Cédric Zeltz

University of Bergen, Bergen, Hordaland, Norway

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Publications (9)32.02 Total impact

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    Cédric Zeltz, Donald Gullberg
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    ABSTRACT: Protein post-translational modifications like glycation, carbamylation and citrullination increase the functional diversity of the proteome but in disease situations might do more harm than good. Post-translational modifications of ECM proteins are thus appearing as mechanisms, which contribute to tissue dysfunction in chronic kidney disease, in diabetes and in various inflammatory diseases. In chronic renal failure, carbamylation could lead to kidney fibrosis. In diabetes, high glucose levels leads to non-enzymatic glycation and cross-linking of collagens, which contribute to tissue stiffening with consequences for cardiovascular and renal functions. In inflammatory diseases, citrullination deiminates arginine residues with possible consequences for integrin-mediated cell adhesion to RGD- and GFOGER sequences in ECM proteins. Citrullination of fibronectin was in one study shown to affect cell adhesion in a mechanism independent of RGD, but instead suggested to affect the heparin-binding site of fibronectin. In a recent publication citrullination of GFOGER sequences in collagen II was demonstrated to selectively affect α10β1 and α11β1 integrin-mediated cell adhesion to collagen II, with consequences for synovial fibroblast and stem cell adhesion and migration. The implications of citrullination affecting integrin binding in disease opens up a new area of study and might have implications for the pathogenesis of inflammatory diseases like rheumatoid arthritis and periodontitis.
    Matrix Biology 08/2014; · 3.19 Impact Factor
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    ABSTRACT: The adhesion of cardiac fibroblasts to the glycated collagen interstitium in diabetics is associated with de novo expression of the α11 integrin, myofibroblast formation and cardiac fibrosis. We examined how methylglyoxal-glycated collagen regulates α11 integrin expression. In cardiac fibroblasts plated on glycated collagen but not glycated fibronectin, there was markedly increased α11 integrin and α-smooth muscle actin expression. Compared with native collagen, binding of purified α11β1 integrin to glycated collagen was reduced by >4-fold, which was consistent with reduced fibroblast attachment to glycated collagen. Glycated collagen strongly enhanced the expression of TGF-β2 but not TGF-β1 or TGF-β3. The increased expression of TGF-β2 was inhibited by triple helical collagen peptides that mimic the α11β1 integrin binding site on type I collagen. In cardiac fibroblasts transfected with α;11 integrin luciferase promoter constructs, glycated collagen activated the α11 integrin promoter. Analysis of α11 integrin promoter truncation mutants showed a novel Smad2/3 binding site located between -809 and -1300 nt that was required for promoter activation. We conclude that glycated collagen in the cardiac interstitium triggers an autocrine TGF-β2 signalling pathway that stimulates α11 integrin expression through Smad2/3 binding elements in the α11 integrin promoter, which is important for myofibroblast formation and fibrosis. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 06/2014; · 4.22 Impact Factor
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    ABSTRACT: Mechanical loading of tendon cells results in an upregulation of mechanotransduction signaling pathways, cell-matrix adhesion and collagen synthesis, but whether unloading removes these responses is unclear. We investigated the response to tension release, with regard to matrix proteins, pro-inflammatory mediators and tendon phenotypic specific molecules, in an in vitro model where tendon-like tissue was engineered from human tendon cells. Tissue sampling was performed 1, 2, 4 and 6 days after surgical de-tensioning of the tendon construct. When tensile stimulus was removed, integrin type collagen receptors showed a contrasting response with a clear drop in integrin subunit α11 mRNA and protein expression, and an increase in α2 integrin mRNA and protein levels. Further, specific markers for tendon cell differentiation declined and normal tendon architecture was disturbed, whereas pro-inflammatory molecules were upregulated. Stimulation with the cytokine TGF-β1 had distinct effects on some tendon-related genes in both tensioned and de-tensioned tissue. These findings indicate an important role of mechanical loading for cellular and matrix responses in tendon, including that loss of tension leads to a decrease in phenotypical markers for tendon, while expression of pro-inflammatory mediators is induced.
    PLoS ONE 01/2014; 9(1):e86078. · 3.53 Impact Factor
  • Cédric Zeltz, Ning Lu, Donald Gullberg
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    ABSTRACT: Integrin α11 is the last addition to the vertebrate integrin family. In this chapter we will summarize some basic facts about this integrin and update with information that has been gained in the last decade. Integrin α11β1 is a major collagen receptor on a subset of fibroblasts. Extensive characterization of the expression pattern in developing mouse embryos has demonstrated expression restricted to subsets of fibroblasts and a transient expression in odontoblasts, but comprehensive characterization of corresponding expression in adult tissues is still lacking. Mice lacking integrin α11 are dwarfed, primarily due to defective incisor eruption defect, which can be traced back to need for α11 on periodontal ligament fibroblasts during incisor eruption. Separate studies have suggested reduced levels of IGF-1 in mice lacking α11. Analysis of lung cancer has identified α11β1 as a functional important collagen receptor on carcinoma associated fibroblasts (CAFs) and a number of disease models are awaiting analysis to see the importance of this collagen receptor in pathological models.
    Advances in experimental medicine and biology 01/2014; 819:73-83. · 1.83 Impact Factor
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    Cédric Zeltz, Joseph Orgel, Donald Gullberg
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    ABSTRACT: Despite detailed knowledge about the structure and signaling properties of individual collagen receptors, much remains to be learned about how these receptors participate in linking cells to fibrillar collagen matrices in tissues. In addition to collagen-binding integrins, a group of proteins with affinity both for fibrillar collagens and integrins link these two protein families together. We have introduced the name COLINBRI (COLlagen INtegrin BRIdging molecules) for this set of molecules. Whereas collagens are the major building blocks in tissues, defects in these structural proteins have severe consequences for tissue integrity; the mild phenotypes of the integrin type of collagen receptors have raised questions about their importance in tissue biology and pathology. Scope of review We will discuss the two types of cell linkages to fibrillar collagen (direct- versus indirect COLINBRI-mediated) and discuss how the parallel existence of direct and indirect linkages to collagens may ensure tissue integrity. Major conclusions The observed mild phenotypes of mice deficient in collagen-binding integrins and the relatively restricted availability of integrin-binding sequences in mature fibrillar collagens matrices support the existence of indirect collagen binding mechanisms in parallel with direct collagen binding in vivo. General significance A continued focus on understanding the molecular details of cell adhesion mechanisms to collagens will be important and will benefit our understanding of diseases like tissue- and tumor fibrosis where collagen dynamics are disturbed.
    Biochimica et Biophysica Acta 12/2013; · 4.66 Impact Factor
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    ABSTRACT: Lumican, an extracellular matrix protein of the small leucine-rich proteoglycan family, has been shown to impede melanoma progression by inhibiting cell migration. In the present study, we show that lumican targets α2β1 integrin thereby inhibiting cell migration. A375 melanoma cells were transfected with siRNA directed against the α2 integrin subunit. Compared to A375 control cells, the anti-migratory effect of lumican was abrogated on transfected A375 cells. Moreover, lumican inhibited the chemotactic migration of Chinese hamster ovary (CHO) cells stably transfected with α2 integrin subunit (CHO-A2) but not that of wild-type CHO cells (CHO-WT) lacking this subunit. In contrast to CHO-WT cells, we observed in time-lapse microscopy a decrease of CHO-A2 cell migration speed in presence of lumican. Focal adhesion kinase phosphorylated at tyrosine-397 (pFAK) and total FAK were analysed in CHO-WT and CHO-A2 cells. A significant decrease of the ratio pFAK/FAK was shown in presence of recombinant human lumican. Using solid phase assays, a direct binding between lumican and the α2β1 integrin was demonstrated. This interaction did not involve the glycan moiety of lumican and was cation independent. Lumican was also able to bind the activated I domain of the α2 integrin subunit with a K(d)≥200nM. In conclusion, we demonstrated for the first time that the inhibition of cell migration by lumican depends on a direct binding between the core protein of lumican and the α2β1 integrin.
    Experimental Cell Research 10/2010; 316(17):2922-31. · 3.56 Impact Factor
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    ABSTRACT: Lumican is a small leucine-rich proteoglycan (SLRP) of the extracellular matrix (ECM) involved in the control of melanoma growth and invasion. The aim of the present study was to analyse the role of lumican in the regulation of the development of lung metastasis. B16F1 melanoma cells stably transfected with lumican expressing plasmid (Lum-B16F1) were injected to syngenic mice. The lung metastasis was compared to mice injected with mock-transfected B16F1 cells (Mock-B16F1). The expression of lumican, cyclin D1, apoptotic markers, vascular endothelium growth factor (VEGF) and Von Willebrand Factor (vWF) within lung metastasis nodules was investigated by immunohistochemistry. In parallel, cells cultured in presence of lumican were assayed for apoptosis and motility. We observed that the number and the size of lung metastasis nodules were significantly decreased in mice injected with Lum-B16F1 cells in comparison to Mock-B16F1 cells. This was associated with an increase of tumour cell apoptosis within metastasis nodules but the cell proliferation rate remained constant in the two mice groups. In contrast, the VEGF immunostaining and the number of blood vessels within the lung metastasis nodules were decreased in the lumican-expressing tumours. In vitro, a significant decrease of apoptotic markers in wild type B16F1 cells incubated with increasing amounts of lumican core protein was observed. In addition, pseudotubes formation on Matrigel(R) and the migratory capacity of endothelial cells was inhibited by lumican. Altogether, our results indicate that lumican decreases lung metastasis development not only by inducing tumour cell apoptosis but also by inhibiting angiogenesis.
    Journal of physiology and pharmacology: an official journal of the Polish Physiological Society 10/2009; 60 Suppl 4:15-22. · 2.48 Impact Factor
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    ABSTRACT: We previously showed that lumican decreases melanoma progression. The aim of the present study was to determine the active sequence of the lumican core protein responsible for the inhibition of melanoma cell migration. Using different recombinant and synthetic peptides derived from lumican, we localized an active site in the leucine-rich repeat 9 domain of the lumican core protein. We propose the name lumcorin (fragment of lumican core protein) for the active peptide derived from this site. Lumcorin was able to inhibit melanoma cell migration in vitro.
    FEBS letters 09/2009; 583(18):3027-32. · 3.54 Impact Factor
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    ABSTRACT: Lumican is a small leucine-rich proteoglycan (SLRP) of the extracellular matrix (ECM) with anti-tumor activity. We recently demonstrated that lumican inhibits the migration of melanoma cells and identified beta1 integrin as mediator of this effect [M.F. D'Onofrio, S. Brézillon, T. Baranek, C. Perreau, P.J. Roughley, F.X. Maquart, Y. Wegrowski, Identification of beta1 integrin as mediator of melanoma cell adhesion to lumican, Biochem. Biophys. Res. Commun. 365 (2008) 266-272]. The aim of the present work was to study beta1 integrin, focal adhesion complexes, actin distribution and expression in the presence of lumican substratum in comparison to type I collagen or fibronectin substrata in A375 human melanoma cells. The protein distribution was investigated by immunocytochemistry and confocal microscopy. In parallel, their expression was evaluated by Western immunoblotting and Real-time Reverse Transcription-PCR analyses. The interaction of melanoma cells with the lumican substratum resulted in heterogeneous distribution of beta1 integrin on cell membrane after 24h of seeding. Concomitantly, a reorganization of actin stress fibers and a significant decrease in vinculin immunostaining at focal adhesion complexes were observed. No alteration of the expression was detected at protein and mRNA levels. However, a cytosolic accumulation of vinculin focal adhesion protein was observed on lumican substratum by confocal microscopy. Moreover, vinculin expression was significantly increased in cytosolic fractions in comparison to cells seeded on type I collagen or fibronectin substrata. Our results suggest that lumican induces an alteration of the link between actin filaments and beta1 integrin, characterized by a cytosolic accumulation of vinculin focal adhesion protein, which could lead to a destabilization of focal adhesion complexes. In addition, focal adhesion kinase phosphorylated at tyrosine-397 (pFAK) was significantly decreased. Therefore, the cytoskeleton remodeling and the decreased pFAK phosphorylation induced by lumican in melanoma cells might explain, at least in part, the anti-invasive effect of this SLRP.
    Cancer letters 05/2009; 283(1):92-100. · 5.02 Impact Factor