Enhancement of osteogenesis in vitro by a novel osteoblast differentiation-promoting compound, TAK-778, partly through the expression of Msx2.
TAK-778 [(2R,4S)-(-)-N-(4-Diethoxyphosphorylmethylphenyl)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide: mw 505.52], a novel compound promoting osteoblast differentiation, promotes osteogenesis in vitro and enhances bone formation during skeletal repair in vivo. In this study, we further evaluated the effects of TAK-778 on the differentiation of cultured bone marrow stromal cells into osteoblasts in the presence of dexamethasone, paying particular attention to the expression of transcription factors involved in regulating osteoblast differentiation. Treatment of TAK-778 (10(-7)-10(-5) M) for 4 h resulted in an increase in the mRNA expression of Msx2, but not Cbfa1 or Dlx5. This transcriptional alteration preceded the changes in other markers related to the osteoblast phenotype, such as alkaline phosphatase and osteocalcin mRNA. The transfection of Msx2-antisense in the cells caused a significant reduction in the levels of alkaline phosphatase mRNA expression induced by TAK-778. These results suggest that TAK-778 promotes osteoblast differentiation partly through the expression of Msx2, a homeobox-related gene.
Gotoh
Masayuki
M
Pharmacology Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd, 17-85, Jusohonmachi 2-chome, Yodogawa, Osaka 532-8686, Japan. Goto_Masayuki@takeda.co.jp
Notoya
Kohei
K
Ienaga
Yuka
Y
Kawase
Masahiro
M
Makino
Haruhiko
H
D000818:Animals; D001582:Benzothiepins / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000096:biosynthesis; D008297:Male; D015345:Oligonucleotide Probes; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D012313:RNA / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D014970:Xanthines / Q000494:pharmacology*
C113601:3-(3-hydroxypropyl)-8-(3-methoxystyryl)-7-methyl-1-propargylxanthine; D001582:Benzothiepins; D018076:DNA, Complementary; D015345:Oligonucleotide Probes; D016376:Oligonucleotides, Antisense; C120450:TAK 778; D014970:Xanthines; D012313:RNA