The procollagen N-proteinases ADAMTS2, 3 and 14 in pathophysiology

Bekhouche, Mourad; Colige, Alain

doi:10.1016/j.matbio.2015.04.001

Cited by 120 publications

(94 citation statements)

References 42 publications

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“…More recently, studies have argued for ADAMTS involvement in a positive TGF β feedback loop, whereby ADAMTS2 is induced by but also targets TGF β [80, 81]. To date the best-described inhibitor of ADAMTS is TIMP3 [70, 82, 83], which we found to be significantly downregulated in our microarray data in both centre (p = 0.026) and margin (p = 0.037) Kd. Interestingly, we identified upregulation of disintegrin and metalloproteinase ADAM12 , the member of a family closely related to the ADAMTS group of proteins and which was also suggested to be involved in a positive feedback loop with TGF β, resulting in continuous collagen production [84].…”

Section: Resultssupporting

confidence: 48%

“…Of these, ADAMTS14 and ADAMTS2 were the most significantly upregulated and are both pro-collagen N peptidases (pNP), responsible for the cleavage of type I and II pro-collagen necessary for fibril assembly and collagen biosynthesis ( Fig 5B ) [70, 71]. Interestingly, BMP1 , responsible for the cleavage of the C-proteinase is also upregulated in centre and margin Kd ( Fig 5B ) [72].…”

Section: Resultsmentioning

confidence: 99%

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Site-specific gene expression profiling as a novel strategy for unravelling keloid disease pathobiology

et al. 2017

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Keloid disease (KD) is a fibroproliferative cutaneous tumour characterised by heterogeneity, excess collagen deposition and aggressive local invasion. Lack of a validated animal model and resistance to a multitude of current therapies has resulted in unsatisfactory clinical outcomes of KD management. In order to address KD from a new perspective, we applied for the first time a site-specific in situ microdissection and gene expression profiling approach, through combined laser capture microdissection and transcriptomic array. The aim here was to analyse the utility of this approach compared with established methods of investigation, including whole tissue biopsy and monolayer cell culture techniques. This study was designed to approach KD from a hypothesis-free and compartment-specific angle, using state-of-the-art microdissection and gene expression profiling technology. We sought to characterise expression differences between specific keloid lesional sites and elucidate potential contributions of significantly dysregulated genes to mechanisms underlying keloid pathobiology, thus informing future explorative research into KD. Here, we highlight the advantages of our in situ microdissection strategy in generating expression data with improved sensitivity and accuracy over traditional methods. This methodological approach supports an active role for the epidermis in the pathogenesis of KD through identification of genes and upstream regulators implicated in epithelial-mesenchymal transition, inflammation and immune modulation. We describe dermal expression patterns crucial to collagen deposition that are associated with TGFβ-mediated signalling, which have not previously been examined in KD. Additionally, this study supports the previously proposed presence of a cancer-like stem cell population in KD and explores the possible contribution of gene dysregulation to the resistance of KD to conventional therapy. Through this innovative in situ microdissection gene profiling approach, we provide better-defined gene signatures of distinct KD regions, thereby addressing KD heterogeneity, facilitating differential diagnosis with other cutaneous fibroses via transcriptional fingerprinting, and highlighting key areas for future KD research.

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Section: Resultssupporting

confidence: 48%

Section: Resultsmentioning

confidence: 99%

Site-specific gene expression profiling as a novel strategy for unravelling keloid disease pathobiology

et al. 2017

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“…2 A ). The Proline in the P1 position was also previously found in the N‐propeptide cleavage site (1), but it is located 3 residues N terminal to the site identified by N terminomics. The discrepancy between the 2 approaches could be related to the presence of BMP1 in the conditioned culture medium, the activity of which is possibly increased when there is prior cleavage by ADAMTS.…”

Section: Resultsmentioning

confidence: 76%

“…The cleavage of these N‐ and C‐terminal propeptides is required to allow the spontaneous assembly of mature trimers into perfectly organized collagen fibrils and fibers. The procollagen N ‐proteinases (pNPs), a disintegrin and metalloproteinase with thrombospondin type I motif (ADAMTS)2, 3, and 14, are principally known for their ability to cleave the amino‐propeptide of fibrillar collagen precursors (types I–III, and V) (1). The critical role of ADAMTS2 in this process is illustrated in the dermatosparactic type of Ehlers‐Danlos syndrome, a genetic disease caused by mutations in the Adamts2 gene.…”

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confidence: 99%

Determination of the substrate repertoire of ADAMTS2, 3, and 14 significantly broadens their functions and identifies extracellular matrix organization and TGF‐β signaling as primary targets

et al. 2016

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A disintegrin and metalloproteinase with thrombospondin type I motif (ADAMTS)2, 3, and 14 are collectively named procollagen N-proteinases (pNPs) because of their specific ability to cleave the aminopropeptide of fibrillar procollagens. Several reports also indicate that they could be involved in other biological processes, such as blood coagulation, development, and male fertility, but the potential substrates associated with these activities remain unknown. Using the recently described N-terminal amine isotopic labeling of substrate approach, we analyzed the secretomes of human fibroblasts and identified 8, 17, and 22 candidate substrates for ADAMTS2, 3, and 14, respectively. Among these newly identified substrates, many are components of the extracellular matrix and/or proteins related to cell signaling such as latent TGF-β binding protein 1, TGF-β RIII, and dickkopf-related protein 3. Candidate substrates for the 3 ADAMTS have been biochemically validated in different contexts, and the implication of ADAMTS2 in the control of TGF-β activity has been further demonstrated in human fibroblasts. Finally, the cleavage site specificity was assessed showing a clear and unique preference for nonpolar or slightly hydrophobic amino acids. This work shows that the activities of the pNPs extend far beyond the classically reported processing of the aminopropeptide of fibrillar collagens and that they should now be considered as multilevel regulators of matrix deposition and remodeling.-Bekhouche, M., Leduc, C., Dupont, L., Janssen, L., Delolme, F., Vadon-Le Goff, S., Smargiasso, N., Baiwir, D., Mazzucchelli, G., Zanella-Cleon, I., Dubail, J., De Pauw, E., Nusgens, B., Hulmes, D. J. S., Moali, C., Colige, A. Determination of the substrate repertoire of ADAMTS2, 3, and 14 significantly broadens their functions and identifies extracellular matrix organization and TGF-β signaling as primary targets.

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“…Interestingly, no difference in collagen amount has been noticed in meprins αβ KO mice, which could be explained with other proteases being activated as a compensatory mechanism. Several proteases, such as BMP-124, ADAMTSs37 or furin like pro-protein convertase38 are involved in pro-collagen processing. Even though we did not observe any difference in the mRNA expression level of BMP-1, we cannot exclude that BMP-1 or other protease´s activity is more pronounced in the αβ KO mice.…”

Section: Discussionmentioning

confidence: 99%

Meprin β contributes to collagen deposition in lung fibrosis

Biasin

Wygrecka

Marsh

et al. 2017

Sci Rep

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Lung fibrosis is a severe disease characterized by epithelial cell injury, inflammation and collagen deposition. The metalloproteases meprinα and meprinβ have been shown to enhance collagen maturation and inflammatory cell infiltration via cleavage of cell-cell contact molecules; therefore we hypothesized that meprins could play a role in lung fibrosis. An exhaustive characterization of bleomycin-treated meprinα, meprinβ and the double meprinsαβ knock-out (KO) with respective wt-littermates was performed by using several different methods. We observed no difference in lung function parameters and no change in inflammatory cells infiltrating the lung between wt and all meprins KO mice after 14 days bleomycin. No difference in epithelial integrity as assessed by e-cadherin protein level was detected in bleomycin-treated lungs. However, morphological analysis in the bleomycin-treated mice revealed decrease collagen deposition and tissue density in meprinβ KO, but not in meprinα and meprinαβ KO mice. This finding was accompanied by localization of meprinβ to epithelial cells in regions with immature collagen in mice. Similarly, in human IPF lungs meprinβ was mostly localized in epithelium. These findings suggest that local environment triggers meprinβ expression to support collagen maturation. In conclusion, our data demonstrate the in vivo relevance of meprinβ in collagen deposition in lung fibrosis.

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The procollagen N-proteinases ADAMTS2, 3 and 14 in pathophysiology

Cited by 120 publications

References 42 publications

Site-specific gene expression profiling as a novel strategy for unravelling keloid disease pathobiology

Site-specific gene expression profiling as a novel strategy for unravelling keloid disease pathobiology

Determination of the substrate repertoire of ADAMTS2, 3, and 14 significantly broadens their functions and identifies extracellular matrix organization and TGF‐β signaling as primary targets

Meprin β contributes to collagen deposition in lung fibrosis

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