Increased Expression of Integrin αvβ3 Contributes to the Establishment of Autocrine TGF-β Signaling in Scleroderma Fibroblasts

Abstract

The constitutive secretion of latent TGF-β by many cell types in culture suggests that extracellular mechanisms to control the activity of this potent cytokine are important in the pathogenesis of the diseases in which this cytokine may be involved, including fibrotic disorders. In this study, we focused on the αvβ3 integrin, which is recently demonstrated to function as an active receptor for latent TGF-β1 through its interaction with latency-associated peptide-β1, and investigated the involvement of this integrin in the pathogenesis of scleroderma. Scleroderma fibroblasts exhibited increased αvβ3 expression compared with normal fibroblasts in vivo and in vitro. In scleroderma fibroblasts, ERK pathway was constitutively activated and such abnormality induced the up-regulation of αvβ3. Transient overexpression of αvβ3 in normal fibroblasts induced the increase in the promoter activity of human α2(I) collagen gene and the decrease in that of human MMP-1 gene. These effects of αvβ3 were almost completely abolished by the treatment with anti-TGF-β Ab or TGF-β1 antisense oligonucleotide. Furthermore, the addition of anti-αvβ3 Ab reversed the expression of type I procollagen protein and MMP-1 protein, the promoter activity of human α2(I) collagen gene, and the myofibroblastic phenotype in scleroderma fibroblasts. These results suggest that the up-regulated expression of αvβ3 contributes to the establishment of autocrine TGF-β loop in scleroderma fibroblasts, and this integrin is a potent target for the treatment of scleroderma.

Thrombin-mediated Proteoglycan Synthesis Utilizes Both Protein-tyrosine Kinase and Serine/Threonine Kinase Receptor Transactivation in Vascular Smooth Muscle Cells

“…Latent TGF-␤ can be activated by various members of the integrin family of cell surface molecules (27)(28)(29)(30). Inside out integrin signaling has been associated with cytoskeletal rearrangement and ROCK signaling cascades.…”

Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib mesylate

“…Accumulating evidence suggests that alterations of TGF␤ signaling may play an essential role in the persistent activation of SSc fibroblasts. The documented changes include up-regulation of ␣v␤5 and ␣v␤3 integrins, which were shown to contribute to activation of latent TGF␤ and establishment of the autocrine TGF␤ loop (10,11). Additional changes include alterations of the TGF␤ receptor ratio (12) and the presence of persistently phosphorylated Smad3 (13).…”

Molecular imaging of ventricular remodeling

“…15 Higuchi et al used this tracer to monitor avB3 integrin expression in rat hearts after ischemia/ reperfusion, and reported results comparable with 111 In-RP748 imaging. 16 Clinical use of the 18 F-Galacto-RGD PET tracer in a patient with MI was reported shortly. 17 Apart from its crucial involvement in angiogenesis, avB3 integrin also has been linked to the development of fibrosis, 18,19 which led our group to evaluate whether avB3 integrin imaging could be used to visualize Figure 2.…”

“…16 Clinical use of the 18 F-Galacto-RGD PET tracer in a patient with MI was reported shortly. 17 Apart from its crucial involvement in angiogenesis, avB3 integrin also has been linked to the development of fibrosis, 18,19 which led our group to evaluate whether avB3 integrin imaging could be used to visualize Figure 2. A, Nuclear imaging showed that no uptake was seen of the avB3 targeted tracer was seen in normal controls and in mice with infarcted hearts injected with a scrambled variant of the targeting peptide.…”

“…Recently, 18 F-Galacto-RGD, a PET tracer targeting specifically avB3 integrin expression, has been introduced. 15 Higuchi et al used this tracer to monitor avB3 integrin expression in rat hearts after ischemia/ reperfusion, and reported results comparable with 111 In-RP748 imaging.…”