Role of discoidin domain receptor 1 in dysregulation of collagen remodeling by cyclosporin A

Staudinger, Lisa A.; Spano, Stephen J.; Lee, W.S.; Coelho, Nuno M.; Moriarty, Tara J.; McCulloch, Christopher A.

doi:10.1016/j.biocel.2015.02.019

Cited by 8 publications

(10 citation statements)

References 38 publications

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“…DDR1 is mainly expressed by epithelial cells but keloid fibroblasts express DDR1 and treatments with anti-sense DDR1 in keloid wounds blocked collagen production [122]. We previously reported that human gingival fibroblasts [123] and periodontal ligament fibroblasts [13] also express DDR1.…”

Section: B Mechanoreceptor Functions Of Ddr1 That Contribute To Tissmentioning

confidence: 99%

Mechanical signaling through the discoidin domain receptor 1 plays a central role in tissue fibrosis

Coelho

McCulloch

2018

Cell Adhesion & Migration

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The preservation of tissue and organ architecture and function depends on tightly regulated interactions of cells with the extracellular matrix (ECM). These interactions are maintained in a dynamic equilibrium that balances intracellular, myosin-generated tension with extracellular resistance conferred by the mechanical properties of the extracellular matrix. Disturbances of this equilibrium can lead to the development of fibrotic lesions that are associated with a wide repertoire of high prevalence diseases including obstructive cardiovascular diseases, muscular dystrophy and cancer. Mechanotransduction is the process by which mechanical cues are converted into biochemical signals. At the core of mechanotransduction are sensory systems, which are frequently located at sites of cell-ECM and cell-cell contacts. As integrins (cell-ECM junctions) and cadherins (cell-cell contacts) have been extensively studied, we focus here on the properties of the discoidin domain receptor 1 (DDR1), a tyrosine kinase that mediates cell adhesion to collagen. DDR1 expression is positively associated with fibrotic lesions of heart, kidney, liver, lung and perivascular tissues. As the most common end-point of all fibrotic disorders is dysregulated collagen remodeling, we consider here the mechanical signaling functions of DDR1 in processing of fibrillar collagen that lead to tissue fibrosis.

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Section: B Mechanoreceptor Functions Of Ddr1 That Contribute To Tissmentioning

confidence: 99%

Mechanical signaling through the discoidin domain receptor 1 plays a central role in tissue fibrosis

Coelho

McCulloch

2018

Cell Adhesion & Migration

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“…Cyclosporine is a well-known promoter of fibrosis with pathogenic consequences in HGF. 3 Therefore, we next evaluated whether Gal-8 plays a role in the response of HGF to cyclosporine. Strikingly, cyclosporine increased fibronectin and Gal-8 mRNA in HGF ( Figure 4A,B).…”

Section: Cyclosporine Increases Fibronectin and Gal-8 Levels In Hgfmentioning

confidence: 99%

“…2 Gingival fibroblasts represent the most abundant cell population in gingival tissues and play a critical role in the pathogenesis of drug-induced gingival overgrowth. 3 Cyclosporineinduced gingival overgrowth encompasses a complex array of pathogenic responses that includes an altered remodeling of connective tissues [3][4][5][6][7] and prolonged inflammation. 8,9 The absence of a specific treatment for this pathologic condition stimulates to search for cellular and molecular pathways that might offer new explanations and therapeutic interventions.…”

Section: Introductionmentioning

confidence: 99%

“…All these results indicate that Gal-8 has the potential to mediate early responses of gingival connective tissue cells to cyclosporine.Cyclosporine treatment may cause gingival overgrowth, 1 characterized by the accumulation of a disorganized extracellular matrix enriched in collagen fibers, fibronectin, and an inflammatory infiltrate 8,9,31,32. Cyclosporine may disrupt connective tissue homeostasis in HGF fibroblasts through different mechanisms, including collagen remodeling,3,4,33 TGF-β signaling[5][6][7] and increased fibronectin protein levels 32. Fibronectin is critical for the deposition of type I collagen fibrils during the development of fibrosis 34.…”

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confidence: 99%

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Galectin‐8 mediates fibrogenesis induced by cyclosporine in human gingival fibroblasts

Metz

Peña

et al. 2020

J of Periodontal Research

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Background and Objective During cyclosporine‐induced gingival overgrowth, the homeostatic balance of gingival connective tissue is disrupted leading to fibrosis. Galectins are glycan‐binding proteins that can modulate a variety of cellular processes including fibrosis in several organs. Here, we study the role of galectin‐8 (Gal‐8) in the response of gingival connective tissue cells to cyclosporine. Methods We used human gingival fibroblasts and mouse NIH3T3 cells treated with recombinant Gal‐8 and/or cyclosporine for analyzing specific mRNA and protein levels through immunoblot, real‐time polymerase chain reaction, ELISA and immunofluorescence, pull‐down with Gal‐8‐Sepharose for Gal‐8‐to‐cell surface glycoprotein interactions, short hairpin RNA for Gal‐8 silencing and Student's t test and ANOVA for statistical analysis. Results Galectin‐8 stimulated type I collagen and fibronectin protein levels and potentiated CTGF protein levels in TGF‐β1‐stimulated human gingival fibroblasts. Gal‐8 interacted with α5β1‐integrin and type II TGF‐β receptor. Gal‐8 stimulated fibronectin protein and mRNA levels, and this response was dependent on FAK activity but not Smad2/3 signaling. Cyclosporine and tumor necrosis factor alpha (TNF‐α) increased Gal‐8 protein levels. Finally, silencing of galectin‐8 in NIH3T3 cells abolished cyclosporine‐induced fibronectin protein levels. Conclusion Taken together, these results reveal for the first time Gal‐8 as a fibrogenic stimulus exerted through β1‐integrin/FAK pathways in human gingival fibroblasts, which can be triggered by cyclosporine. Further studies should explore the involvement of Gal‐8 in human gingival tissues and its role in drug‐induced gingival overgrowth.

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“…4,5 Furthermore, due to a number of biological properties such as high biocompatibility, rare adverse reactions and weak antigenicity, 6 collagens have been widely used as a natural material for diverse biomedical applications, including its clinical use as biomimetic scaffold and drug delivery system. 7 Therefore, the understanding of how these properties are derived from its fundamental structural units requires a comprehensive knowledge of the mechanisms underlying its structure and stability.…”

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confidence: 99%

Quantum binding energy features of the T3-785 collagen-like triple-helical peptide

et al. 2017

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Collagen-based biomaterials are expected to become a useful matrix substance for various biomedical applications in the future. By taking advantage of the crystallographic data of the triple-helical peptide T3-785, a collagen-like peptide whose homotrimeric structure presents large conformational similarity to the human type III collagen, we present a quantum biochemistry study to unveil its detailed binding energy features, taking into account the inter-chain interaction energies of 90 amino acid residues distributed into three interlaced monomers. Our theoretical model is based on the density functional theory (DFT) formalism within the molecular fragmentation with conjugate caps (MFCC) approach. We predict the individual relevance (energetically) of the amino acid triplets Pro-Hyp-Gly, Ile-Thr-Gly, AlaArg-Gly and Leu-Gly-Ala, as well as the influence of the N-terminal, central and C-terminal regions, looking for the integrity of the collagen's triple helix. We found that the amino acid residues comprising the peptide T3-785 have an interaction energy that depends not only on the chemical nature of the side chain, but also the surrounding solvent molecules and inter-chain intermolecular interactions. The energy profile of this collagen-model molecule depicts a character essentially attractive to its conformational stability, encouraging research focusing on the development and synthesis of artificial collagen with high stability for bioengineering applications.

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Role of discoidin domain receptor 1 in dysregulation of collagen remodeling by cyclosporin A

Cited by 8 publications

References 38 publications

Mechanical signaling through the discoidin domain receptor 1 plays a central role in tissue fibrosis

Mechanical signaling through the discoidin domain receptor 1 plays a central role in tissue fibrosis

Galectin‐8 mediates fibrogenesis induced by cyclosporine in human gingival fibroblasts

Quantum binding energy features of the T3-785 collagen-like triple-helical peptide

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