Evaluating the bromodomain protein
Evaluating the bromodomain protein BRD1 as a therapeutic target in rheumatoid arthritis
Kerstin Klein, Masaru Kato, Mojca Frank-Bertoncelj, Christoph Kolling, Adrian Ciurea, Steffen Gay & Caroline Ospelt
Targeting epigenetic reader proteins by small molecule inhibitors represents a new therapeutic concept in autoimmune diseases such as rheumatoid arthritis (RA). Although inhibitors targeting bromodomain protein 1 (BRD1) are in development, the function of BRD1 has hardly been studied. We investigated the therapeutic potential of BRD1 inhibition in joint-resident cells in RA, synovial fibroblasts (SF) and macrophages. The proliferation of SF was decreased upon BRD1 silencing, accompanied by the downregulation of genes involved in cell cycle regulation. Silencing of BRD1 in SF decreased the basal expression of MMP1 but increased TNF-α- and LPS-induced levels of MMP3, IL6 and IL8. In monocyte-derived macrophages (MDM), silencing of BRD1 decreased the LPS-induced expression of TNF-α, but did not significantly affect basal and the TNF-α- and LPS-induced expression of IL6 and IL8.
Our data point to a cell type- and a stimulus-specific function of BRD1. Therefore, inhibitors should be tested in a variety of cell types and under different stimulatory conditions. Inhibiting BRD1 could have potential beneficial effects in RA via decreasing the proliferation of SF. Anti-inflammatory effects were limited and only observed in MDM.
Kerstin Klein is a senoir postdoctoral scientist at the Centre of Experimental Rheumatology, University Hospital Zurich since 2010. Her major scientific interest is the the role of epigenetic mechanisms in rheumatoid arthritis and the potential of epigenetic enzymes as future therapeutic targets.
- Synovial fibroblasts