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Identification of Cell Cycle-Arrested Quiescent Osteoclast Precursors In Vivo

  • Naoyuki Takahashi
  • Akinori Muto
  • Atsushi Arai
  • Toshihide Mizoguchi
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 658)

Abstract

How are sites suitable for osteoclastogenesis determined? We addressed this issue using in vivo and in vitro experimental systems. We first examined the formation of osteoclasts in ectopic bone induced by BMP-2. When collagen disks which contained BMP-2 (BMP-2-disks) or vehicle (control-disks) were implanted into wild-type mice, osteoclasts and osteoblasts appeared in the BMP-2-disks, but not in the control disks. RANKL-deficient (RANKL–/–) mice exhibited osteopetrosis, with an absence of osteoclasts. BMP-2 and control disks were implanted into RANKL–/– mice, which were intraperitoneally injected with RANKL. Osteoclasts formed in the BMP-2-disks, but not in the control disks. In the BMP-2-disks, osteoclasts were observed in the vicinity of osteoblasts. Cell cycle-arrested quiescent osteoclast precursors (QOP) were identified as the committed osteoclast precursors in vitro. Experiments in vivo showed that QOPs survived for several weeks, and differentiated into osteoclasts in response to M-CSF and RANKL. QOPs were identified as RANK and c-Fms double-positive cells, and detected along bone surfaces in the vicinity of osteoblasts in RANKL–/– mice. QOPs were also observed in the ectopic bone induced by BMP-2 implanted into RANKL–/– mice, suggesting that QOPs were circulating. These results imply that osteoblasts support the homing of QOPs to bone tissues. In response to bone-resorbing stimuli, QOPs promptly differentiate into osteoclasts. Therefore, the distribution of QOPs appears to determine the correct site of osteoclastic development.

Keywords

Osteoclast precursor Osteoclastogenesis Osteoblast Osteoclast miche 

Abbreviations

M-CSF

macrophage colony-stimulating factor

RANK

receptor activator of NF κB

RANKL

receptor activator of NF κB ligand

PTH

parathyroid hormone

1α,25(OH)2D3

1α,25-dihydroxyvitamin D3

OPG

osteoprotegerin

WT

wild-type

Cdk

cyclin-dependent kinase

QOP

cell cycle-arrested quiescent osteoclast precursor

BMP-2

bone morphogenetic protein 2

TRAP

tartrate-resistant acid phosphatise

ALP

alkaline phosphatise

BrdU

bromodeoxyuridine

HSC

hematopoietic stem cell

References

  1. 1.
    Boyle, W.J., Simonet, W.S., Lacey, D.L. (2003). Osteoclast differentiation and activation. Nature, 423, 337–342.CrossRefPubMedGoogle Scholar
  2. 2.
    Calvi, L.M., Adams, G.B., Weibrecht, K.W. et al. (2003). Osteoblastic cells regulate the haematopoietic stem cell niche. Nature, 425, 841–846.CrossRefPubMedGoogle Scholar
  3. 3.
    Felix, R., Cecchini, M.G., & Fleisch, H. (1990). Macrophage colony stimulating factor restores in vivo bone resorption in the op/op osteopetrotic mouse. Endocrinology, 127, 2592–2594.CrossRefPubMedGoogle Scholar
  4. 4.
    Itoh, K., Udagawa, N., Matsuzaki, K. et al. (2000). Importance of membrane- or matrix-associated forms of M-CSF and RANKL/ODF in osteoclastogenesis supported by SaOS-4/3 cells expressing recombinant PTH/PTHrP Receptors. J Bone Miner Res, 15, 1766–1775.CrossRefPubMedGoogle Scholar
  5. 5.
    Kong, Y.Y., Feige, U., Sarosi, I. et al. (1999). Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature, 402, 304–309.CrossRefPubMedGoogle Scholar
  6. 6.
    Mizoguchi, T., Muto, A., Udagawa, N. et al. (2009). Identification of cell cycle-arrested quiescent osteoclast precursors in vivo. J Cell Biol, 184, 541–554.Google Scholar
  7. 7.
    Morgan, D.O. (1995). Principles of CDK regulation. Nature, 374, 131–134.CrossRefPubMedGoogle Scholar
  8. 8.
    Muto, A., Mizoguchi, T., Kobayashi, Y. et al. (2008). Cell cycle-arrested quiescent osteoclast precursors (QOP) circulate to settle in the osteoclast niche. Aegean Conference Series, 35, 95.Google Scholar
  9. 9.
    Riggs, B.L., & Parfitt, A.M. (2005). Drugs used to treat osteoporosis: the critical need for a uniform nomenclature based on their action on bone remodeling. J Bone Miner Res, 20, 177–184.CrossRefPubMedGoogle Scholar
  10. 10.
    Sherr, C.J., Roberts, J.M. (1995). Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev, 9, 1149–1163.CrossRefPubMedGoogle Scholar
  11. 11.
    Simonet, W.S., Lacey, D.L., Dunstan, C.R. et al. (1997). Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell, 89, 309–319.CrossRefPubMedGoogle Scholar
  12. 12.
    Suda, T., Takahashi, N., & Martin, T.J. (1992). Modulation of osteoclast differentiation. Endocrine Rev, 13, 66–80.Google Scholar
  13. 13.
    Suda, T., Takahashi, N., Udagawa, N. et al. (1999). Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev, 20, 345–357.CrossRefPubMedGoogle Scholar
  14. 14.
    Takahashi, N., Akatsu, T., Udagawa, N. et al. (1988). Osteoblastic cells are involved in osteoclast formation. Endocrinology, 123, 2600–2602.CrossRefPubMedGoogle Scholar
  15. 15.
    Takahashi, N., Udagawa, N., Takami, N. et al. (2002). Cells of bone: osteoclast generation. In: Raisz LG, Rodan GA, Bilezikian JP (eds.), Principles of bone biology. Academic Press, San Diego, pp. 109–126.Google Scholar
  16. 16.
    Takahashi, N., Udagawa, N., Tanaka, S. et al. (1994). Postmitotic osteoclast precursors are mononuclear cells which express macrophage-associated phenotypes. Dev Biol, 163, 212–221.CrossRefPubMedGoogle Scholar
  17. 17.
    Takayanagi, H. (2007). Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol, 7, 292–304.CrossRefPubMedGoogle Scholar
  18. 18.
    Tsuda, E., Goto, M., Mochizuki, S. et al. (1997). Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochem Biophys Res Commun, 234, 137–142.CrossRefPubMedGoogle Scholar
  19. 19.
    Yamamoto, Y., Udagawa, N., Matsuura, S. et al. (2006). Osteoblasts provide a suitable microenvironment for the action of receptor activator of NF-κB ligand. Endocrinology, 147, 3366–3374.CrossRefPubMedGoogle Scholar
  20. 20.
    Zhang, J., Niu, C., Ye, L. et al. (2003). Identification of the haematopoietic stem cell niche and control of the niche size. Nature, 425, 836–841.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Naoyuki Takahashi
    • 1
  • Akinori Muto
    • 2
  • Atsushi Arai
    • 2
  • Toshihide Mizoguchi
    • 2
  1. 1.Division of Hard Tissue ResearchInstitute for Oral Science, Matsumoto Dental UniversityNaganoJapan
  2. 2.Division of Hard Tissue ResearchInstitute for Oral Science, Matsumoto Dental UniversityNaganoJapan

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