{
  "abstract": "Introduction Scleroderma, systemic sclerosis (SSc) is an autoimmune rheumatic disease characterized by fibrosis of the skin and internal organs that has the highest case fatality among all rheumatic diseases. The hallmark of SSc is the presence of skin fibrosis, driven initially by inflammation that then evolves to fibrosis of the dermis and subcutis. Currently available drugs used for treating patients with SSc are not highly effective against dermal fibrosis and have not been shown to prolong survival of SSc patients; therefore, there is an urgent and unmet need for new therapeutic strategies for scleroderma. Our goal is to develop a novel peptide, M10, recently discovered in our laboratory, as an efficacious therapeutic agent with a lead indication for the treatment of patients suffering from SSc. Previously, we observed that M10 diminishes experimental pulmonary fibrosis in mouse models of SSc-associated interstitial lung disease (ILD). This study was initiated to determine whether M10 exerts antifibrotic effects in dermal fibrosis.Material and Methods The experiments were performed in skin fibroblasts isolated from SSc-ILD patients and in two different animal models of experimental dermal fibrosis: constitutively active (CA) TGF-beta receptor 1 (TbR1CA) mouse model of SSc and bleomycin-induced mouse models of skin fibrosis.Results M10 reduced basal levels and TGF-beta-induced collagen type I and fibronectin in a concentration-dependent manner in cultured dermal fibroblasts isolated from SSc patients and from healthy controls. The statistically significant effect (p < 0.05) was observed at a concentration of M10 as low as 0.1 µg/ml. M10 inhibited Smad2 and Smad3 phosphorylation, decreased expression of smooth muscle alpha-actin and suppressed contractile activity of SSc skin fibroblasts in a dose-dependent manner. In the TbR1CA and bleomycin-induced skin fibrosis models, subcutaneous administration of M10 suppressed the expression of fibrotic cytokines, diminished dermal thickening, and reduced hydroxyproline content attenuating established dermal fibrosis.Conclusions M10 counteracts fibrogenic pathways in SSc skin fibroblasts and suppresses established dermal fibrosis in two different preclinical models of scleroderma strongly suggesting that it has great potential to be developed as an effective therapeutic agent for SSc.",
  "authors": [
    {
      "affiliations": [
        "Medical University of South Carolina, Charleston, USA"
      ],
      "name": "Galina Bogatkevich"
    },
    {
      "affiliations": [
        "Medical University of South Carolina, Charleston, USA"
      ],
      "name": "Ilia Atanelishvili"
    },
    {
      "affiliations": [
        "Medical University of South Carolina, Charleston, USA"
      ],
      "name": "Dilyn Clarke"
    },
    {
      "affiliations": [
        "Medical University of South Carolina, Charleston, USA"
      ],
      "name": "Richard Silver"
    }
  ],
  "title": "P.264 M10 as a novel drug candidate for skin fibrosis",
  "uid": "ee9af60c-6fc1-5d24-89cf-7664f2204c13"
}