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BMP2 Differentially Regulates the Expression of Gremlin1 and Gremlin2, the Negative Regulators of BMP Function, During Osteoblast Differentiation

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Abstract

Bone morphogenetic proteins (BMPs) control the expressions of many genes involved in bone formation. On the basis of our hypothesis that BMP2 stimulation-regulated gene expression plays a critical role in osteoblast differentiation, we performed genome-wide screening of messenger RNA from BMP2-treated and -untreated C2C12 cells using a DNA microarray technique. We found that the expressions of Gremlin1 and Gremlin2, which are known BMP antagonists, were bidirectionally regulated by BMP2. Gremlin1 was down-regulated by BMP2, while Gremlin2 was up-regulated in both time- and dose-dependent manners. Ablation of Gremlin1 or Gremlin2 enhanced osteoblast differentiation induced by BMP2. On the other hand, treatment with recombinant Gremlin1 inhibited BMP2-induced osteoblast differentiation. Furthermore, treatment with Smad4 siRNA and the p38 MAPK inhibitor SB203580 suppressed BMP2-induced Gremlin2 gene expression. The differential regulation of Gremlin1 and Gremlin2 gene expressions by BMP2 may explain the critical function of these genes during osteoblast differentiation.

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Abbreviations

DAN:

Differential screening-selected gene aberrative in neuroblastoma

DRM:

Down-regulated by v-mos

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Acknowledgments

This work was supported in part by the Project to Establish Strategic Research from the Center for Innovative Dentistry by MEXT and Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan

    Dai Suzuki, Atsushi Yamada, Ryo Aizawa, Sakie Funato, Takashi Matsumoto, Wataru Suzuki, Masamichi Takami, Yoichi Miyamoto, Tetsuo Suzawa & Ryutaro Kamijo

  2. Department of Periodontology, School of Dentistry, Showa University, 2-1-1 Kitasenzoku, Ohta, Tokyo, 145-8515, Japan

    Ryo Aizawa & Matsuo Yamamoto

  3. Department of Prosthodontics, School of Dentistry, Showa University, 2-1-1 Kitasenzoku, Ohta, Tokyo, 145-8515, Japan

    Takashi Matsumoto, Wataru Suzuki & Kazuyoshi Baba

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  1. Dai Suzuki
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  2. Atsushi Yamada
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Correspondence to Atsushi Yamada.

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Suzuki, D., Yamada, A., Aizawa, R. et al. BMP2 Differentially Regulates the Expression of Gremlin1 and Gremlin2, the Negative Regulators of BMP Function, During Osteoblast Differentiation. Calcif Tissue Int 91, 88–96 (2012). https://doi.org/10.1007/s00223-012-9614-5

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  • DOI: https://doi.org/10.1007/s00223-012-9614-5

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