Kuriyama Kohji, Higuchi Chikahisa, Tanaka Keiichi, Yoshikawa Hideki, Itoh Kazuyuki
Department of Biology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-2 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan.
Biochem Biophys Res Commun. 2002 Dec 20;299(5):903-9. doi: 10.1016/s0006-291x(02)02754-7.
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.
T-614（N-[3-(甲酰氨基)-4-氧代-6-苯氧基-4H-色烯-7-基]甲磺酰胺）是一种正在进行临床试验的新开发的抗风湿药物，是一种抗炎剂，据报道在体内关节炎模型中具有抑制骨破坏的作用。我们发现，无论有无重组人骨形态发生蛋白-2（rhBMP-2），T-614均可刺激基质细胞系（ST2）和成骨前体细胞系（MC3T3-E1）的成骨细胞分化。在ST2细胞中，在rhBMP-2存在的情况下添加T-614可使矿化结节的钙含量提高14倍，但在MC3T3-E1细胞中则不然。对小鼠口服T-614也可促进rhBMP-2在体内诱导的骨形成。Northern印迹分析表明，在ST2细胞中，T-614与rhBMP-2共同作用可使成骨细胞分化所必需的转录因子osterix的转录水平提高3倍。综上所述，这些结果表明，T-614除了具有抑制骨吸收的作用外，还通过增加osterix的表达对骨代谢具有合成代谢作用。
