Scleroderma-like properties of skin from caveolin-1-deficient mice: Implications for new treatment strategies in patients with fibrosis and systemic sclerosis

Remedios Castello-Cros, Diana Whitaker-Menezes, Alex Molchansky, George Purkins, Louis J. Soslowsky, David P. Beason, Federica Sotgia, Renato V. Iozzo, Michael P. Lisanti

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Caveolin-1 (Cav-1), the principal structural component of caveolae, participates in the pathogenesis of several fibrotic diseases, including systemic sclerosis (SSc). Interestingly, affected skin and lung samples from patients with SSc show reduced levels of Cav-1, as compared to normal skin. In addition, restoration of Cav-1 function in skin fibroblasts from SSc patients reversed their pro-fibrotic phenotype. Here, we further investigated whether Cav-1 mice are a useful preclinical model for studying the pathogenesis of SSc. For this purpose, we performed quantitative transmission electron microscopy, as well as biochemical, biomechanical, and immuno-histochemical analysis, of the skin from Cav-1 -/- null mice. Using these complementary approaches, we now show that skin from Cav-1 null mice exhibits many of the same characteristics as SSc skin from patients. These changes include a decrease in collagen fiber diameter, increased maximum stress (a measure tensile strength) and modulus (a measure of stiffness), as well as mononuclear cell infiltration. Furthermore, an increase in autophagy/mitophagy was observed in the stromal cells of the dermis from Cav-1 -/- mice. These findings suggest that changes in cellular energy metabolism (e.g., a shift towards aerobic glycolysis) in these stromal cells may provide a survival mechanism in this "hostile" or pro-inflammatory microenvironment. Taken together, our results demonstrate that Cav-1 -/- mice are a valuable new pre-clinical model for studying scleroderma. Most importantly, our results suggest that inhibition of autophagy and/or aerobic glycolysis may represent a new promising therapeutic strategy for halting fibrosis in SSc patients. Finally, Cav-1 -/- mice are also a pre-clinical model for a "lethal" tumor microenvironment, possibly explaining the link between fibrosis, tumor progression and cancer metastasis. © 2011 Landes Bioscience.
    Original languageEnglish
    Pages (from-to)2140-2150
    Number of pages10
    JournalCell Cycle
    Volume10
    Issue number13
    DOIs
    Publication statusPublished - 1 Jul 2011

    Keywords

    • Autophagy
    • Caveolin-1
    • Fibrosis
    • Matrix
    • Metabolism
    • Mitophagy
    • Preclinical model
    • Scleroderma
    • Skin
    • Systemic sclerosis

    Fingerprint

    Dive into the research topics of 'Scleroderma-like properties of skin from caveolin-1-deficient mice: Implications for new treatment strategies in patients with fibrosis and systemic sclerosis'. Together they form a unique fingerprint.

    Cite this