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The dynamin inhibitor dynasore inhibits bone resorption by rapidly disrupting actin rings of osteoclasts

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Abstract

The cytoskeletal organization of osteoclasts is required for bone resorption. Binding of dynamin with guanosine triphosphate (GTP) was previously suggested to be required for the organization of the actin cytoskeleton. However, the role of the GTPase activity of dynamin in the organization of the actin cytoskeleton as well as in the bone-resorbing activity of osteoclasts remains unclear. This study investigated the effects of dynasore, an inhibitor of the GTPase activity of dynamin, on the bone-resorbing activity of and actin ring formation in mouse osteoclasts in vitro and in vivo. Dynasore inhibited the formation of resorption pits in osteoclast cultures by suppressing actin ring formation and rapidly disrupting actin rings in osteoclasts. A time-lapse image analysis showed that dynasore shrank actin rings in osteoclasts within 30 min. The intraperitoneal administration of dynasore inhibited receptor activator of nuclear factor κB ligand (RANKL)-induced trabecular bone loss in mouse femurs. These in vitro and in vivo results suggest that the GTPase activity of dynamin is critical for the bone-resorbing activity of osteoclasts and that dynasore is a seed for the development of novel anti-resorbing agents.

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Acknowledgments

This work was supported by Grants-in-Aid for Scientific Research, Kakenhi [Grant number: 25221310 (N.T.), 24390417(N.U.), 25293423 (Y.K.), 25462904 (S.U.)].

Conflict of interest

None of the authors have any conflicts of interest.

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Author notes

    Authors and Affiliations

    1. Institute for Oral Science, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri-shi, Nagano, 399-0781, Japan

      Gnanasagar J. Thirukonda, Teruhito Yamashita, Toshihide Mizoguchi, Naoyuki Takahashi & Yasuhiro Kobayashi

    2. Department of Biochemistry, Matsumoto Dental University, Nagano, 399-0781, Japan

      Shunsuke Uehara & Nobuyuki Udagawa

    3. Department of Periodontology, Matsumoto Dental University, Nagano, 399-0781, Japan

      Takahiro Nakayama

    4. Department of Orthopaedic Surgery, School of Medicine, Shinshu University, Nagano, 390-8621, Japan

      Yukio Nakamura

    5. Department of Oral Implantology, Matsumoto Dental University, Nagano, 399-0781, Japan

      Kimitoshi Yagami

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    1. Gnanasagar J. Thirukonda
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    2. Shunsuke Uehara
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    3. Takahiro Nakayama
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    Correspondence to Yasuhiro Kobayashi.

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    G. J. Thirukonda and S. Uehara contributed equally to this work.

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    Thirukonda, G.J., Uehara, S., Nakayama, T. et al. The dynamin inhibitor dynasore inhibits bone resorption by rapidly disrupting actin rings of osteoclasts. J Bone Miner Metab 34, 395–405 (2016). https://doi.org/10.1007/s00774-015-0683-1

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    • DOI: https://doi.org/10.1007/s00774-015-0683-1

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