Decreased expression of α₂β₁ integrin in scleroderma fibroblasts

Abstract

Systemic scleroderma (SSc) is a complex connective tissue disorder of unknown etiology. In early stages of the disease, fibroblasts are activated to produce large amounts of collagen with subsequent fibrosis. Collagen metabolism of fibroblasts is modulated by their contact with the extracellular matrix (ECM), which involves distinct receptors on the cell surface, mainly belonging to the integrins. We investigated the expression of collagen receptor alpha 2 beta 1 in SSc and normal fibroblasts, since this receptor has been shown to be utilized by fibroblasts for adhesion to and reorganization of collagen I. 9 strains of scleroderma fibroblasts grown as monolayer cultures were first analyzed with respect to their collagen I expression. 6 of these strains were similar to controls "low" producers) and 3 strains showed up to 2-3 x higher levels of collage I mRNA expression ("high" producers). Northern hybridization using a cDNA probe specific for the alpha 2 integrin subunit revealed a decrease of the corresponding mRNA in SSc fibroblasts as compared to controls (75% versus 100%). "High" collagen producing cell strains displayed the lowest values for alpha 2 integrin mRNA. The decrease of alpha 2 integrin subunit expression at the mRNA level in selected fibroblasts was further substantiated by radioimmunoprecipitation using specific mAbs directed against alpha 2 integrin subunit. No significant changes in beta 1 integrin expression could be observed - neither at mRNA nor at the protein level. Our data indicate a correlation between excessive synthesis of collagen and low levels of alpha 2 integrin subunit expression in SSc fibroblasts. Further experiments should clarify whether this observation is a phenomenon specific for scleroderma or whether it reflects an "activated" state of fibroblasts.

Increased expression of integrin α2 and abnormal response to TGF‐β1 in hereditary gingival fibromatosis

“…However, the response was much stronger in three‐dimensional collagen gels than in monolayer cultures (Ivarsson et al , 1993; Langholz et al , 1995; Riikonen et al , 1995). Changes in the expression of these two integrins are associated with fibrotic diseases such as scleroderma, keloids, and hypertrophic scars, but the results were partly contradictory (Kozlowska et al , 1996; Herzhoff et al , 1999; Szulgit et al , 2002). Excess ECM accumulation is a common feature of HGF and the above conditions.…”

Drug-Induced Gingival Overgrowth—a Review

“…58,59) Systemic scleroderma is a disease characterized by an excessive deposition of collagens in the skin and various organs, and the low expression of a2b1 integrin on fibroblasts isolated from systemic scleroderma patients has been reported. 60,61) We showed significantly decreased collagen phagocytosis in fibroblasts in rat overgrown gingiva induced by cyclosporin A, 25) and a2 integrin expression suppressed in fibroblasts isolated from overgrown gingiva compared to the control. 62) Furthermore, Chou et al showed a reduction in collagen phagocytosis of gingival fibroblasts by TNF-a treatment through the inhibition of collagen binding to cells by the inactivation of a2b1 integrin.…”

α4β1 integrin-dependent cell sorting dictates T-cell recruitment in oral submucous fibrosis

“…Changes in the expression of these integrins are associated with fibrotic diseases such as scleroderma, keloids, and hypertrophic scars, but the results were partly contradictory. [2324] Excess extracellular matrix (ECM) accumulation is a common feature of OSF as well as in the other conditions. However, it has never been studied in OSF whether integrins are related to the disease.…”