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.

• Authors: Kohji Kuriyama, Chikahisa Higuchi, Keiichi Tanaka, Hideki Yoshikawa, Kazuyuki Itoh
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 299 Issue 5 Pg. 903-9 (Dec 20 2002) ISSN: 0006-291X [Print] United States
• PMID: 12470665 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antirheumatic Agents
• BMP2 protein, human
• Benzopyrans
• Bmp2 protein, mouse
• Bone Morphogenetic Protein 2
• Bone Morphogenetic Proteins
• Neoplasm Proteins
• RNA, Messenger
• Sulfonamides
• Transcription Factors
• Transforming Growth Factor beta
• Osteocalcin
• T 614
• Alkaline Phosphatase

Topics

• Alkaline Phosphatase (analysis, metabolism)
• Animals
• Antirheumatic Agents (metabolism, pharmacology)
• Benzopyrans (metabolism, pharmacology)
• Bone Morphogenetic Protein 2
• Bone Morphogenetic Proteins (pharmacology)
• Bone and Bones (anatomy & histology, drug effects)
• Cell Differentiation (drug effects)
• Cell Line
• Dose-Response Relationship, Drug
• Drug Synergism
• Mice
• Neoplasm Proteins
• Osteoblasts (cytology, drug effects, physiology)
• Osteocalcin (genetics, metabolism)
• Osteogenesis (drug effects)
• RNA, Messenger (biosynthesis)
• Stromal Cells (drug effects, metabolism)
• Sulfonamides (metabolism, pharmacology)
• Transcription Factors (biosynthesis, genetics)
• Transforming Growth Factor beta