Inhibition of branched chain amino acid aminotransferase 1 suppresses the severity of collagen-induced arthritis in mice (THER5P.905)

Abstract

Abstract BCAT is the enzyme responsible for the reverse transamination of branched chain amino acids to corresponding α-keto acids. It exists as two distinct isozymes with mutually exclusive tissue distribution: a mitochondrial one (BCAT2) and a cytosolic one (BCAT1). The present study reports on the effect of BCAT1 inhibition on CIA, a murine model of rheumatoid arthritis (RA). Oral administration of ERG240, a small molecular weight BCAT1 inhibitor, alleviated the severity of the clinical development of CIA and exerted a strong protective effect on the integrity of the joints of affected animals. When the drug was given at 1000 mg/kg 5x per week for 4 weeks the clinical score and paw thickness was reduced by 40%. Immunohistochemical (IHC) analysis of preserved tissues revealed that ERG240 treatment reduced inflammation by ~50%, pannus formation by ~90%, cartilage damage by ~75%, and bone erosion by ~90%. Further IHC analysis indicated that the mechanism of action of ERG240 involved a reduction in the number of macrophages and osteoclasts present in the joints and CD45R+ cells in the bone marrow of the animals. Analysis of terminal sera, collected from treated and control animals, suggested that ERG240 administration also suppresses the levels of secreted cytokines such as TNF-α and RANKL. In vitro, ERG240 inhibited serum-driven migration of bone marrow derived macrophages. Collectively, the data indicate that BCAT1 constitutes a new druggable target for the treatment of RA.