Session Type: Abstract Submissions (ACR)
Background/Purpose: Systemic sclerosis (SSc) is a complex pro-inflammatory scarring disease, characterised by elevated deposition of extracellular matrix (ECM) proteins, in particular collagen type I. The disease is heterogeneous affecting both the skin and visceral organs including kidney, lung and heart. The SSc fibroblast is a key cell which promotes a pro-inflammatory and fibrotic microenvironment that can lead to the loss of normal tissue architecture and organ function. The mechanisms that contribute to the formation and persistence of the SSc dermal fibroblast remain unclear. We have previously shown the epigenetic bromodomain and extra-terminal domain-containing proteins (Brd) which bind to acetylated histone residues, play a significant role in pulmonary fibrosis. Here we seek to explore the contribution of Brd proteins in the development of dermal fibrosis using a specific inhibitor of Brd proteins (Brd 2, 3, 4 and T), JQ1.
Methods: We investigated the dose-response of JQ1 on SSc and healthy control (HC) donor (n≥3) dermal fibroblasts. We assessed the effects on collagen deposition and processing using the Scar-in-a-Jar in vitrofibrosis assay, by western blot and immuno-florescence microscopy for collagen type I (n=4). To determine the effect of JQ1 in a pre-clinical model of skin fibrosis, female C57BL/6 mice were given three weekly subcutaneous injections of 100µl sterile saline (n≥6) or 0.1U/ml bleomycin (n≥6) for 14 days and treated with 12mg/kg/day JQ1 (n≥6) or vehicle (n≥6). After 14 days histological analysis for fibrogenic proteins and ECM was performed on skin, and pro-inflammatory chemokines in sera assessed by ELISA.
Results: IL-6 and MCP-1 secretion by SSc and HC donor fibroblasts was significantly (P<0.05) inhibited in a dose dependent manner by JQ1. Consistent with this JQ1 attenuated SSc collagen deposition and processing (P˂0.05). Assessment of JQ1 in a pre-clinical model of dermal fibrosis demonstrated a markedly attenuation of dermal thickening in vivo(P˂0.05). Consistent with this we observed significant reduction in fibrogenic markers including αSMA, and collagen expression in the skin (P˂0.05). Furthermore secretion of the inflammatory marker, IL-6 was significantly attenuated (P˂0.05).
Conclusion: We have assessed the functional effects of the Brd inhibitor, JQ1, on SSc dermal fibroblasts and the development of dermal fibrosis in a pre-clinical model of dermal fibrosis. We demonstrate that JQ1 markedly attenuated the excessive deposition and processing of collagen type I by SSc fibroblasts. In keeping with Brd proteins playing a pivotal role in the development and progression of dermal fibrosis, JQ1 significantly inhibited ECM deposition in vivo. Our data suggests a key role for Brd proteins in the persistence of the SSc dermal fibroblast phenotype.
A. M. Holmes,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/bromodomain-inhibitor-jq1-modulates-collagen-processing-and-ameliorates-bleomycin-induced-dermal-fibrosis-in-mice/