Elsevier

Bone

Volume 48, Issue 1, 1 January 2011, Pages 100-105
Bone

Review
Involvement of acidic microenvironment in the pathophysiology of cancer-associated bone pain

https://doi.org/10.1016/j.bone.2010.07.009Get rights and content

Abstract

Bone pain is one of the most common complications in cancer patients with bone metastases. Although the mechanism of cancer-associated bone pain is poorly understood, clinical observations that inhibitors of osteoclasts such as bisphosphonates (BPs) efficiently reduce bone pain suggest a potential role of osteoclasts, which play a central role in the development and progression of bone metastasis. Osteoclasts dissolve bone minerals by releasing protons through the a3 isoform of the vacuolar-H+-ATPase, creating acidic microenvironments. In addition, cancer cells, inflammatory cells and immune cells that reside in bone metastases also produce acidic conditions by releasing protons. It has been well-known that acidic conditions due to proton release cause pain. Our study showed that the sensory nociceptive neurons innervate bone and these neurons express acid-sensing nociceptors such as the acid-sensing ion channels and transient receptor potential channel-vanilloid subfamily members. Acid signals received by these nociceptors subsequently activate intracellular signaling pathways and transcription factors in sensory neurons. The understanding of the nociceptive events following proton release and subsequent creation of acidic microenvironments leads us to design novel molecular-based approaches for reducing bone pain associated with cancer and inflammation.

Introduction

More than one third of the people in the world experiences persistent or recurrent pain [1]. Pain is one of the most common and feared complications in patients with any diseases. Pain causes discomfort, depression and anxiety and has significant influences on the quality of life (QOL) of patients, making prognosis worse. Furthermore, patients occasionally become susceptible to secondary diseases due to immunosuppressive effects of pain.

Patients with malignant diseases most frequently suffer from pain. Over 80% of cancer patients experience pain during the clinical course of the illness [2]. Among cancer-induced pain, bone pain associated with bone metastases is most common and cancers that colonize bone cause particularly intolerable bone pain [3], [4]. Bone pain is most frequently seen in lumbar bones, pelvis and femoral bones that bear mechanical stresses or physical loadings, while more than 60% of bones with metastases exhibit no pain. Paradoxically, anatomical location, size and number of tumor and the extent of bone destruction are not necessarily correlated with the severity of bone pain. Majority of cancer patients complain bone pain during nighttime for unknown reasons. Bone pain seriously and devastatingly affects QOL, causing diverse and complex problems in the management of cancer patients. Our understanding of the molecular mechanisms underlying bone pain is still very poor. Consequently, currently-available therapies for bone pain are inadequate and ineffective or cause uncomfortable adverse effects. The determination of the mechanism of bone pain is therefore an immediate public demand.

Section snippets

Proposed mechanisms of bone cancer pain

Generally, local nociceptive stimuli that are released from cancer cells, inflammatory cells, bone-resorbing osteoclasts or injured tissues are recognized and converted into electrochemical signals by the specialized afferent sensory neurons called nociceptors. The nociceptors can sense diverse noxious stimuli including thermal, mechanical and chemical agents. These signals are subsequently transmitted to the spinal cord (secondary afferent neuron) or the central nervous system (CNS) and brain

Study of bone pain

To conduct bone pain study, the establishment of animal models of bone pain and appropriate quantitative assessments for bone pain are essential. The examination of the expression of nociceptors and neurochemical nociceptive markers and the extent of osteoclastic bone destruction is also important for objective understanding of the pathophysiology of bone pain. In addition, the development of in vitro model of pain is helpful to investigate the mechanism underlying bone pain at cellular and

Acidic microenvironment and bone pain

One condition that progresses in bone metastases is local acidosis. Bone-resorbing osteoclasts [21], metastatic cancer cells [22], [23], [24] and inflammatory cells [4], [25] all produce protons, making bone microenvironment acidic. Local acidosis is a well-known cause of pain [5]. However, the role of local acidosis in bone pain is yet to be elucidated. The nociceptors that sense local acidosis are shown to be acid-sensing nociceptors (ASNs).

Conclusion

Our understanding of bone pain has been substantially poor, because bone pain is sensory, emotional, heterogeneous and subjective and is extremely difficult to evaluate it in objective and quantitative manners. Furthermore, the molecular basis of bone pain has been unclear. However, the breakthrough discovery of TRPV1 in 1997 [28] allows us to begin to understand the pathophysiology of bone pain at cellular and molecular levels. Since osteoclasts produce large amounts of protons during bone

Acknowledgments

This work was supported in part by Grant-in-Aid for Scientific Research on Priority Areas (TY) and Grant-in-Aid for Young Scientists B (MN) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the 21st Century COE Program (TY) and by the Research Grant of the Princess Takamatsu Cancer Research Fund (grant # 08-24020).

References (59)

  • F. Fulfaro et al.

    The role of bisphosphonates in the treatment of painful metastatic bone disease: a review of phase III trials

    Pain

    (1998)
  • T. Yoneda et al.

    Crosstalk between cancer cells and bone microenvironment in bone metastasis

    Biochem Biophys Res Commun

    (2005)
  • P. Honore et al.

    Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons

    Neuroscience

    (2000)
  • T. Toyomura et al.

    From lysosomes to the plasma membrane: localization of vacuolar-type H+-ATPase with the a3 isoform during osteoclast differentiation

    J Biol Chem

    (2003)
  • C.L. Stucky et al.

    Mechanisms of pain

    Proc Natl Acad Sci USA

    (2001)
  • E. Bruela et al.

    Cancer pain

    (2003)
  • P.W. Mantyh et al.

    Molecular mechanism of cancer pain

    Nature Rev. Cancer

    (2002)
  • D. Julius et al.

    Molecular mechanism of nociception

    Nature

    (2001)
  • G. Jancso et al.

    Pharmacologically induced selective degeneration of chemosensitive primary sensory neurons

    Nature

    (1977)
  • P.J. Saylor et al.

    Bone health and prostate cancer

    Prostate Cancer Prostatic Dis

    (2010)
  • D.R. Clohisy et al.

    Bone cancer pain

    Cancer

    (2003)
  • C. Pacharinsak et al.

    Animal models of cancer pain

    Comp Med

    (2008)
  • M. Nagae et al.

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

    J Bone Miner Metab

    (2007)
  • P. Honore et al.

    Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord

    Nature Med.

    (2000)
  • H. Wakabayashi et al.

    Role of acid-sensing TRPV1 in bone pain associated with cancer colonization in bone

    J Bone Miner Res

    (2005)
  • S.P. Hunt et al.

    Induction of Fos-like protein in spinal cord neurons following sensory stimulation

    Nature

    (1987)
  • M. Nakanishi et al.

    Acid activation of acid-sensing calcium channel Trpv1 leads to an up-regulation of calcitonin gene related peptide expression in dorsal root ganglion neurons via the CaMK-CREB cascade: a potential mechanism of inflammatory pain

    Mol. Biol. Cell

    (2010)
  • A.V. Rousselle et al.

    Osteoclast acidification pathways during bone resorption

    Bone

    (2002)
  • J.R. Griffiths

    Are cancer cells acidic?

    Br J Cancer

    (1991)
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