Decreased expression of caveolin 1 in patients with systemic sclerosis: Crucial role in the pathogenesis of tissue fibrosis

Abstract

Objective. Recent studies have implicated caveolin 1 in the regulation of transforming growth factor ␤ (TGF␤) downstream signaling. Given the crucial role of TGF␤ in the pathogenesis of systemic sclerosis (SSc), we sought to determine whether caveolin 1 is also involved in the pathogenesis of tissue fibrosis in SSc. We analyzed the expression of CAV1 in affected SSc tissues, studied the effects of lack of expression of CAV1 in vitro and in vivo, and analyzed the effects of restoration of caveolin 1 function on the fibrotic phenotype of SSc fibroblasts in vitro.Methods. CAV1 expression in tissues was analyzed by immunofluorescence and confocal microscopy. The extent of tissue fibrosis in Cav1-knockout mice was assessed by histologic/histochemical analyses and quantified by hydroxyproline assays. Cav1-null and SSc fibroblast phenotypes and protein production were analyzed by real-time polymerase chain reaction, immunofluorescence, Western blot, and multiplexed enzymelinked immunosorbent assay techniques. The effects of restoration of caveolin 1 function in SSc fibroblasts in vitro were also examined using a cell-permeable recombinant CAV1 peptide.

Genetic ablation of caveolin-2 sensitizes mice to bleomycin-induced injury

“…10 Interestingly, while bleomycin induces Cav-1 and Thus, Cav-2 modulates the fibrotic response by a mechanism that involves signal transduction pathways implicated in the control of apoptosis and proliferation, rather than the induction of molecules of the extracellular matrix, such as collagen. Since Cav-1 −/− mice also lack Cav-2 expression and are less severely affected by bleomycin treatment as compared with Cav-2 −/− mice (which still express Cav-1), we suggest that the balance of Cav-1 and Cav-2 determines the outcome of bleomycin-induced injury.…”

Role of Growth Factors in the Pathogenesis of Tissue Fibrosis in Systemic Sclerosis

“…Numerous studies have supported this role of caveolin-1 in the development of tissue fibrosis [65][66][67][68]. For example, it was shown that caveolin-1 knockdown in vitro markedly increased collagen gene expression in normal human lung fibroblasts and that caveolin-1 was reduced in affected SSc lungs and skin [66] and in lung tissues and fibroblasts from patients with idiopathic pulmonary fibrosis [67,68]. Increasing caveolin-1 expression markedly improved bleomycin-induced pulmonary fibrosis [67].…”

“…The localization of the TβRs in the EEA-1 positive compartment was responsible for downstream Smad activation, whereas their localization in caveolae lipid rafts caused recruitment of Smurf/Smad7 with subsequent receptor ubiquitination and rapid receptor degradation and turnover [63,64]. Numerous studies have supported this role of caveolin-1 in the development of tissue fibrosis [65][66][67][68]. For example, it was shown that caveolin-1 knockdown in vitro markedly increased collagen gene expression in normal human lung fibroblasts and that caveolin-1 was reduced in affected SSc lungs and skin [66] and in lung tissues and fibroblasts from patients with idiopathic pulmonary fibrosis [67,68].…”

The Early Growth Response Gene Egr2 (Alias Krox20) Is a Novel Transcriptional Target of Transforming Growth Factor-β that Is Up-Regulated in Systemic Sclerosis and Mediates Profibrotic Responses

“…Each biopsy specimen is represented as the mean of four integrated density of fluorescence values per specimen. 31 Egr-2 expression was also examined in lungs from patients with SSc-associated pulmonary fibrosis undergoing lung transplantation and in normal donor lungs. The biopsy protocols were approved by the Institutional Review Board for Human Studies at the University of Pittsburgh, Pittsburgh.…”