title: Involvement of acidic microenvironment in the pathophysiology of cancer-associated bone pain.
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.
authors.affiliation: Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan. tyoneda@dent.osaka-u.ac.jp
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yoneda
authors.forename: Kenji
authors.initials: K
authors.lastname: Hata
authors.forename: Masako
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Maho
authors.initials: M
authors.lastname: Nagae
authors.forename: Tomotaka
authors.initials: T
authors.lastname: Nagayama
authors.forename: Hiroki
authors.initials: H
authors.lastname: Wakabayashi
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Nishisho
authors.forename: Teruhisa
authors.initials: T
authors.lastname: Sakurai
authors.forename: Toru
authors.initials: T
authors.lastname: Hiraga
mesh_terms: D062565:Acid Sensing Ion Channels; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000473:pathology / Q000503:physiopathology*; D001842:Bone and Bones / Q000294:innervation* / Q000378:metabolism / Q000503:physiopathology; D004164:Diphosphonates / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007249:Inflammation / Q000150:complications; D023421:Models, Animal; D009369:Neoplasms / Q000150:complications*; D009419:Nerve Tissue Proteins; D009619:Nociceptors / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D010146:Pain / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D011522:Protons; D015222:Sodium Channels; D059016:Tumor Microenvironment
chemical_list: D062565:Acid Sensing Ion Channels; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D009419:Nerve Tissue Proteins; D011522:Protons; D015222:Sodium Channels