Objectives Systemic sclerosis (SSc) is characterised by extensive tissue fibrosis maintained by mechanotranductive/proadhesive signalling. Drugs targeting this pathway are therefore of likely therapeutic benefit. The mechanosensitive transcriptional co-activator, yes activated protein-1 (YAP1), is activated in SSc fibroblasts. The terpenoid celastrol is a YAP1 inhibitor; however, if celastrol can alleviate SSc fibrosis is unknown. Moreover, the cell niches required for skin fibrosis are unknown.
Methods Human dermal fibroblasts from healthy individuals and patients with diffuse cutaneous SSc were treated with or without transforming growth factor β1 (TGFβ1), with or without celastrol. Mice were subjected to the bleomycin-induced model of skin SSc, in the presence or absence of celastrol. Fibrosis was assessed using RNA Sequencing, real-time PCR, spatial transcriptomic analyses, Western blot, ELISA and histological analyses.
Results In dermal fibroblasts, celastrol impaired the ability of TGFβ1 to induce an SSc-like pattern of gene expression, including that of cellular communication network factor 2, collagen I and TGFβ1. Celastrol alleviated the persistent fibrotic phenotype of dermal fibroblasts cultured from lesions of SSc patients. In the bleomycin-induced model of skin SSc, increased expression of genes associated with reticular fibroblast and hippo/YAP clusters was observed; conversely, celastrol inhibited these bleomycin-induced changes and blocked nuclear localisation of YAP.
Conclusions Our data clarify niches within the skin activated in fibrosis and suggest that compounds, such as celastrol, that antagonise the YAP pathway may be potential treatments for SSc skin fibrosis.
- Scleroderma, Systemic
- Arthritis, Experimental
Data availability statement
Data are available in a public, open access repository. Data are available on reasonable request.
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Handling editor Josef S Smolen
Contributors Data acquisition and analysis (PC, JN, SX, BAA, DEC, SS and RA), paper writing (AL, PC, DEC and RS), project design (PC, RS and AL), funding acquisition (AL and JB), data guarantor (AL)
Funding AL was funded by the CIHR (MOP-77603, 179860 and 183830), NSERC (CPG-146479), and the Arthritis Society (17-0039). JB was funded by CIHR (PJT-401394). PC is the recipient of an award from the School of Graduate Studies at University of Saskatchewan. SS was supported by CIHR Vanier, Alberta Innovates (AI), and Killam doctoral scholarships. JN is the recipient of a postdoctoral fellowship from the Arthritis Society.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Raw RNAseq data for cell culture, skin and spatial transcriptomics are available at GSE226376. The full list of state, group and sample-specific gene expression can be visualised on Celastrol Spatial Atlas (http://www.leasklab.net/Celastrol_Spatial_Atlas).
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