A novel anti-rheumatic drug, T-614, stimulates osteoblastic differentiation in vitro and bone morphogenetic protein-2-induced bone formation in vivo.
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.
Kuriyama
Kohji
K
Department of Biology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-2 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan.
Higuchi
Chikahisa
C
Tanaka
Keiichi
K
Yoshikawa
Hideki
H
Itoh
Kazuyuki
K
D000469:Alkaline Phosphatase / Q000032:analysis / Q000378:metabolism; D000818:Animals; D018501:Antirheumatic Agents / Q000378:metabolism / Q000494:pharmacology*; D001578:Benzopyrans / Q000378:metabolism / Q000494:pharmacology*; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D001842:Bone and Bones / Q000033:anatomy & histology / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D051379:Mice; D009363:Neoplasm Proteins; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta
D018501:Antirheumatic Agents; C525718:BMP2 protein, human; D001578:Benzopyrans; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D013449:Sulfonamides; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D015675:Osteocalcin; C077313:T 614; D000469:Alkaline Phosphatase