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Caveolin-1, transforming growth factor- receptor internalization, and the pathogenesis of systemic sclerosis

Del Galdo, Francescoa; Lisanti, Michael Pb; Jimenez, Sergio Aa

Current Opinion in Rheumatology:
doi: 10.1097/BOR.0b013e3283103d27
Raynaud phenomenon, scleroderma, overlap syndromes and other fibrosing syndromes: Edited by John Varga
Abstract

Purpose of review: To review the scientific literature supporting the participation of caveolin-1 in the pathogenesis of tissue fibrosis and the notion that modulation of the caveolin-1 pathway may represent a novel treatment for systemic sclerosis and other fibrotic diseases.

Recent findings: Caveolin-1 plays an important role in the regulation of transforming growth factor-β (TGF-β) signaling owing to its participation in TGF-β receptor internalization. TGF-β receptor internalized through caveolin-1 lipid rafts undergoes rapid degradation, effectively decreasing TGF-β signaling. Studies have shown that caveolin-1 knockdown in vitro markedly increased collagen gene expression in normal human lung fibroblasts. Caveolin-1 was reduced in affected systemic sclerosis lungs and skin and in idiopathic pulmonary fibrosis lung tissues and fibroblasts. Increasing caveolin-1 expression markedly improved bleomycin-induced pulmonary fibrosis. Restoration of caveolin bioavailability employing penetratin, a cell-permeable peptide carrier for a bioactive caveolin-1 fragment, abrogated TGF-β activation of cultured human dermal fibroblasts. Systemic administration of penetratin-caveolin-1 peptide to mice with bleomycin-induced lung fibrosis reduced fibrosis.

Summary: Caveolin-1 plays an important role in the regulation of TGF-β signaling and participates in the pathogenesis of systemic sclerosis and idiopathic pulmonary fibrosis. Restoration of caveolin function employing active caveolin-1 fragments coupled to cell-permeable carrier peptides may represent a novel approach for their treatment.

Author Information

aJefferson Institute of Molecular Medicine, Scleroderma Center and Department of Dermatology and Cutaneous Biology, USA

bKimmel Cancer Center, Departments of Cancer Biology, Medical Oncology, and Biochemistry, Stem Cell Biology and Regenerative Medicine Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA

Correspondence to Sergio A. Jimenez, MD, Jefferson Institute of Molecular Medicine, Thomas Jefferson University 233 S. 10th Street, Room 509 BLSB, Philadelphia, PA 19107-5541, USA Tel: +1 215 503 5042; fax: +1 215 923 4649; e-mail: sergio.jimenez@jefferson.edu

© 2008 Lippincott Williams & Wilkins, Inc.