| dc.description.abstract | Fibroblasts have well described roles in production of the extracellular matrix and are key players in wound healing. However, it has become clear that these cells are important disease-drivers in a number of pathologies, such as fibrosis. Systemic sclerosis (SSc) is an exemplar condition where fibroblasts contribute significantly to disease development and progression. SSc patients may present with widespread, multi-organ fibrosis, and there are no curative nor disease-modifying treatments available. Recent work from our lab has demonstrated that in another pathology driven by fibroblasts, rheumatoid arthritis, senescence induction in synovial fibroblasts, achieved using compound reported to be selective for the melanocortin 1 receptor, BMS-470539, resulted in a reduced aggressive phenotype and amelioration of the disease. Here, an investigation into the mechanism and utility of this pro-senescence programme as a common therapeutic strategy for fibroblast-mediated autoimmune diseases, like SSc, was investigated using dermal fibroblasts from healthy volunteers and SSc patients. Dermal fibroblasts treated with the same compound, BMS-470539, exhibited many hallmarks of senescence including reduced proliferation rates with increased metabolic activity, increased cell size, and substantial lysosomal expansion, thereby demonstrating this novel mechanism of senescence induction to be functional in distinct fibroblast populations. This occurred in the absence of DNA or mitochondrial damage, and the induced senescence-like phenotype was demonstrated to be reversible. The pro-fibrotic phenotype of dermal fibroblasts from SSc patients was also reversed by BMS-470539 administration, observed by modulated alpha-smooth muscle actin expression, fibroblast migration inhibition and reduced fibroblast contraction. The anti-fibrotic efficacy of BMS-470539 was recapitulated in the bleomycin model of dermal fibrosis. In summary, our data show therapeutic potential for this pro-senescence mechanism in the treatment of diseases mediated by aberrantly activated fibroblasts, evidencing the usefulness for pathway-centred approaches, rather than organ-specific ones, for the development of innovative therapeutic strategies exploiting shared mechanisms in autoimmune diseases. | en_US |
