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Published online
doi:10.1083/jcb.200806139
The Journal of Cell Biology, Vol. 184, No. 4, 541-554
The Rockefeller University Press, 0021-9525 $30.00
© Mizoguchi et al.
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Article

Identification of cell cycle–arrested quiescent osteoclast precursors in vivo



Toshihide Mizoguchi1, Akinori Muto1,4, Nobuyuki Udagawa2, Atsushi Arai1, Teruhito Yamashita1, Akihiro Hosoya3, Tadashi Ninomiya1, Hiroaki Nakamura3, Yohei Yamamoto1, Saya Kinugawa1, Midori Nakamura2, Yuko Nakamichi1, Yasuhiro Kobayashi1, Sakae Nagasawa1, Kimimitsu Oda5, Hirofumi Tanaka6, Mitsuo Tagaya6, Josef M. Penninger7, Michio Ito1, and Naoyuki Takahashi1

1 Institute for Oral Science, 2 Department of Biochemistry, and 3 Department of Oral Histology, Matsumoto Dental University, Nagano 399-0781, Japan
4 Department of Periodontology, School of Dentistry, Aichi Gakuin University, Aichi 464-8651, Japan
5 Department of Biochemistry, School of Dentistry, Niigata University, Niigata 951-8514, Japan
6 School of Life Science, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan
7 Institute of Molecular Biotechnology of the Austrian Academy of Sciences, A-1030 Vienna, Austria

Correspondence to Naoyuki Takahashi: takahashinao{at}po.mdu.ac.jp

Osteoclasts are multinucleated cells that resorb bone. Although osteoclasts originate from the monocyte/macrophage lineage, osteoclast precursors are not well characterized in vivo. The relationship between proliferation and differentiation of osteoclast precursors is examined in this study using murine macrophage cultures treated with macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-{kappa}B (RANK) ligand (RANKL). Cell cycle–arrested quiescent osteoclast precursors (QuOPs) were identified as the committed osteoclast precursors in vitro. In vivo experiments show that QuOPs survive for several weeks and differentiate into osteoclasts in response to M-CSF and RANKL. Administration of 5-fluorouracil to mice induces myelosuppression, but QuOPs survive and differentiate into osteoclasts in response to an active vitamin D3 analogue given to those mice. Mononuclear cells expressing c-Fms and RANK but not Ki67 are detected along bone surfaces in the vicinity of osteoblasts in RANKL-deficient mice. These results suggest that QuOPs preexist at the site of osteoclastogenesis and that osteoblasts are important for maintenance of QuOPs.

Abbreviations used in this paper: ALP, alkaline phosphatase; HSC, hematopoietic stem cell; HU, hydroxyurea; LPS, lipopolysaccharide; M-CSF, macrophage colony-stimulating factor; PTH, parathyroid hormone; QuOP, quiescent osteoclast precursor; RANK, receptor activator of NF-{kappa}B; RANKL, RANK ligand; TRAP, tartrate-resistant acid phosphatase.

© 2009 Mizoguchi et al.
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