Evaluating the bromodomain protein BRD1 as a therapeutic target in rheumatoid arthritis.
Kerstin KleinMasaru KatoMojca Frank-BertonceljChristoph KollingAdrian CiureaSteffen GayCaroline OspeltPublished in: Scientific reports (2018)
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. 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.
Keyphrases
- lps induced
- rheumatoid arthritis
- inflammatory response
- disease activity
- cell cycle
- poor prognosis
- small molecule
- signaling pathway
- ankylosing spondylitis
- binding protein
- interstitial lung disease
- cell proliferation
- protein protein
- induced apoptosis
- long non coding rna
- systemic lupus erythematosus
- dna methylation
- cell death
- climate change
- cancer therapy
- risk assessment
- electronic health record
- human health
- mass spectrometry
- drug delivery
- patient safety
- extracellular matrix
- single molecule
- immune response
- pi k akt
- oxidative stress