Constitutively active PTH/PTHrP receptor specifically expressed in osteoblasts enhances bone formation induced by bone marrow ablation

Authors

  • Noriaki Ono,

    1. Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
    2. Global Center of Excellence Program for the International Research Center for Molecular Science in Tooth and Diseases, Tokyo Medical and Dental University, Tokyo, Japan
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  • Kazuhisa Nakashima,

    Corresponding author
    1. Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
    2. Global Center of Excellence Program for the International Research Center for Molecular Science in Tooth and Diseases, Tokyo Medical and Dental University, Tokyo, Japan
    • Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 5-45 Yushima 1-Chome, Bunkyo-ku, Tokyo, Japan.
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  • Ernestina Schipani,

    1. Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
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  • Tadayoshi Hayata,

    1. Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
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  • Yoichi Ezura,

    1. Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
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  • Kunimichi Soma,

    1. Orthodontic Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
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  • Henry M. Kronenberg,

    1. Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
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  • Masaki Noda

    Corresponding author
    1. Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
    2. Global Center of Excellence Program for the International Research Center for Molecular Science in Tooth and Diseases, Tokyo Medical and Dental University, Tokyo, Japan
    3. ABJS Integrated Action Initiative in JSPS Core to Core Program, Tokyo Medical and Dental University, Tokyo, Japan
    4. Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Tokyo, Japan
    • Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 5-45 Yushima 1-Chome, Bunkyo-ku, Tokyo, Japan.
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Abstract

Bone is maintained by continuous bone formation by osteoblasts provided by proliferation and differentiation of osteoprogenitors. Parathyroid hormone (PTH) activates bone formation, but because of the complexity of cells in the osteoblast lineage, how these osteoprogenitors are regulated by PTH in vivo is incompletely understood. To elucidate how signals by PTH in differentiated osteoblasts regulate osteoprogenitors in vivo, we conducted bone marrow ablation using Col1a1-constitutively active PTH/PTHrP receptor (caPPR) transgenic mice. These mice express caPPR specifically in osteoblasts by using 2.3 kb Col1a1 promoter and showed higher trabecular bone volume under steady-state conditions. In contrast, after bone marrow ablation, stromal cells recruited from bone surface extensively proliferated in the marrow cavity in transgenic mice, compared to limited proliferation in wild-type mice. Whereas de novo bone formation was restricted to the ablated area in wild-type mice, the entire marrow cavity, including not only ablated area but also outside the ablated area, was filled with newly formed bone in transgenic mice. Bone mineral density was significantly increased after ablation in transgenic mice. Bone marrow cell culture in osteogenic medium revealed that alkaline phosphatase-positive area was markedly increased in the cells obtained from transgenic mice. Furthermore, mRNA expression of Wnt-signaling molecules such as LRP5, Wnt7b, and Wnt10b were upregulated after marrow ablation in bone marrow cells of transgenic mice. These results indicate that constitutive activation of PTH/PTHrP receptor in differentiated osteoblasts enhances bone marrow ablation-induced recruitment, proliferation, and differentiation of osteoprogenitors. J. Cell. Physiol. 227: 408–415, 2012. © 2011 Wiley Periodicals, Inc.

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