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Am J Physiol Endocrinol Metab 285: E614-E621, 2003. First published March 25, 2003; doi:10.1152/ajpendo.00267.2002
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Targeting of iNOS with antisense DNA plasmid reduces cytokine-induced inhibition of osteoblastic activity

Takahiro Abe,1 Hisako Hikiji,1,3 Wee Soo Shin,2,3 Noboru Koshikiya,1,3 Sei-ichi Shima,1,3 Jumi Nakata,1,3 Takafumi Susami,1 Tsuyoshi Takato,1 and Teruhiko Toyo-oka2,3

Departments of 1Oral and Maxillofacial Surgery and 2Organ Pathophysiology and Internal Medicine and 3Health Service Centre, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan

Submitted 17 June 2002 ; accepted in final form 14 March 2003

Proinflammatry cytokines, tumor necrosis factor-{alpha} combined with interleukin-1{beta}, induce excessive production of nitric oxide (NO) and its cytotoxic metabolite peroxynitrite (ONOO-) via inducible nitric oxide synthase (iNOS) in murine osteoblasts. In this study, to properly estimate the effects of antisense DNA of iNOS on osteoblastic activity, we produced transformed cell lines with antisense plasmid that specifically targets the iNOS gene for potential long-lasting inhibition. Transformed antisense cell lines were identified by 1) the detection of antisense transcripts, 2) the attenuated expression of iNOS protein, 3) the reduction of NO synthase activity, and 4) the level of NO production. These cell lines targeting iNOS, which showed decreased production of both NO and ONOO-, prevented the inhibition of osteoblastic differentiation as was assayed by the mRNA expression of type I collagen, alkaline phosphatase, osteocalcin, and Core binding factor in the presence of proinflammatory cytokines. Present results indicate that the antisense DNA plasmid of iNOS is potent to reduce the cytokine-induced inhibition of osteoblastic activity.

inducible nitric oxide synthase; antisense; peroxynitrite; osteoblast


Address for reprint requests and other correspondence: H. Hikiji, Dept. of Oral and Maxillofacial Surgery, Faculty of Medicine, Univ. of Tokyo, 7-3-1, Hongo, Bunkyo-ku 113-8655, Tokyo, Japan (E-mail: hikiji-ora{at}h.u-tokyo.ac.jp).






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