Skip to main content

Advertisement

SpringerLink
Log in

Docetaxel inhibits bone resorption through suppression of osteoclast formation and function in different manners

  • Original Article
  • Published:
Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Osteoclasts are formed from the monocyte-macrophage lineage in response to receptor activator of nuclear factor κB ligand (RANKL) expressed by osteoblasts. Bone is the most common site of breast cancer metastasis, and osteoclasts play roles in the metastasis. The taxane-derived compounds paclitaxel and docetaxel are used for the treatment of malignant diseases, including breast cancer. Here we explored the effects of docetaxel on osteoclastic bone resorption in mouse culture systems. Osteoclasts were formed within 6 days in cocultures of osteoblasts and bone marrow cells treated with 1,25-dihydroxyvitamin D3 plus prostaglandin E2. Docetaxel at 10−8 M inhibited osteoclast formation in the coculture when added for the entire culture period or for the first 3 days. Docetaxel, even at 10−6 M added for the final 3 days, failed to inhibit osteoclast formation. Osteoprotegerin, a decoy receptor of RANKL, completely inhibited osteoclast formation when added for the final 3 days. Docetaxel at 10−8 M inhibited the proliferation of osteoblasts and bone marrow cells. RANKL mRNA expression induced by 1,25-dihydroxyvitamin D3 plus prostaglandin E2 in osteoblasts was not affected by docetaxel even at 10−6 M. Docetaxel at 10−6 M, but not at 10−8 M, inhibited pit-forming activity of osteoclasts cultured on dentine. Actin ring formation and l-glutamate secretion by osteoclasts were also inhibited by docetaxel at 10−6 M. Thus, docetaxel inhibits bone resorption in two different manners: inhibition of osteoclast formation at 10−8 M and of osteoclast function at 10−6 M. These results suggest that taxanes have beneficial effects in the treatment of bone metastatic cancers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Lipton A (2006) Future treatment of bone metastases. Clin Cancer Res 12:6305s–6308s

    Article  PubMed  CAS  Google Scholar 

  2. Mundy GR (2002) Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2:584–593

    Article  PubMed  CAS  Google Scholar 

  3. Clines GA, Guise TA (2005) Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone. Endocr Relat Cancer 12:549–583

    Article  PubMed  CAS  Google Scholar 

  4. Roodman GD (2004) Mechanisms of bone metastasis. N Engl J Med 350:1655–1664

    Article  PubMed  CAS  Google Scholar 

  5. Hiraga T, Myoui A, Choi ME, Yoshikawa H, Yoneda T (2006) Stimulation of cyclooxygenase-2 expression by bone-derived transforming growth factor-β enhances bone metastases in breast cancer. Cancer Res 66:2067–2073

    Article  PubMed  CAS  Google Scholar 

  6. Crown J, O’Leary M (2000) The taxanes: an update. Lancet 355:1176–1178

    Article  PubMed  CAS  Google Scholar 

  7. Piechocki MP, Lonardo F, Ensley JF, Nguyen T, Kim H, Yoo GH (2002) Anticancer activity of docetaxel in murine salivary gland carcinoma. Clin Cancer Res 8:870–877

    PubMed  CAS  Google Scholar 

  8. Morse DL, Gray H, Payne CM, Gillies RJ (2005) Docetaxel induces cell death through mitotic catastrophe in human breast cancer cells. Mol Cancer Ther 4:1495–1504

    Article  PubMed  CAS  Google Scholar 

  9. Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D, Anton A, Lluch A, Kennedy J, O’Byrne K, Conte P, Green M, Ward C, Mayne K, Extra JM (2005) Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol 23:4265–4274

    Article  PubMed  CAS  Google Scholar 

  10. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V et al (2006) Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354:809–820

    Article  PubMed  CAS  Google Scholar 

  11. Amos LA, Lowe J (1999) How Taxol stabilises microtubule structure. Chem Biol 6:R65–R69

    Article  PubMed  CAS  Google Scholar 

  12. Orr GA, Verdier-Pinard P, McDaid H, Horwitz SB (2003) Mechanisms of Taxol resistance related to microtubules. Oncogene 22:7280–7295

    Article  PubMed  CAS  Google Scholar 

  13. Subbaramaiah K, Hart JC, Norton L, Dannenberg AJ (2000) Microtubule-interfering agents stimulate the transcription of cyclooxygenase-2. Evidence for involvement of ERK1/2 AND p38 mitogen-activated protein kinase pathways. J Biol Chem 275:14838–14845

    Article  PubMed  CAS  Google Scholar 

  14. Lee LF, Li G, Templeton DJ, Ting JP (1998) Paclitaxel (Taxol)-induced gene expression and cell death are both mediated by the activation of c-Jun NH2-terminal kinase (JNK/SAPK). J Biol Chem 273:28253–28360

    Article  PubMed  CAS  Google Scholar 

  15. Wang TH, Wang HS, Soong YK (2000) Paclitaxel-induced cell death: where the cell cycle and apoptosis come together. Cancer (Phila) 88:2619–2628

    Article  CAS  Google Scholar 

  16. Subbaramaiah K, Marmo TP, Dixon DA, Dannenberg AJ (2003) Regulation of cyclooxgenase-2 mRNA stability by taxanes: evidence for involvement of p38, MAPKAPK-2, and HuR. J Biol Chem 278:37637–37647

    Article  PubMed  CAS  Google Scholar 

  17. Kawasaki K, Akashi S, Shimazu R, Yoshida T, Miyake K, Nishijima M (2000) Mouse toll-like receptor 4-MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol. J Biol Chem 275:2251–2254

    Article  PubMed  CAS  Google Scholar 

  18. Byrd-Leifer CA, Block EF, Takeda K, Akira S, Ding A (2001) The role of MyD88 and TLR4 in the LPS-mimetic activity of Taxol. Eur J Immunol 31:2448–2457

    Article  PubMed  CAS  Google Scholar 

  19. Yamamoto M, Takeda K, Akira S (2004) TIR domain-containing adaptors define the specificity of TLR signaling. Mol Immunol 40:861–868

    Article  PubMed  CAS  Google Scholar 

  20. Kawasaki K, Gomi K, Kawai Y, Shiozaki M, Nishijima M (2003) Identification of mouse MD-2 residues important for forming the cell surface TLR4-MD-2 complex recognized by anti-TLR4-MD-2 antibodies, and for conferring LPS and taxol responsiveness on mouse TLR4 by alanine-scanning mutagenesis. J Immunol 170:413–420

    PubMed  CAS  Google Scholar 

  21. Chambers TJ (2000) Regulation of the differentiation and function of osteoclasts. J Pathol 192:4–13

    Article  PubMed  CAS  Google Scholar 

  22. Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ (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

    Article  PubMed  CAS  Google Scholar 

  23. Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature (Lond) 423:337–342

    Article  CAS  Google Scholar 

  24. Väänänen HK, Zhao H, Mulari M, Halleen JM (2000) The cell biology of osteoclast function. J Cell Sci 113:377–381

    PubMed  Google Scholar 

  25. Jurdic P, Saltel F, Chabadel A, Destaing O (2006) Podosome and sealing zone: specificity of the osteoclast model. Eur J Cell Biol 85:195–202

    Article  PubMed  CAS  Google Scholar 

  26. Okumura S, Mizoguchi T, Sato N, Yamaki M, Kobayashi Y, Yamauchi H, Ozawa H, Udagawa N, Takahashi N (2006) Coordination of microtubules and the actin cytoskeleton is important in osteoclast function, but calcitonin disrupts sealing zones without affecting microtubule networks. Bone (NY) 39:684–693

    CAS  Google Scholar 

  27. Nesbitt SA, Horton MA (1997) Trafficking of matrix collagens through bone-resorbing osteoclasts. Science 276:266–269

    Article  PubMed  CAS  Google Scholar 

  28. Salo J, Lehenkari P, Mulari M, Metsikko K, Väänänen HK (1997) Removal of osteoclast bone resorption products by transcytosis. Science 276:270–273

    Article  PubMed  CAS  Google Scholar 

  29. Morimoto R, Uehara S, Yatsushiro S, Juge N, Hua Z, Senoh S, Echigo N, Hayashi M, Mizoguchi T, Ninomiya T, Udagawa N, Omote H, Yamamoto A, Edwards RH, Moriyama Y (2006) Secretion of l-glutamate from osteoclasts through transcytosis. EMBO J 25:4175–4186

    Article  PubMed  CAS  Google Scholar 

  30. Moriyama Y, Yamamoto A (2004) Glutamatergic chemical transmission: look! Here, there, and anywhere. J Biochem (Tokyo) 135:155–163

    CAS  Google Scholar 

  31. Hall TJ, Jeker H, Schaueblin M (1995) Taxol inhibits osteoclastic bone resorption. Calcif Tissue Int 57:463–465

    Article  PubMed  CAS  Google Scholar 

  32. Inoue K, Karashima T, Fukata S, Nomura A, Kawada C, Kurabayashi A, Furihata M, Ohtsuki Y, Shuin T (2005) Effect of combination therapy with a novel bisphosphonate, minodronate (YM529), and docetaxel on a model of bone metastasis by human transitional cell carcinoma. Clin Cancer Res 11:6669–6677

    Article  PubMed  CAS  Google Scholar 

  33. Li X, Udagawa N, Takami M, Sato N, Kobayashi Y, Takahashi N (2003) p38 MAPK is crucially involved in osteoclast differentiation but not in cytokine production, phagocytosis or dendritic cell differentiation of bone marrow macrophages. Endocrinology 144:4999–5005

    Article  PubMed  CAS  Google Scholar 

  34. Suda T, Jimi E, Nakamura I, Takahashi N (1997) Role of 1α, 25-dihydroxyvitamin D3 in osteoclast differentiation and function. Methods Enzymol 282:223–235

    Article  PubMed  CAS  Google Scholar 

  35. Sato N, Takahashi N, Suda K, Nakamura M, Yamaki M, Ninomiya T, Kobayashi Y, Takada H, Shibata K, Yamamoto M, Takeda K, Akira S, Noguchi T, Udagawa N (2004) MyD88 but not TRIF is essential for osteoclastogenesis induced by lipopolysaccharide, diacyllipopeptide, and IL-1α. J Exp Med 200:601–611

    Article  PubMed  CAS  Google Scholar 

  36. Tanaka S, Takahashi N, Udagawa N, Tamura T, Akatsu T, Stanley ER, Kurokawa T, Suda T (1993) Macrophage colony-stimulating factor is indispensable for both proliferation and differentiation of osteoclast progenitors. J Clin Invest 91:257–263

    Article  PubMed  CAS  Google Scholar 

  37. Jimi E, Akiyama S, Tsurukai T, Okahashi N, Kobayashi K, Udagawa N, Nishihara T, Takahashi N, Suda T (1999) Osteoclast differentiation factor acts as a multifunctional regulator in murine osteoclast differentiation and function. J Immunol 163:434–442

    PubMed  CAS  Google Scholar 

  38. Destaing O, Saltel F, Geminard JC, Jurdic P, Bard F (2003) Podosomes display actin turnover and dynamic self-organization in osteoclasts expressing actin-green fluorescent protein. Mol Biol Cell 14:407–416

    Article  PubMed  CAS  Google Scholar 

  39. Tsuboi H, Udagawa N, Hashimoto J, Yoshikawa H, Takahashi N, Ochi T (2005) Nurse-like cells from patients with rheumatoid arthritis support the survival of osteoclast precursors via macrophage colony-stimulating factor production. Arthritis Rheum 52:3819–3828

    Article  PubMed  CAS  Google Scholar 

  40. Brown I, Shalli K, McDonald SL, Moir SE, Hutcheon AW, Heys SD, Schofield AC (2004) Reduced expression of p27 is a novel mechanism of docetaxel resistance in breast cancer cells. Breast Cancer Res 6:R601–R607

    Article  PubMed  CAS  Google Scholar 

  41. Li Y, Kucuk O, Hussain M, Abrams J, Cher ML, Sarkar FH (2006) Antitumor and antimetastatic activities of docetaxel are enhanced by genistein through regulation of osteoprotegerin/receptor activator of nuclear factor-κB (RANK)/RANK ligand/MMP-9 signaling in prostate cancer. Cancer Res 66:4816–4825

    Article  PubMed  CAS  Google Scholar 

  42. Stewart AF (2002) Hyperparathyroidism, humoral hypercalcemia of malignancy, and the anabolic actions of parathyroid hormone and parathyroid hormone-related protein on the skeleton. J Bone Miner Res 17:758–762

    Article  PubMed  Google Scholar 

  43. Lee MK, Vincent AM, Jyoti P, John C, Christopher GA, Jorge G, Mark GK, Robert TH, Barbara P, Leslie T, Christine S, Jeffrey SR, Ennapadam V (2005) Randomized phase II study of weekly docetaxel plus trastuzumab versus weekly paclitaxel plus trastuzumab in patients with previously untreated advanced non-small cell lung carcinoma. Cancer (Phila) 10:2149–2155

    Google Scholar 

  44. Tamila KK, Gregory AO, Donn Y, Anterpreet N, Tamara C, Gerard N, Richie S, Robert D, Miguel A, Villalona C (2005) Phase II evaluation of docetaxel-modulated capecitabine in previously treated patients with non-small cell lung cancer. Clin Cancer Res 11:1870–1876

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Oral Maxillofacial Surgery, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri, Nagano, 399-0781, Japan

    Masahiro Takahashi, Shuhua Yang, Hiroko Naramoto, Minoru Yamaoka, Kiyofumi Furusawa & Takashi Uematsu

  2. Institute for Oral Science, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri, Nagano, 399-0781, Japan

    Toshihide Mizoguchi, Yuko Nakamichi, Teruhito Yamashita, Yasuhiro Kobayashi & Naoyuki Takahashi

  3. Department of Biochemistry, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri, Nagano, 399-0781, Japan

    Shunsuke Uehara & Nobuyuki Udagawa

Authors
  1. Masahiro Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshihide Mizoguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shunsuke Uehara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuko Nakamichi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shuhua Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroko Naramoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Teruhito Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yasuhiro Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Minoru Yamaoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kiyofumi Furusawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Nobuyuki Udagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Takashi Uematsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Naoyuki Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Naoyuki Takahashi.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary pdf (PDF 83 KB)

About this article

Cite this article

Takahashi, M., Mizoguchi, T., Uehara, S. et al. Docetaxel inhibits bone resorption through suppression of osteoclast formation and function in different manners. J Bone Miner Metab 27, 24–35 (2009). https://doi.org/10.1007/s00774-008-0013-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00774-008-0013-y

Keywords

Search

Navigation