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Signaling and Regulation

The Osterix Transcription Factor Down-Regulates Interleukin-1 Expression in Mouse Osteosarcoma Cells

¹ Division of Pediatrics, ² Department of Head and Neck Surgery, and ³ Department of Molecular Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Eugenie S. Kleinerman, Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Unit 87, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-8110; Fax: 713-794-5042. E-mail: ekleiner{at}mdanderson.org

K7M2 mouse osteosarcoma cells form lytic tumors and are deficient in osterix (Osx), a zinc finger–containing transcription factor required for osteoblast differentiation and bone formation. Our previous studies showed that replacement of Osx suppresses lytic bone destruction. Cytokines, including interleukin (IL)-1, IL-6, IL-11, and prostaglandin E2, have been shown to stimulate osteoclast activity. We showed that IL-1 production by K7M2 cells was significantly suppressed following Osx transfection through a transcription-mediated mechanism. Osx had no effect on IL-6, IL-11, or prostaglandin E2. Site-directed mutagenesis and chromatin immunoprecipitation indicated that Osx down-regulated IL-1 through an Sp1-binding site on the IL-1 promoter. Inhibiting Osx by small interfering RNA in two cell lines (Dunn and DLM8) that expressed high levels of Osx led to enhanced IL-1 promoter activity and protein production and altered the phenotype from blastic to lytic. These data suggest that Osx down-regulates IL-1 expression in mouse osteosarcoma cells via transcriptional repression of IL-1 and this may in turn affect the lytic activity of the tumor cells. (Mol Cancer Res 2008;6(1):119–26)