Cyclosporin inhibition of collagen remodeling is mediated by gelsolin
| Autor: | Pamela D. Arora, Christopher A. McCulloch, Matthew W. C. Chan |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Physiology Phagocytosis macromolecular substances Biology Mice Cyclosporin a medicine Animals Fibroblast Gelsolin Actin Mice Knockout Cell adhesion molecule Cell Biology Periodontium Fibroblasts musculoskeletal system Actins Extracellular Matrix Cell biology medicine.anatomical_structure Biochemistry Knockout mouse Cyclosporine Calcium Collagen Immunosuppressive Agents |
| Zdroj: | American Journal of Physiology-Cell Physiology. 293:C1049-C1058 |
| ISSN: | 1522-1563 0363-6143 |
| DOI: | 10.1152/ajpcell.00027.2007 |
| Popis: | Cyclosporin A (CsA) inhibits collagen remodeling by interfering with the collagen-binding step of phagocytosis. In rapidly remodeling connective tissues such as human periodontium this interference manifests as marked tissue overgrowth and loss of function. Previous data have shown that CsA inhibits integrin-induced release of Ca2+from internal stores, which is required for the binding step of collagen phagocytosis. Because gelsolin is a Ca2+-dependent actin-severing protein that mediates collagen phagocytosis, we determined whether gelsolin is a CsA target. Compared with vehicle controls, CsA treatment of wild-type mice increased collagen accumulation by 60% in periodontal tissues; equivalent increases were seen in vehicle-treated gelsolin-null mice. Collagen degradation by phagocytosis in cultured gelsolin wild-type fibroblasts was blocked by CsA, comparable to levels of vehicle-treated gelsolin-null fibroblasts. In wild-type cells treated with CsA, collagen binding was similar to that of gelsolin-null fibroblasts transfected with a gelsolin-severing mutant and treated with vehicle. CsA blocked collagen-induced Ca2+fluxes subjacent to bound collagen beads, gelsolin recruitment, and actin assembly at bead sites. CsA reduced gelsolin-dependent severing of actin in wild-type cells to levels similar to those in gelsolin-null fibroblasts. We conclude that CsA-induced accumulation of collagen in the extracellular matrix involves disruption of the actin-severing properties of gelsolin, thereby inhibiting the binding step of collagen phagocytosis. |
| Databáze: | OpenAIRE |
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