Bone pain induced by multiple myeloma is reduced by targeting V-ATPase and ASIC3

Masahiro Hiasa, Tatsuo Okui, Yohance M. Allette, Matthew S. Ripsch, Ge Hong Sun-Wada, Hiroki Wakabayashi, G. David Roodman, Fletcher White, Toshiyuki Yoneda

Research output: Contribution to journalArticle

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Abstract

Multiple myeloma patients experience severe bone pain (MMBP) that is undertreated and poorly understood. In this study, we studied MMBP in an intratibial mouse xenograft model that employs JJN3 human multiple myeloma cells. In this model, mice develop MMBP associated in bone with increased sprouting of calcitonin gene-related peptide-positive (CGRP+) sensory nerves and in dorsal root ganglia (DRG) with upregulation of phosphorylated ERK1/2 (pERK1/2) and pCREB, two molecular indicators of neuron excitation. We found that JJN3 cells expressed a vacuolar proton pump (V-ATPase) that induced an acidic bone microenvironment. Inhibition of JJN3-colonized bone acidification by a single injection of the selective V-ATPase inhibitor, bafilomycin A1, decreased MMBP, CGRP+ sensory neuron sprouting, and pERK1/2 and pCREB expression in DRG. CGRP+ sensory nerves also expressed increased levels of the acid-sensing nociceptor ASIC3. Notably, a single injection of the selective ASIC3 antagonist APETx2 dramatically reduced MMBP in the model. Mechanistic investigations in primary DRG neurons cocultured with JJN3 cells showed increased neurite outgrowth and excitation inhibited by bafilomycin A1 or APETx2. Furthermore, combining APETx2 with bafilomycin A1 reduced MMBP to a greater extent than either agent alone. Finally, combining bafilomycin A1 with the osteoclast inhibitor zoledronic acid was sufficient to ameliorate MMBP, which was refractory to zoledronic acid. Overall, our results show that osteoclasts and multiple myeloma cooperate to induce an acidic bone microenvironment that evokes MMBP as a result of the excitation of ASIC3-activated sensory neurons. Furthermore, they present a mechanistic rationale for targeting ASIC3 on neurons along with the multiple myeloma-induced acidic bone microenvironment as a strategy to relieve MMBP in patients. Cancer Res; 77(6); 1283-95.

Original languageEnglish (US)
Pages (from-to)1283-1295
Number of pages13
JournalCancer Research
Volume77
Issue number6
DOIs
StatePublished - Mar 15 2017

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Multiple Myeloma
Adenosine Triphosphatases
zoledronic acid
Bone and Bones
Pain
Spinal Ganglia
Sensory Receptor Cells
Osteoclasts
Neurons
Proton Pumps
Nociceptors
Injections
Calcitonin Gene-Related Peptide
Heterografts
Up-Regulation
Acids
bafilomycin A1
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Hiasa, M., Okui, T., Allette, Y. M., Ripsch, M. S., Sun-Wada, G. H., Wakabayashi, H., ... Yoneda, T. (2017). Bone pain induced by multiple myeloma is reduced by targeting V-ATPase and ASIC3. Cancer Research, 77(6), 1283-1295. https://doi.org/10.1158/0008-5472.CAN-15-3545

Bone pain induced by multiple myeloma is reduced by targeting V-ATPase and ASIC3. / Hiasa, Masahiro; Okui, Tatsuo; Allette, Yohance M.; Ripsch, Matthew S.; Sun-Wada, Ge Hong; Wakabayashi, Hiroki; Roodman, G. David; White, Fletcher; Yoneda, Toshiyuki.

In: Cancer Research, Vol. 77, No. 6, 15.03.2017, p. 1283-1295.

Research output: Contribution to journalArticle

Hiasa, M, Okui, T, Allette, YM, Ripsch, MS, Sun-Wada, GH, Wakabayashi, H, Roodman, GD, White, F & Yoneda, T 2017, 'Bone pain induced by multiple myeloma is reduced by targeting V-ATPase and ASIC3', Cancer Research, vol. 77, no. 6, pp. 1283-1295. https://doi.org/10.1158/0008-5472.CAN-15-3545
Hiasa M, Okui T, Allette YM, Ripsch MS, Sun-Wada GH, Wakabayashi H et al. Bone pain induced by multiple myeloma is reduced by targeting V-ATPase and ASIC3. Cancer Research. 2017 Mar 15;77(6):1283-1295. https://doi.org/10.1158/0008-5472.CAN-15-3545
Hiasa, Masahiro ; Okui, Tatsuo ; Allette, Yohance M. ; Ripsch, Matthew S. ; Sun-Wada, Ge Hong ; Wakabayashi, Hiroki ; Roodman, G. David ; White, Fletcher ; Yoneda, Toshiyuki. / Bone pain induced by multiple myeloma is reduced by targeting V-ATPase and ASIC3. In: Cancer Research. 2017 ; Vol. 77, No. 6. pp. 1283-1295.
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abstract = "Multiple myeloma patients experience severe bone pain (MMBP) that is undertreated and poorly understood. In this study, we studied MMBP in an intratibial mouse xenograft model that employs JJN3 human multiple myeloma cells. In this model, mice develop MMBP associated in bone with increased sprouting of calcitonin gene-related peptide-positive (CGRP+) sensory nerves and in dorsal root ganglia (DRG) with upregulation of phosphorylated ERK1/2 (pERK1/2) and pCREB, two molecular indicators of neuron excitation. We found that JJN3 cells expressed a vacuolar proton pump (V-ATPase) that induced an acidic bone microenvironment. Inhibition of JJN3-colonized bone acidification by a single injection of the selective V-ATPase inhibitor, bafilomycin A1, decreased MMBP, CGRP+ sensory neuron sprouting, and pERK1/2 and pCREB expression in DRG. CGRP+ sensory nerves also expressed increased levels of the acid-sensing nociceptor ASIC3. Notably, a single injection of the selective ASIC3 antagonist APETx2 dramatically reduced MMBP in the model. Mechanistic investigations in primary DRG neurons cocultured with JJN3 cells showed increased neurite outgrowth and excitation inhibited by bafilomycin A1 or APETx2. Furthermore, combining APETx2 with bafilomycin A1 reduced MMBP to a greater extent than either agent alone. Finally, combining bafilomycin A1 with the osteoclast inhibitor zoledronic acid was sufficient to ameliorate MMBP, which was refractory to zoledronic acid. Overall, our results show that osteoclasts and multiple myeloma cooperate to induce an acidic bone microenvironment that evokes MMBP as a result of the excitation of ASIC3-activated sensory neurons. Furthermore, they present a mechanistic rationale for targeting ASIC3 on neurons along with the multiple myeloma-induced acidic bone microenvironment as a strategy to relieve MMBP in patients. Cancer Res; 77(6); 1283-95.",
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AU - Sun-Wada, Ge Hong

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