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Administration of BMP2/7 in utero partially reverses Rubinstein-Taybi syndrome–like skeletal defects induced by Pdk1 or Cbp mutations in mice
Jae-Hyuck Shim,1 Matthew B. Greenblatt,1,2 Anju Singh,1 Nicholas Brady,1 Dorothy Hu,1 Rebecca Drapp,1 Wataru Ogawa,3 Masato Kasuga,4 Tetsuo Noda,5 Sang-Hwa Yang,6 Sang-Kyou Lee,6 Vivienne I. Rebel,7 and Laurie H. Glimcher1,2
1Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA. 2Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 3Department of Internal Medicine, Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan. 4Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan. 5Department of Cell Biology, Cancer Institute, Tokyo, Japan. 6Department of Biotechnology and National Creative Research Initiatives Center for Inflammatory Response Modulation, Yonsei University, Seoul, Republic of Korea. 7Department of Cellular and Structural Biology, Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
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1Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA. 2Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 3Department of Internal Medicine, Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan. 4Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan. 5Department of Cell Biology, Cancer Institute, Tokyo, Japan. 6Department of Biotechnology and National Creative Research Initiatives Center for Inflammatory Response Modulation, Yonsei University, Seoul, Republic of Korea. 7Department of Cellular and Structural Biology, Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
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1Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA. 2Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 3Department of Internal Medicine, Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan. 4Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan. 5Department of Cell Biology, Cancer Institute, Tokyo, Japan. 6Department of Biotechnology and National Creative Research Initiatives Center for Inflammatory Response Modulation, Yonsei University, Seoul, Republic of Korea. 7Department of Cellular and Structural Biology, Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
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1Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA. 2Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 3Department of Internal Medicine, Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan. 4Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan. 5Department of Cell Biology, Cancer Institute, Tokyo, Japan. 6Department of Biotechnology and National Creative Research Initiatives Center for Inflammatory Response Modulation, Yonsei University, Seoul, Republic of Korea. 7Department of Cellular and Structural Biology, Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
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1Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA. 2Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 3Department of Internal Medicine, Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan. 4Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan. 5Department of Cell Biology, Cancer Institute, Tokyo, Japan. 6Department of Biotechnology and National Creative Research Initiatives Center for Inflammatory Response Modulation, Yonsei University, Seoul, Republic of Korea. 7Department of Cellular and Structural Biology, Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
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1Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA. 2Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 3Department of Internal Medicine, Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan. 4Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan. 5Department of Cell Biology, Cancer Institute, Tokyo, Japan. 6Department of Biotechnology and National Creative Research Initiatives Center for Inflammatory Response Modulation, Yonsei University, Seoul, Republic of Korea. 7Department of Cellular and Structural Biology, Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
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1Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA. 2Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 3Department of Internal Medicine, Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan. 4Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan. 5Department of Cell Biology, Cancer Institute, Tokyo, Japan. 6Department of Biotechnology and National Creative Research Initiatives Center for Inflammatory Response Modulation, Yonsei University, Seoul, Republic of Korea. 7Department of Cellular and Structural Biology, Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
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1Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA. 2Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 3Department of Internal Medicine, Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan. 4Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan. 5Department of Cell Biology, Cancer Institute, Tokyo, Japan. 6Department of Biotechnology and National Creative Research Initiatives Center for Inflammatory Response Modulation, Yonsei University, Seoul, Republic of Korea. 7Department of Cellular and Structural Biology, Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
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1Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA. 2Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 3Department of Internal Medicine, Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan. 4Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan. 5Department of Cell Biology, Cancer Institute, Tokyo, Japan. 6Department of Biotechnology and National Creative Research Initiatives Center for Inflammatory Response Modulation, Yonsei University, Seoul, Republic of Korea. 7Department of Cellular and Structural Biology, Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
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1Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA. 2Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 3Department of Internal Medicine, Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan. 4Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan. 5Department of Cell Biology, Cancer Institute, Tokyo, Japan. 6Department of Biotechnology and National Creative Research Initiatives Center for Inflammatory Response Modulation, Yonsei University, Seoul, Republic of Korea. 7Department of Cellular and Structural Biology, Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
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1Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA. 2Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 3Department of Internal Medicine, Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan. 4Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan. 5Department of Cell Biology, Cancer Institute, Tokyo, Japan. 6Department of Biotechnology and National Creative Research Initiatives Center for Inflammatory Response Modulation, Yonsei University, Seoul, Republic of Korea. 7Department of Cellular and Structural Biology, Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
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1Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA. 2Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 3Department of Internal Medicine, Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan. 4Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan. 5Department of Cell Biology, Cancer Institute, Tokyo, Japan. 6Department of Biotechnology and National Creative Research Initiatives Center for Inflammatory Response Modulation, Yonsei University, Seoul, Republic of Korea. 7Department of Cellular and Structural Biology, Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
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1Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA. 2Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 3Department of Internal Medicine, Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan. 4Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan. 5Department of Cell Biology, Cancer Institute, Tokyo, Japan. 6Department of Biotechnology and National Creative Research Initiatives Center for Inflammatory Response Modulation, Yonsei University, Seoul, Republic of Korea. 7Department of Cellular and Structural Biology, Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
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Published May 1, 2012 - More info
J Clin Invest. 2012;122(5):1948–1948. https://doi.org/10.1172/JCI63413.
© 2012 The American Society for Clinical Investigation
Related article:
Abstract
Mutations in the coactivator CREB-binding protein (CBP) are a major cause of the human skeletal dysplasia Rubinstein-Taybi syndrome (RTS); however, the mechanism by which these mutations affect skeletal mineralization and patterning is unknown. Here, we report the identification of 3-phosphoinositide-dependent kinase 1 (PDK1) as a key regulator of CBP activity and demonstrate that its functions map to both osteoprogenitor cells and mature osteoblasts. In osteoblasts, PDK1 activated the CREB/CBP complex, which in turn controlled runt-related transcription factor 2 (RUNX2) activation and expression of bone morphogenetic protein 2 (BMP2). These pathways also operated in vivo, as evidenced by recapitulation of RTS spectrum phenotypes with osteoblast-specific Pdk1 deletion in mice (Pdk1osx mice) and by the genetic interactions observed in mice heterozygous for both osteoblast-specific Pdk1 deletion and either Runx2 or Creb deletion. Finally, treatment of Pdk1osx and Cbp+/– embryos with BMPs in utero partially reversed their skeletal anomalies at birth. These findings illustrate the in vivo function of the PDK1-AKT-CREB/CBP pathway in bone formation and provide proof of principle for in utero growth factor supplementation as a potential therapy for skeletal dysplasias.
Authors
Jae-Hyuck Shim, Matthew B. Greenblatt, Anju Singh, Nicholas Brady, Dorothy Hu, Rebecca Drapp, Wataru Ogawa, Masato Kasuga, Tetsuo Noda, Sang-Hwa Yang, Sang-Kyou Lee, Vivienne I. Rebel, Laurie H. Glimcher
Original citation: J. Clin. Invest. 2012;122(1): 91–106. doi:10.1172/JCI59466.
Citation for this corrigendum: J. Clin. Invest. 2012;122(5):1948. doi:10.1172/JCI63413.
The affiliation for Sang-Hwa Yang and Sang-Kyou Lee was incorrect. In addition, the sentence in Acknowledgments providing the source for Sang-Kyou Lee’s research grant was omitted. The correct affiliations list appears above. The omitted sentence is below.
This work was supported by National Creative Research Initiatives, a grant from the National Research Foundation of Korea funded by a Korean government grant (2011-0000425 to S.-K. Lee) and the Brain Korea 21 (BK21) Program.
The authors regret the error.
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)