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Background <p>Conditions like fibrosis, rheumatoid arthritis or cancer, once seen as distinct diseases, are now recognized to share strikingly common pathogenic mechanisms. The key to this convergence lies in the fibroblast, a pivotal driver of disease progression, tissue injury and chronicity. Despite this central pathogenic role and growing recognition as a therapeutic target, effective treatments targeting fibroblasts remain elusive, leaving a critical gap in disease intervention.</p> Methods <p>Here we present a novel approach to target fibrosis using the melanocortin compound BMS-470539 to treat in vitro cultured human dermal fibroblasts obtained from healthy volunteers and systemic sclerosis patients and measuring various markers of senescence and fibroblast activation combining microscopy, DNA sequencing, cell migration and RNA sequencing and PCR techniques. We also used the in vivo bleomycin induced skin fibrosis in mice to determine pre-clinical efficacy of BMS-470539.</p> Results <p>BMS-470539 induced a ‘senescence-like’ state in human dermal fibroblasts from systemic sclerosis patients, characterised by proliferation arrest, lack of pro-inflammatory secretome and inability to induce secondary senescence. This senescence-like activity (accompanied by β-galactosidase activity, lipofuscin accumulation and other markers) resulted in the downregulation of fibrosis markers including ⍺-smooth muscle actin, migration, CCL2 and genes related to TGFβ and fibroblast activation. In vivo, the compound reduced skin thickness on the bleomycin-induced skin fibrosis murine model when administered intraperitoneally, and importantly, this senescence-like activity did not cause signs of fibrosis when administered intradermally.</p> Conclusions <p>Here, we introduce a novel strategy to disarm pathogenic fibroblasts in the context of skin fibrosis using a therapeutic pro-senescence-like approach using the unconventional melanocortin compound BMS-470539, to reset fibroblast behaviour and disrupt disease progression. This work also emphasizes the translational potential of how understanding shared pathogenic mechanisms across diseases may lead to new therapeutic opportunities to manage multiple diseases like arthritis and fibrosis.</p>

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The senescence-like activity of BMS-470539 is associated with anti-fibrotic actions in models of dermal fibrosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月30日

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  • Camilla SA Davan-Wetton,
  • Natalya Khodeneva,
  • Christopher P. Denton,
  • David J. Abraham,
  • Mauro Perretti,
  • Trinidad Montero-Melendez

摘要

Background

Conditions like fibrosis, rheumatoid arthritis or cancer, once seen as distinct diseases, are now recognized to share strikingly common pathogenic mechanisms. The key to this convergence lies in the fibroblast, a pivotal driver of disease progression, tissue injury and chronicity. Despite this central pathogenic role and growing recognition as a therapeutic target, effective treatments targeting fibroblasts remain elusive, leaving a critical gap in disease intervention.

Methods

Here we present a novel approach to target fibrosis using the melanocortin compound BMS-470539 to treat in vitro cultured human dermal fibroblasts obtained from healthy volunteers and systemic sclerosis patients and measuring various markers of senescence and fibroblast activation combining microscopy, DNA sequencing, cell migration and RNA sequencing and PCR techniques. We also used the in vivo bleomycin induced skin fibrosis in mice to determine pre-clinical efficacy of BMS-470539.

Results

BMS-470539 induced a ‘senescence-like’ state in human dermal fibroblasts from systemic sclerosis patients, characterised by proliferation arrest, lack of pro-inflammatory secretome and inability to induce secondary senescence. This senescence-like activity (accompanied by β-galactosidase activity, lipofuscin accumulation and other markers) resulted in the downregulation of fibrosis markers including ⍺-smooth muscle actin, migration, CCL2 and genes related to TGFβ and fibroblast activation. In vivo, the compound reduced skin thickness on the bleomycin-induced skin fibrosis murine model when administered intraperitoneally, and importantly, this senescence-like activity did not cause signs of fibrosis when administered intradermally.

Conclusions

Here, we introduce a novel strategy to disarm pathogenic fibroblasts in the context of skin fibrosis using a therapeutic pro-senescence-like approach using the unconventional melanocortin compound BMS-470539, to reset fibroblast behaviour and disrupt disease progression. This work also emphasizes the translational potential of how understanding shared pathogenic mechanisms across diseases may lead to new therapeutic opportunities to manage multiple diseases like arthritis and fibrosis.