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Elevated expression of Runx2 as a key parameter in the etiology of osteosarcoma

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Abstract

To understand the molecular etiology of osteosarcoma, we isolated and characterized a human osteosarcoma cell line (OS1). OS1 cells have high osteogenic potential in differentiation induction media. Molecular analysis reveals OS1 cells express the pocket protein pRB and the runt-related transcription factor Runx2. Strikingly, Runx2 is expressed at higher levels in OS1 cells than in human fetal osteoblasts. Both pRB and Runx2 have growth suppressive potential in osteoblasts and are key factors controlling competency for osteoblast differentiation. The high levels of Runx2 clearly suggest osteosarcomas may form from committed osteoblasts that have bypassed growth restrictions normally imposed by Runx2. Interestingly, OS1 cells do not exhibit p53 expression and thus lack a functional p53/p21 DNA damage response pathway as has been observed for other osteosarcoma cell types. Absence of this pathway predicts genomic instability and/or vulnerability to secondary mutations that may counteract the anti-proliferative activity of Runx2 that is normally observed in osteoblasts. We conclude OS1 cells provide a valuable cell culture model to examine molecular events that are responsible for the pathologic conversion of phenotypically normal osteoblast precursors into osteosarcoma cells.

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Acknowledgments

We thank Yoshiaki Ito and Kosei Ito, Institute of Molecular and Cell Biology, Singapore, for providing the Runx2 antibody used in our studies and all the members of the laboratories participating in the Singapore Osteobiology group for stimulating discussions. In particular we thank Ren Xia Fei, Mario Galindo, Nadiya Teplyuk, Kakoli Das, David Leong, Dietmar Hutmacher, Lee Eng Hin, Wong Hee Kit, Jane Lian and Janet Stein for stimulating discussions. This study was co-supported by funding from NIH (grant R01 AR049069 to AvW and grant P01 CA082834 to GS) and Singapore Cancer Syndicate, A*STAR (grants MN-005 and MN-077, to MST).

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Authors and Affiliations

  1. Musculoskeletal Oncology Research Laboratory, Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 10 Lower Kent Ridge Road, Singapore, 119074, Singapore

    Saminathan S. Nathan, Barry P. Pereira, Robert W. H. Pho & Andre J. van Wijnen

  2. Oncology Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, 28 Medical Drive, Singapore, 117456, Singapore

    Ye-fang Zhou, Anurag Gupta, Ritchie Soong, Manuel Salto-Tellez & Andre J. van Wijnen

  3. Laboratory of Stem Cells and Tissue Repair, Institute of Medical Biology, 61 Biopolis Place, Proteos, Singapore, 138673, Singapore

    Christian Dombrowski & Simon M. Cool

  4. Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA

    Gary S. Stein & Andre J. van Wijnen

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  1. Saminathan S. Nathan
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  2. Barry P. Pereira
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  3. Ye-fang Zhou
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  4. Anurag Gupta
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  6. Ritchie Soong
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  7. Robert W. H. Pho
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  8. Gary S. Stein
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  9. Manuel Salto-Tellez
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  10. Simon M. Cool
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  11. Andre J. van Wijnen
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Correspondence to Saminathan S. Nathan or Andre J. van Wijnen.

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Each author certifies that his or her institution has approved the human protocol for this investigation that all investigations were conducted in conformity with ethical principles of research, and that informed consent for participation in the study was obtained.

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Nathan, S.S., Pereira, B.P., Zhou, Yf. et al. Elevated expression of Runx2 as a key parameter in the etiology of osteosarcoma. Mol Biol Rep 36, 153–158 (2009). https://doi.org/10.1007/s11033-008-9378-1

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  • DOI: https://doi.org/10.1007/s11033-008-9378-1

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