Session Type: Abstract Submissions (ACR)
Skin fibrosis in scleroderma is associated with the loss of subcutaneous adipose tissue (lipodystrophy). The mechanisms underlying lipodystrophy and its relationship to fibrosis are not known. Monocytes are precursors of several cell types including myofibroblasts and adipocytes. We recently showed that this myofibroblast differentiation is inhibited by the master regulatory protein caveolin-1. Similarly, caveolin-1-deficient mice are lean with small adipocytes. The nuclear receptor PPARγ also regulates adipose differentiation and lipid homeostasis. Here we examine the coordinate roles of caveolin-1 and PPARγ in adipogenesis and fibrosis.
Mini-osmotic pumps are implanted into 10 week-old CD1 male mice. The pump delivers 100 U/kg bleomycin or saline and is removed on day 10. Mice are injected i.p. daily with 100 µl caveolin-1 scaffolding domain peptide (CSD, final concentration 0.1 mM) or phosphate-buffered saline (PBS) vehicle over the entire course of the experiment and sacrificed on day 28. Cutaneous fibrosis and lipodystrophy are analyzed histologically and immunohistologically. Monocytes are obtained from scleroderma patients and healthy controls. Monocyte differentiation to adipocytes and myofibroblasts is evaluated using Oil red O stain and ASMA stain. PPARγ and caveolin-1 expression are determined by Western blot and immunohistochemistry.
We previously observed a loss of subcutaneous adipose tissue concomitant with dermal fibrosis in bleomycin treated mice, both of which were blocked by CSD. We now show that levels of caveolin-1 and PPARγ are reduced in adipocytes of SSc patients and bleomycin-treated mice. CSD significantly enhances the expression of PPARγ and FABP4 in adipocytes in bleomycin-treated mice. Low levels of PPARγ are observed in monocytes from SSc patients and are increased by CSD treatment. PPARγ ligand triglitazone (TRLZ) and CSD inhibit, and TGFβ promotes human monocytes differentiation to myofibroblasts. Conversely, these treatments have the opposite effects on monocyte differentiation into adipocytes. These treatments affected PPARγ signaling through their effects on PPARγ levels and localization.
The present studies demonstrate the importance of both caveolin-1 and PPARγ in the regulation of adipogenesis in fibrotic skin. These studies further validate CSD as a novel therapy for both fibrotic disease and lipodystrophy.
R. M. Silver,
R. P. Visconti,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/caveolin-1-and-peroxisome-proliferator-activated-receptor-gamma-co-regulate-the-differentiation-of-monocytes-to-adipocytes-and-myofibroblasts-in-vivo-and-in-vitro/