Conditional deletion of Bmpr1a in differentiated osteoclasts increases osteoblastic bone formation, increasing volume of remodeling bone in mice

Authors

  • Mina Okamoto,

    1. Department of Bone and Cartilage Biology, Osaka University Graduate School of Medicine, Osaka, Japan
    2. Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
    3. Japan Science and Technology Agency, Tokyo, Japan
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  • Junko Murai,

    1. Department of Bone and Cartilage Biology, Osaka University Graduate School of Medicine, Osaka, Japan
    2. Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
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  • Yuuki Imai,

    1. Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan
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  • Daisuke Ikegami,

    1. Department of Bone and Cartilage Biology, Osaka University Graduate School of Medicine, Osaka, Japan
    2. Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
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  • Nobuhiro Kamiya,

    1. Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX, USA
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  • Shigeaki Kato,

    1. Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan
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  • Yuji Mishina,

    1. School of Dentistry, University of Michigan, Ann Arbor, MI, USA
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  • Hideki Yoshikawa,

    1. Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
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  • Noriyuki Tsumaki

    Corresponding author
    1. Department of Bone and Cartilage Biology, Osaka University Graduate School of Medicine, Osaka, Japan
    2. Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
    3. Japan Science and Technology Agency, Tokyo, Japan
    4. Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
    • Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
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Abstract

Bone undergoes remodeling consisting of osteoclastic bone resorption followed by osteoblastic bone formation throughout life. Although the effects of bone morphogenetic protein (BMP) signals on osteoblasts have been studied extensively, the function of BMP signals in osteoclasts has not been fully elucidated. To delineate the function of BMP signals in osteoclasts during bone remodeling, we deleted BMP receptor type IA (Bmpr1a) in an osteoclast-specific manner using a knock-in Cre mouse line to the cathepsin K locus (CtskCre/+;Bmpr1aflox/flox, designated as Bmpr1aΔOc/ΔOc). Cre was specifically expressed in multinucleated osteoclasts in vivo. Cre-dependent deletion of the Bmpr1a gene occurred at 4 days after cultivation of bone marrow macrophages obtained from Bmpr1aΔOc/ΔOc with RANKL. These results suggested that Bmpr1a was deleted after formation of osteoclasts in Bmpr1aΔOc/ΔOc mice. Expression of bone-resorption markers increased, thus suggesting that BMPRIA signaling negatively regulates osteoclast differentiation. Trabeculae in tibia and femurs were thickened in 3.5-, 8-, and 12-week-old Bmpr1aΔOc/ΔOc mice. Bone histomorphometry revealed increased bone volume associated with increased osteoblastic bone-formation rates (BFR) in the remodeling bone of the secondary spongiosa in Bmpr1aΔOc/ΔOc tibias at 8 weeks of age. For comparison, we also induced an osteoblast-specific deletion of Bmpr1a using Col1a1-Cre. The resulting mice showed increased bone volume with marked decreases in BFR in tibias at 8 weeks of age. These results indicate that deletion of Bmpr1a in differentiated osteoclasts increases osteoblastic bone formation, thus suggesting that BMPR1A signaling in osteoclasts regulates coupling to osteoblasts by reducing bone-formation activity during bone remodeling. © 2011 American Society for Bone and Mineral Research

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