Journal of Bone and Mineral Metabolism

, Volume 25, Issue 2, pp 99–104 | Cite as

Acidic microenvironment created by osteoclasts causes bone pain associated with tumor colonization

ORIGINAL ARTICLE

Abstract

Bone pain is one of the most common complications in cancer patients with bone metastases. Previous findings that inhibitors of osteoclastic bone resorption such as bisphosphonates (BPs) reduce bone pain suggest a critical role of osteoclasts. Osteoclasts destroy bone by secreting protons, thereby making adjacent microenvironment acidic. Because acidosis is a well-known cause of pain, it is plausible that an osteoclasts-created acidic microenvironment may cause bone pain associated with cancer colonization in bone. To test this notion, we studied an animal model in which inoculation of MRMT-1 rat breast cancer cells into the tibiae in female rats induced hyperalgesia. Radiographic and histological analyses demonstrated that MRMT-1 cells caused aggressive bone destruction with an increased number of osteoclasts. Behavioral analyses showed that rats exhibited hyperalgesia in the tumor-inoculated legs. The BP zoledronic acid (ZOL) significantly reduced the hyperalgesia. In addition, immunohistochemical examinations revealed that c-Fos expression in the ipsilateral spinal cord neurons was increased. ZOL decreased these c-Fos-positive neurons. To investigate the role of acidosis, mRNA expression of acid-sensing receptors including acid-sensing channels (ASICs) and transient receptor potential channel-vanilloid subfamily member 1 (TRPV1) in the dorsal root ganglions (DRGs) was determined. The expression of ASIC1a and ASIC1b was increased in the ipsilateral DRGs, whereas the ASIC3 and TRPV1 expression was not changed. Of note, ZOL reduced the expression of ASIC1a and ASIC1b. In conclusion, our data suggest that an acidic microenvironment created by osteoclasts, at least in part, contributes to the induction of hyperalgesia through upregulating ASICs expression.

Key words

bone pain bone metastasis bisphosphonates osteoclastic bone resorption acidosis 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Mercadante, M 1997Malignant bone pain pathophysiology and treatmentPain69118PubMedCrossRefGoogle Scholar
  2. 2.
    Mantyh, PW, Clohisy, DR, Koltzenburg, M, Hunt, S 2002Molecular mechanism of cancer painNat Rev Cancer2201209PubMedCrossRefGoogle Scholar
  3. 3.
    Luger, NM, Mach, DB, Sevcik, MA, Mantyh, PW 2005Bone cancer pain: from model to mechanism to therapyJ Pain Symptom Manag29S32S46CrossRefGoogle Scholar
  4. 4.
    Mundy, GR 2002Metastasis to bone: causes, consequences and therapeutic opportunitiesNat Rev Cancer2584593PubMedCrossRefGoogle Scholar
  5. 5.
    Smith, MR 2005Zoledronic acid to prevent skeletal complications in cancer: corroborating the evidenceCancer Treat Rev311925PubMedCrossRefGoogle Scholar
  6. 6.
    Clohisy, DR, Mantyh, PW 2004Bone cancer pain and the role of RANKL/OPGJ Musculoskelet Neuronal Interact4293300PubMedGoogle Scholar
  7. 7.
    Teitelbaum, SL 2000Bone resorption by osteoclastsScience28915041508PubMedCrossRefGoogle Scholar
  8. 8.
    Rousselle, AV, Heymann, D 2002Osteoclastic acidification pathways during bone resorptionBone (NY)30533540Google Scholar
  9. 9.
    Reeh, PW, Kress, M 2001Molecular physiology of proton transduction in nociceptorsCurr Opin Pharmacol14551PubMedCrossRefGoogle Scholar
  10. 10.
    Julius, D, Basbaum, AI 2001Molecular mechanisms of nociceptionNature (Lond)413203210CrossRefGoogle Scholar
  11. 11.
    Nagae, M, Hiraga, T, Wakabayashi, H, Wang, L, Iwata, K, Yoneda, T 2006Osteoclasts play a part in pain due to the inflammation adjacent to boneBone3911071115PubMedCrossRefGoogle Scholar
  12. 12.
    Medhurst, SJ, Walker, K, Bowes, M, Kidd, BL, Glatt, M, Muller, M, Hattenberger, M, Vaxelaire, J, O’Reilly, T, Wotherspoon, G, Winter, J, Green, J, Urban, L 2002A rat model of bone cancer painPain96129140PubMedCrossRefGoogle Scholar
  13. 13.
    Hargreaves, K, Dubner, R, Brown, F, Flores, C, Joris, J 1988A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesiaPain327788PubMedCrossRefGoogle Scholar
  14. 14.
    Tagawa, K, Taya, C, Hayashi, Y, Nakagawa, M, Ono, Y, Fukuda, R, Karasuyama, H, Toyama-Sorimachi, N, Katsui, Y, Hata, S, Ishiura, S, Nonaka, I, Seyama, Y, Arahata, K, Yonekawa, H, Sorimachi, H, Suzuki, K 2000Myopathy phenotype of transgenic mice expressing active site-mutated inactive p94 skeletal muscle-specific calpain, the gene product responsible for limb girdle muscular dystrophy type 2AHum Mol Genet913931402PubMedCrossRefGoogle Scholar
  15. 15.
    Hiraga, T, Myoui, A, Choi, ME, Yoshikawa, H, Yoneda, T 2006Stimulation of cyclooxygenase-2 expression by bone-derived transforming growth factor-β enhances bone metastases in breast cancerCancer Res6620672073PubMedCrossRefGoogle Scholar
  16. 16.
    Iwata, K, Takahashi, O, Tsuboi, Y, Ochiai, H, Hibiya, J, Sasaki, T, Yamaguchi, Y, Sumino, R 1998Fos protein induction in the medullary dorsal horn and first segment of the spinal cord by tooth-pulp stimulation in catsPain752736PubMedCrossRefGoogle Scholar
  17. 17.
    Hunt, SP, Pini, A, Evan, G 1987Induction of Fos-like protein in spinal cord neurons following sensory stimulationNature (Lond)328632634CrossRefGoogle Scholar
  18. 18.
    Bullitt, E 1990Expression of c-fos-like protein as a marker for neural activity following noxious stimulation in the ratJ Comp Neurol296517530PubMedCrossRefGoogle Scholar
  19. 19.
    Mach, DB, Rogers, SD, Sabino, MC, Luger, NM, Schwei, MJ, Pomonis, JD, Keyser, CP, Clohisy, DR, Adams, DJ, O’Leary, P, Mantyh, PW 2002Origins of skeletal pain: sensory and sympathetic innervation of the mouse femurNeuroscience113155166PubMedCrossRefGoogle Scholar
  20. 20.
    Reeh, PW, Kress, M 2001Molecular physiology of proton transduction in nociceptorsCurr Opin Pharmacol14551PubMedCrossRefGoogle Scholar
  21. 21.
    Julius, D, Basbaum, AI 2001Molecular mechanisms of nociceptionNature (Lond)413203210CrossRefGoogle Scholar
  22. 22.
    Caterina, MJ, Schumacher, MA, Tominaga, M, Rosen, TA, Levine, JD, Julius, D 1997The capsaicin receptor: a heat-activated ion channel in the pain pathwayNature (Lond)389816824CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 2007

Authors and Affiliations

  1. 1.Department of BiochemistryOsaka University Graduate School of DentistryOsakaJapan
  2. 2.Department of Histology and Cell BiologyMatsumoto Dental UniversityShiojiriJapan

Personalised recommendations