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3-Methylcholanthrene, Which Binds to the Arylhydrocarbon Receptor, Inhibits Proliferation and Differentiation of Osteoblasts in Vitro and Ossification in Vivo

Department of Biological Sciences (M.N., A.K., H.H.), Tokyo Institute of Technology, Tokyo 226-8501, Japan; First Department of Hygiene and Public Health (Y.I.) and Department of Pediatric Cardiology (S.M.-T.), The Heart Institute of Japan, School of Medicine, Tokyo Women’s Medical University, Tokyo 162-8666, Japan

Address all correspondence and requests for reprints to: Hiromi Hagiwara, Ph.D., Department of Biological Sciences, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan. E-mail: hhagiwar{at}bio.titech.ac.jp.

3-Methylcholanthrene (3MC) is a ligand for arylhydrocarbon receptor (AhR), which binds dioxin. We examined the effects of 3MC on the proliferation and differentiation of osteoblasts using cultures of rat calvarial osteoblast-like cells (ROB cells) and mouse calvarial clonal preosteoblastic cells (MC3T3-E1 cells). Analysis by RT-PCR revealed that the mRNAs for AhR and AhR nuclear translocators were expressed in both ROB and MC3T3-E1 cells. Cell proliferation and the synthesis of DNA by ROB cells and MC3T3-E1 cells were markedly inhibited on exposure of cells to 3MC. Furthermore, 3MC reduced the activity of alkaline phosphatase and the rate of deposition of calcium by cells. The level of expression of mRNA for osteocalcin, which is a marker of osteoblastic differentiation, was also depressed by 3MC. Moreover, when 3MC (1 mg/kg body weight) was administered sc to pregnant mice at 10.5, 12.5, and 14.5 d post coitus, fetuses examined subsequently at 15.5 or 17.5 d post coitus revealed evidence of inhibition of appropriate calcification of bones. The treated metacarpals showed no subperiosteal bone matrix histologically. Our findings indicate that 3MC might have critical effects on the formation of bone both in vivo and in vitro.