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Physiologic osteoclasts are not sufficient to induce skeletal pain in mice

De Clauser, L; Santana-Varela, S; Wood, JN; Sikandar, S; (2020) Physiologic osteoclasts are not sufficient to induce skeletal pain in mice. European Journal of Pain 10.1002/ejp.1662. (In press). Green open access

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Abstract

Background: Increased bone resorption is driven by augmented osteoclast activity in pathological states of the bone, including osteoporosis, fracture and metastatic bone cancer. Pain is a frequent co‐morbidity in bone pathologies and adequate pain management is necessary for symptomatic relief. Bone cancer is associated with severe skeletal pain and dysregulated bone remodelling, while increased osteoclast activity and bone pain are also observed in osteoporosis and during fracture repair. However, the effects of altered osteoclast activity and bone resorption on nociceptive processing of bone afferents remain unclear. / Methods: This study investigates whether physiologic osteoclasts and resulting changes in bone resorption can induce skeletal pain. We first assessed correlation between changes in bone microarchitecture (through µCT) and skeletal pain using standardized behavioural phenotyping assays in a mouse model of metastatic bone cancer. We then investigated whether increased activity of physiologic osteoclasts, and the associated bone resorption, is sufficient to induce skeletal pain using mouse models of localized and widespread bone resorption following administration of exogenous receptor activator of nuclear factor kappa‐B ligand (RANKL). / Results: Our data demonstrates that mice with bone cancer exhibit progressive pain behaviours that correlate with increased bone resorption at the tumour site. Systemic RANKL injections enhance osteoclast activity and associated bone resorption, without producing any changes in motor function or pain behaviours at both early and late timepoints. / Conclusion: These findings suggest that activation of homeostatic osteoclasts alone is not sufficient to induce skeletal pain in mice. / Significance statement: The role of osteoclasts in peripheral sensitization of sensory neurones is not fully understood. This study reports on the direct link between oestrogen‐independent osteoclast activation and skeletal pain. Administration of exogenous receptor activator of nuclear factor kappa‐B ligand (RANKL) increases bone resorption, but does not produce pro‐nociceptive changes in behavioural pain thresholds. Our data demonstrates that physiologic osteoclasts are not essential for skeletal pain behaviours.

Type: Article
Title: Physiologic osteoclasts are not sufficient to induce skeletal pain in mice
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/ejp.1662
Publisher version: https://doi.org/10.1002/ejp.1662
Language: English
Additional information: Copyright © 2020 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC®. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research
URI: https://discovery.ucl.ac.uk/id/eprint/10114612
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