title: Scleroderma-like properties of skin from caveolin-1-deficient mice: implications for new treatment strategies in patients with fibrosis and systemic sclerosis.
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 pre-clinical model for studying the pathogenesis of SSc. For this purpose, we performed quantitative transmission electron microscopy, as well as biochemical 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, including a decrease in collagen fiber diameter, increased tensile strength, and 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 be a survival mechanism in this "hostile" or pro-inflammatory microenvironment. Taken together, our results demonstrate that Cav-1 (-/-) null 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 (-/-) null mice are also a pre-clinical model for a "lethal" tumor micro-environment, possibly explaining the link between fibrosis, tumor progression, and cancer metastasis.
authors.affiliation: The Jefferson Stem Cell Biology and Regenerative Medicine Center, Thomas Jefferson University, Philadelphia, PA, USA. remedios.castello@jefferson.edu
authors.forename: Remedios
authors.initials: R
authors.lastname: Castello-Cros
authors.forename: Diana
authors.initials: D
authors.lastname: Whitaker-Menezes
authors.forename: Alex
authors.initials: A
authors.lastname: Molchansky
authors.forename: George
authors.initials: G
authors.lastname: Purkins
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Soslowsky
authors.forename: David P
authors.initials: DP
authors.lastname: Beason
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D000818:Animals; D001343:Autophagy; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism; D012594:Scleroderma, Localized / Q000378:metabolism / Q000473:pathology; D012595:Scleroderma, Systemic / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D051242:Caveolin 1; D005353:Fibronectins; D003094:Collagen