A novel anti-rheumatic drug, T-614, stimulates osteoblastic differentiation in vitro and bone morphogenetic protein-2-induced bone formation in vivo

Abstract

T-614 (N-[3-(formylamino)-4-oxo-6-phenoxy-4H-chromen-7-yl]methanesulfonamide), a newly developed anti-rheumatic drug under clinical trial, is an anti-inflammatory agent which has been reported to show the inhibitory effect of bone destruction in vivo arthritis model. We found that T-614 stimulated osteoblastic differentiation of stromal cell line (ST2) and preosteoblastic cell line (MC3T3-E1) in the presence or absence of recombinant human bone morphogenetic protein-2 (rhBMP-2). Calcium content of mineralized nodules was 14-fold elevated by the addition of T-614 in the presence of rhBMP-2 in ST2 but not MC3T3-E1. Oral administration of T-614 to mice also promoted rhBMP-2 induced bone formation in vivo. Northern blot analysis showed that transcriptional level of osterix, an essential transcription factor for osteoblastic differentiation, was 3-fold increased by T-614 with rhBMP-2 in ST2. Taken together, these results suggested that T-614 possessed anabolic effects on bone metabolism, besides suppressor of bone resorption, by increased expression of osterix.