Compressive Force-Produced CCN2 Induces Osteocyte Apoptosis Through ERK1/2 Pathway

Authors

  • Kenji Hoshi,

    1. Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Japan
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  • Harumi Kawaki,

    1. Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Japan
    2. Department of Oral Biochemistry, Asahi University School of Dentistry, Mizuho, Japan
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  • Ichiro Takahashi,

    1. Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Japan
    2. Section of Orthodontics and Dentofacial Orthopedics, Kyushu University Faculty of Dental Science, Fukuoka, Japan
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  • Nobuo Takeshita,

    1. Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Japan
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  • Masahiro Seiryu,

    1. Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Japan
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  • Sakhr A Murshid,

    1. Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Japan
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  • Taisuke Masuda,

    1. Department of Micro-Nano Systems Engineering, Graduate School of Engineering, Nagoya University, Nagoya, Japan
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  • Takahisa Anada,

    1. Division of Craniofacial Function Engineering, Tohoku University Graduate School of Dentistry, Sendai, Japan
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  • Ryushi Kato,

    1. Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Japan
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  • Hideki Kitaura,

    1. Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Japan
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  • Osamu Suzuki,

    1. Division of Craniofacial Function Engineering, Tohoku University Graduate School of Dentistry, Sendai, Japan
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  • Teruko Takano-Yamamoto

    Corresponding author
    1. Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Japan
    • Address correspondence to: Teruko Takano-Yamamoto, DDS, PhD, Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Seiryo-machi 4-1, Aoba-ku, Sendai 980-8575, Japan. E-mail: t-yamamo@m.tohoku.ac.jp

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ABSTRACT

Osteocytes produce various factors that mediate the onset of bone formation and resorption and play roles in maintaining bone homeostasis and remodeling in response to mechanical stimuli. One such factor, CCN2, is thought to play a significant role in osteocyte responses to mechanical stimuli, but its function in osteocytes is not well understood. Here, we showed that CCN2 induces apoptosis in osteocytes under compressive force loading. Compressive force increased CCN2 gene expression and production, and induced apoptosis in osteocytes. Application of exogenous CCN2 protein induced apoptosis, and a neutralizing CCN2 antibody blocked loading-induced apoptosis. We further examined how CCN2 induces loaded osteocyte apoptosis. In loaded osteocytes, extracellular signal-regulated kinase 1/2 (ERK1/2) was activated, and an ERK1/2 inhibitor blocked loading-induced apoptosis. Furthermore, application of exogenous CCN2 protein caused ERK1/2 activation, and the neutralizing CCN2 antibody inhibited loading-induced ERK1/2 activation. Therefore, this study demonstrated for the first time to our knowledge that enhanced production of CCN2 in osteocytes under compressive force loading induces apoptosis through activation of ERK1/2 pathway. © 2014 American Society for Bone and Mineral Research.

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