Journal of Bone and Mineral Metabolism

, Volume 26, Issue 6, pp 642–647

Involvement of cell-cell and cell-matrix interactions in bone destruction induced by metastatic MDA-MB-231 human breast cancer cells in nude mice

  • Hiroaki Nakamura
  • Toru Hiraga
  • Tadashi Ninomiya
  • Akihiro Hosoya
  • Noboru Fujisaki
  • Toshiyuki Yoneda
  • Hidehiro Ozawa
Short Communication

Abstract

To clarify the mechanisms of bone destruction associated with bone metastases, we studied an animal model in which inoculation of MDA-MB-231 human breast cancer cells into the left cardiac ventricle of female nude mice causes osteolytic lesions in bone using morphological techniques. On the bone surfaces facing the metastatic tumor cells, there existed many tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts. TRAP-positive mononuclear osteoclast precursor cells were also observed in the tumor nests. Immunohistochemical studies showed that the cancer cells produced parathyroid hormone-related protein (PTHrP) but not receptor activator of NF-κB ligand (RANKL). Histochemical and immunohistochemical examinations demonstrated that alkaline phosphatase and RANKL-positive stromal cells were frequently adjacent to TRAP-positive osteoclast-like cells. Immunoelectron microscopic observation revealed that osteoclast-like cells were in contact with RANKL-positive stromal cells. MDA-MB-231 cells and osteoclastlike cells in the tumor nests showed CD44-positive reactivity on their plasma membranes. Hyaluronan (HA) and osteopontin (OPN), the ligands for CD44, were occasionally colocalized with CD44. These results suggest that tumorproducing osteoclastogenic factors, including PTHrP, upregulate RANKL expression in bone marrow stromal cells, which in turn stimulates the differentiation and activation of osteoclasts, leading to the progression of bone destruction in the bone metastases of MDA-MB-231 cells. Because the interactions between CD44 and its ligands, HA and OPN, have been shown to upregulate osteoclast differentiation and function, in addition to the cell-cell interactions mediated by RANK and RANKL, the cell-matrix interactions mediated by these molecules may also contribute to the progression of osteoclastic bone destruction.

Key words

bone destruction bone metastasis breast cancer osteoclast bone marrow stromal cell 

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Copyright information

© Springer Japan 2008

Authors and Affiliations

  • Hiroaki Nakamura
    • 1
  • Toru Hiraga
    • 1
  • Tadashi Ninomiya
    • 2
  • Akihiro Hosoya
    • 1
  • Noboru Fujisaki
    • 3
  • Toshiyuki Yoneda
    • 4
  • Hidehiro Ozawa
    • 2
  1. 1.Department of Oral HistologyMatsumoto Dental UniversityNaganoJapan
  2. 2.Institute for Oral ScienceMatsumoto Dental UniversityNaganoJapan
  3. 3.Graduate School of Oral MedicineMatsumoto Dental UniversityNaganoJapan
  4. 4.Department of BiochemistryOsaka University Graduate School of DentistryOsakaJapan

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