Regulation of gene expression by MF63, a selective inhibitor of microsomal PGE synthase 1 (mPGES1) in human osteoarthritic chondrocytes

BACKGROUND AND PURPOSE: mPGES1 catalyses the production of PGE(2), the most abundant prostanoid related to inflammation and pain in arthritis. mPGES1 is suggested to be a safer and more selective drug target in inflammatory conditions compared to the COX enzymes inhibited by NSAIDs. In the present study, we investigated the effects of the selective mPGES1 inhibitor MF63 on gene expression in primary human chondrocytes from patients with osteoarthritis (OA). EXPERIMENTAL APPROACH: Chondrocytes were isolated from articular cartilage obtained from osteoarthritis patients undergoing knee replacement surgery. The effects of MF63 were studied in the primary chondrocytes with RNA‐sequencing based genome‐wide expression analysis. The main results were confirmed with qRT‐PCR and compared with the effects of the NSAID ibuprofen. Functional analysis was performed with the GO database and interactions between the genes were studied with STRING. KEY RESULTS: MF63 enhanced the expression of multiple metallothionein 1 (MT1) isoforms as well as endogenous antagonists of IL‐1 and IL‐36. The expression of IL‐6, by contrast, was down‐regulated. These genes were also essential in functional and interaction network analyses. The effects of MF63 were consistent in qRT‐PCR analysis, whereas the effects of ibuprofen overlapped only partly with MF63. There were no evident findings of catabolic effects by MF63. CONCLUSION AND IMPLICATIONS: Metallothionein 1 has been suggested to have anti‐inflammatory and protective effects in cartilage. Up‐regulation of the antagonists of IL‐1 superfamily and down‐regulation of the pro‐inflammatory cytokine IL‐6 also support novel anti‐inflammatory and possibly disease‐modifying effects of mPGES1 inhibitors in arthritis.