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

The International Journal of Biochemistry & Cell Biology
L A StaudingerC A McCulloch

Abstract

The anti-transplant rejection drug cyclosporin A (CsA) causes loss of collagen homeostasis in rapidly remodeling connective tissues, such as human gingiva. As a result of CsA treatment, collagen degradation by fibroblasts is inhibited, which leads to a net increase of tissue collagen and gingival overgrowth. Since fibrillar collagen is the primary ligand for the discoidin domain receptor 1 (DDR1), we hypothesized that CsA perturbs DDR1-associated functions that affect collagen homeostasis. For these experiments, human fibroblasts obtained from gingival explants or mouse 3T3 fibroblasts (wild type, over-expressing DDR1 or DDR1 knockdown) or mouse GD25 cells (expressing DDR1 but null for β1 integrin), were treated with vehicle (dimethyl sulfoxide) or with CsA. The effect of CsA on cell binding to collagen was examined by flow cytometry; cell-mediated collagen remodeling was analyzed with contraction, compaction and migration assays. We found that CsA inhibited cell binding to collagen, internalization of collagen, contraction of collagen gels and cell migration over collagen in a DDR1-dependent manner. CsA also enhanced collagen compaction around cell extensions. Treatment with CsA strongly reduced surface levels of β1 integrins ...Continue Reading

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Citations

Mar 8, 2018·Cell Adhesion & Migration·Nuno M Coelho, Christopher A McCulloch
Sep 5, 2017·The Open Dentistry Journal·Albert Ramírez-RámizJaume Miranda-Rius
May 26, 2020·Journal of Periodontal Research·Patricio C SmithAndrea Soza

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