4‐Phenylbutyric acid, a potent endoplasmic reticulum stress inhibitor, attenuates the severity of collagen‐induced arthritis in mice via inhibition of proliferation and inflammatory responses of synovial fibroblasts

4‐Phenylbutyric acid (4‐PBA) exerts potent pharmacological effects, including anti‐inflammatory properties, via inhibition of endoplasmic reticulum (ER) stress. However, it is not known whether 4‐PBA attenuates the severity of rheumatoid arthritis. The present study aimed to determine whether the inhibition of ER stress by 4‐PBA ameliorated experimentally induced arthritis. The proliferation of synovial fibroblasts (SFs) and expression of matrix metalloproteinases (MMPs) were evaluated in the presence of interleukin (IL)‐1β with or without 4‐PBA. The effect of 4‐PBA on the phosphorylation of Mitogen‐activated protein kinase (MAPK) and the activation of Nuclear factor‐κB (NF‐κB) in IL‐1β‐stimulated SFs was assessed. In an in vivo study, the effects of 4‐PBA were investigated using DBA/1 mice with collagen‐induced arthritis (CIA). Clinical, histological, and serological assessments of CIA treated with 4‐PBA were performed to determine the therapeutic effect of 4‐PBA. In vitro, 4‐PBA inhibited the proliferation and expression of IL‐1β‐stimulated SFs and MMP‐1 and MMP‐3 through the suppression of both the phosphorylation of MAPKs and NF‐κB in IL‐1β‐stimulated SFs. The 4‐PBA treatment markedly attenuated the severity of arthritis in CIA mice. The 4‐PBA treatment ameliorated joint swelling and the degree of bone erosion and destruction and decreased the level of inflammatory cytokines and MMP‐3 and Cox‐2. Furthermore, remarkable improvements in histopathological findings occurred in 4‐PBA‐treated mice. These findings suggested that 4‐PBA could attenuate the severity of arthritis in CIA mice by partially blocking the phosphorylation of MAPKs and the activation of NF‐κB in SFs. Thus, through the inhibition of ER stress, 4‐PBA may be a potent agent for the treatment of RA.