p130Cas, Crk-Associated Substrate, Plays Important Roles in Osteoclastic Bone Resorption

Authors

  • Yoshie Nagai,

    1. Division of Molecular Signaling and Biochemistry, Department of Health Improvement, Kyushu Dental University, Fukuoka, Japan
    2. Division of Developmental Stomatognathic Function Science, Department of Health Improvement, Kyushu Dental University, Fukuoka, Japan
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  • Kenji Osawa,

    1. Division of Molecular Signaling and Biochemistry, Department of Health Improvement, Kyushu Dental University, Fukuoka, Japan
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  • Hidefumi Fukushima,

    1. Division of Molecular Signaling and Biochemistry, Department of Health Improvement, Kyushu Dental University, Fukuoka, Japan
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  • Yukihiko Tamura,

    1. Section of Pharmacology, Department of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
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  • Kazuhiro Aoki,

    1. Section of Pharmacology, Department of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
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  • Keiichi Ohya,

    1. Section of Pharmacology, Department of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
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  • Hisataka Yasuda,

    1. Planning and Development, Bioindustry Division, Oriental Yeast Co., Ltd., Tokyo, Japan
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  • Hisako Hikiji,

    1. Department of Oral Functional Management, Kyushu Dental University, Fukuoka, Japan
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  • Mariko Takahashi,

    1. Section of Pharmacology, Department of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
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  • Yuji Seta,

    1. Division of Oral Histology and Neurobiology, Department of Health Improvement, Kyushu Dental University, Fukuoka, Japan
    2. Center for Oral Biological Research, Kyushu Dental University, Fukuoka, Japan
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  • Sachiko Seo,

    1. Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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  • Mineo Kurokawa,

    1. Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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  • Shigeaki Kato,

    1. Soma Central Hospital, Fukushima, Japan
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  • Hiroaki Honda,

    1. Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
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  • Ichiro Nakamura,

    1. Department of Orthopedic Surgery, Mitsui Memorial Hospital, Tokyo, Japan
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  • Kenshi Maki,

    1. Division of Developmental Stomatognathic Function Science, Department of Health Improvement, Kyushu Dental University, Fukuoka, Japan
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  • Eijiro Jimi

    Corresponding author
    1. Division of Molecular Signaling and Biochemistry, Department of Health Improvement, Kyushu Dental University, Fukuoka, Japan
    2. Center for Oral Biological Research, Kyushu Dental University, Fukuoka, Japan
    • Address correspondence to: Eijiro Jimi, DDSC, PhD, Division of Molecular Signaling and Biochemistry, Department of Health Improvement, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka 803-8580, Japan. E-mail: ejimi@kyu-dent.ac.jp

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ABSTRACT

p130Cas, Crk-associated substrate (Cas), is an adaptor/scaffold protein that plays a central role in actin cytoskeletal reorganization. We previously reported that p130Cas is not tyrosine-phosphorylated in osteoclasts derived from Src-deficient mice, which are congenitally osteopetrotic, suggesting that p130Cas serves as a downstream molecule of c-Src and is involved in osteoclastic bone resorption. However, the physiological role of p130Cas in osteoclasts has not yet been confirmed because the p130Cas-deficient mice displayed embryonic lethality. Osteoclast-specific p130Cas conditional knockout (p130CasΔOCL–) mice exhibit a high bone mass phenotype caused by defect in multinucleation and cytoskeleton organization causing bone resorption deficiency. Bone marrow cells from p130CasΔOCL– mice were able to differentiate into osteoclasts and wild-type cells in vitro. However, osteoclasts from p130CasΔOCL– mice failed to form actin rings and resorb pits on dentine slices. Although the initial events of osteoclast attachment, such as β3-integrin or Src phosphorylation, were intact, the Rac1 activity that organizes the actin cytoskeleton was reduced, and its distribution was disrupted in p130CasΔOCL– osteoclasts. Dedicator of cytokinesis 5 (Dock5), a Rho family guanine nucleotide exchanger, failed to associate with Src or Pyk2 in osteoclasts in the absence of p130Cas. These results strongly indicate that p130Cas plays pivotal roles in osteoclastic bone resorption. © 2013 American Society for Bone and Mineral Research.

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