Cyclosporin A decreases the degradation of type I collagen in rat gingival overgrowth

Abstract

Cyclosporin A (CsA) is used as an immunosuppressive agent and its prominent side effect is the induction of fibrous gingival overgrowth. The purpose of this study was to investigate the effect of CsA on the type I collagen metabolism in the gingiva of rats fed a powdered diet either containing or lacking CsA. Immunohistochemical analysis revealed that type I collagen was more prevalent in the connective tissue of CsA-treated gingiva than in those of control rats on days 15, 30, and 55 after the start of feeding. Total RNAs were isolated from mandibular molar gingiva on days 0, 3, 8, 15, 30, and 55. Quantitative analysis of mRNA by reverse transcriptase-polymerase chain reaction revealed that the CsA-treated groups showed a gradual decrease in expression of type I collagen and collagenase mRNAs, 0.4% and 18.0% on day 55 compared with those on day 0, respectively. In the control groups, type I collagen and collagenase mRNAs also decreased to 19.7% and 63.0%, respectively, however, both mRNA expressions were significantly lower in the CsA-treated group than in the controls. An electron microscopic analysis of fibroblasts was performed to count the number of cells with collagen fibrils in the cytoplasm, a marker of phagocytosis of collagen by fibroblasts. The collagen fibrils were detected in 4.7% +/- 2.7% and 24.3% +/- 13.7% of fibroblasts in the overgrown gingiva treated with CsA rat for 8 days and 30 days, but in 57.0% +/- 5.3% and 81.3% +/- 9.2% of fibroblasts in the each control group gingiva, respectively. Furthermore, in vitro analysis was performed to measure the phagocytosis of cultured fibroblasts by flow cytometry using collagen-coated latex beads. Fibroblasts isolated from CsA-treated gingiva on day 8 and day 30 contained 5.7% +/- 0.6% and 9.9% +/- 1.5% phagocytic cells, whereas control fibroblasts contained 50.3% +/- 5.5% and 33.3% +/- 4.9% phagocytic cells, respectively. The inhibition rate of phagocytic activity was similar between in vivo and in vitro assays. These findings suggest that the decrease of the collagen degradation due to the lower phagocytosis and the lower collagenase mRNA expression are closely associated with the increase of type I collagen accumulation in CsA-treated rat gingiva.

In vivo association of immunophenotyped macrophages expressing CD163 with PDGF-B in gingival overgrowth-induced by three different categories of medications

“…j o u r n a l o f o r a l b i o l o g y a n d c r a n i o f a c i a l r e s e a r c h 6 ( 2 0 1 6 ) 1 0 -1 7 collagen fiber in group IV, it was less than that of groups II and III; this is in agreement with Kataoka et al 34 as they noted reduction in collagen fiber phagocytosis by fibroblast after 30 days of CsA use before macroscopic detection of GO. CD163 antibody aids in identifying cells of monocyte/ macrophage lineage in normal and neoplastic conditions.…”

Connective Tissue Metabolism and Gingival Overgrowth

“…In vitro studies have shown that phenytoin and cyclosporin A inhibit production of the lysozomal proteinase cathepsin L, but not cathepsin B, by human gingival fibroblasts (Yamada et al, 2000). Cyclosporin may also inhibit phagocytosis of type I collagen in vitro and in vivo (Kataoka et al, 2000;Arora et al, 2001). Consistent results were found in cathepsin-L-deficient mice that exhibited enlarged gingival epithelial and connective tissues (Nishimura et al, 2002).…”

Drug-Induced Gingival Overgrowth—a Review

“…2), and severe inhibition was observed in cyclosporine A-induced gingival overgrowth. 25,26) Interestingly, type I collagen and collagenase mRNA expressions were significantly suppressed by cyclosporin A and nifedipine administration in these rat experimental models. 25,26) From these results, drug-induced gingival overgrowth is not due to the increased synthesis of type I collagen but the decreased degradation of type I collagen in gingival connective tissue through the reduction of collagen phagocytosis of fibroblasts.…”

“…[36][37][38][39] These drug-induced gingival overgrowth is shown to be induced by the excessive accumulation of type I collagen in gingival connective tissue by immunohistochemical analysis with rat experimental models. 25,26) These disorders are therefore suitable to be considered as fibrosis in gingival connective tissue. "Gingival overgrowth" or "gingival enlargement" is the preferred term for all drug-related gingival lesions previously termed "gingival hypertrophy" or "gingival hyperplasia".…”

“…Although the pathology of drug-induced gingival overgrowth is not definitively known, these disorders seem to be induced through the disruption of the homeostasis of collagen synthesis and degradation in gingival connective tissues. [23][24][25][26][27] In this review, we focused on excess collagen fibers, especially type I collagen, the most abundant protein in mammals, 28) in gingival connective tissue, and discussed the role of collagen phagocytosis of gingival fibroblasts for the induction of drug-induced gingival overgrowth.…”