen cross-linking in organ fibrosis has led to an increase in anti-cross-linking therapeutics
Biomarkers specifically targeting protein fragments of cross-linked collagens or enzymes catalyzing collagen cross-linking could provide novel tools for organ fibrosis diagnosis, prognosis, and efficacy of treatment
Abbreviations
| α smooth muscle actin: α-SMA | = | |
| Advanced glycation end-products: AGE | = | |
| Allysine: LysAld | = | |
| Basement membrane: BM | = | |
| Bone morphogenic protein-1: BMP-1 | = | |
| Bromide: Br− | = | |
| Calcium: Ca2+ | = | |
| Copper: Cu2+ | = | |
| Cysteine: Cys | = | |
| Extracellular matrix: ECM | = | |
| Glutamine: Gln | = | |
| Hydrogen peroxide: H2O2 | = | |
| Hydroxyallysine: HylAld | = | |
| Hydroxylysine: Hyl | = | |
| HylAld derived collagen cross-links: HLCCs | = | |
| Hypobromous acid: HOBr | = | |
| Integrin-associated-complexes: IACs | = | |
| Iron: Fe2+ | = | |
| Latent transforming growth factor-β1 binding protein: LTBP-1 | = | |
| LysAld derived collagen cross-links: LCCs | = | |
| Lysine: Lys | = | |
| Lysine tyrosylquinone: LTQ | = | |
| Lysyl hydroxylases: LHs | = | |
| Lysyl oxidase: LOX | = | |
| Lysyl oxidase like-enzymes 1-4: LOX(L)s | = | |
| Matrix metalloproteases: MMPs | = | |
| Methionine: Met | = | |
| Myocardin-related transcription factor: MRTF | = | |
| Non-collagenous: NC | = | |
| Peroxidasin: PXDN | = | |
| Post-translational modifications: PTMs | = | |
| Rho-associated protein kinase: ROCK | = | |
| Transcriptional coactivation with PDZ-binding motif: TAZ | = | |
| Transforming growth factor-β: TGF-β | = | |
| Transglutaminase 2: TG2 | = | |
| Yes-associated protein: YAP | = |
Declaration of interest
M Pehrsson is affiliated with Nordic Biosciences A/S. JH Mortensen is employed by Nordic Biosciences A/S. T Manon-Jensen, AC Bay-Jensen, & MA Karsdal are employed by and have stocks in Nordic Biosciences A/S. The author(s) have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Supplementary material
Supplemental data for this article can be accessed here.