{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:50:06Z","timestamp":1792673406107,"version":"4.5.0"},"reference-count":62,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2020,10,12]],"date-time":"2020-10-12T00:00:00Z","timestamp":1602460800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["642720"],"award-info":[{"award-number":["642720"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Pain"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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\u2010morbidity 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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 \u00b5CT) 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\u2010B ligand (RANKL).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings suggest that activation of homeostatic osteoclasts alone is not sufficient to induce skeletal pain in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance statement<\/jats:title>\n                    <jats:p>The role of osteoclasts in peripheral sensitization of sensory neurones is not fully understood. This study reports on the direct link between oestrogen\u2010independent osteoclast activation and skeletal pain. Administration of exogenous receptor activator of nuclear factor kappa\u2010B ligand (RANKL) increases bone resorption, but does not produce pro\u2010nociceptive changes in behavioural pain thresholds. Our data demonstrates that physiologic osteoclasts are not essential for skeletal pain behaviours.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejp.1662","type":"journal-article","created":{"date-parts":[[2020,9,21]],"date-time":"2020-09-21T15:20:27Z","timestamp":1600701627000},"page":"199-212","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Physiologic osteoclasts are not sufficient to induce skeletal pain in mice"],"prefix":"10.1002","volume":"25","author":[{"given":"Larissa","family":"de Clauser","sequence":"first","affiliation":[{"name":"Molecular Nociception Group, Wolfson Institute for Biomedical Research University College London London UK"},{"name":"Wolfson Centre for Age\u2010Related Diseases Institute of Psychiatry, Psychology and Neuroscience (IoPPN) King's College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Santana\u2010Varela","sequence":"additional","affiliation":[{"name":"Molecular Nociception Group, Wolfson Institute for Biomedical Research University College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John N","family":"Wood","sequence":"additional","affiliation":[{"name":"Molecular Nociception Group, Wolfson Institute for Biomedical Research University College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shafaq","family":"Sikandar","sequence":"additional","affiliation":[{"name":"Molecular Nociception Group, Wolfson Institute for Biomedical Research University College London London UK"},{"name":"William Harvey Research Institute Barts and the London School of Medicine &amp; Dentistry Mary University of London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,10,12]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00774-014-0574-x"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bonr.2019.100201"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.12688\/wellcomeopenres.14641.1"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2010.12.016"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2004.07.011"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0039765"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-017-1415-9"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/jor.20423"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.5435\/00124635-200600001-00027"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0270(94)90144-9"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1053\/jpmn.2002.126070"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2013.02.033"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF03350919"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.5483\/BMBRep.2020.53.3.147"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2010.08.023"},{"issue":"1","key":"e_1_2_9_17_1","first-page":"34","article-title":"Cortical and trabecular bone microarchitecture predicts incident fracture independently of DXA bone minderal density and FRAX in older women and men","volume":"7","author":"Elizabeth J. S.","year":"2019","journal-title":"The Bone Microarchitecture International Consortium"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.51.7219"},{"issue":"5","key":"e_1_2_9_19_1","first-page":"1963","article-title":"Influence of sex differences on the progression of cancer\u2010induced bone pain","volume":"33","author":"Falk S.","year":"2013","journal-title":"Anticancer Research"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.3758\/BF03193146"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2004.12.020"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S8756-3282(03)00199-6"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0221534"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000000514"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1526-4637.2000.00047.x"},{"issue":"2","key":"e_1_2_9_26_1","first-page":"115","article-title":"Establishment and evaluation of a bone cancer pain model","volume":"33","author":"Huang D.","year":"2008","journal-title":"Zhong Nan Da Xue Xue Bao. Yi Xue Ban"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2011.02.008"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20020439"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2009.05.065"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00537801"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/jor.23047"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)62269-9"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.1595"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.spinee.2006.04.013"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07623"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/16852"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1201345"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.3171\/2013.5.SPINE12473"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep17056"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0094312"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2474-11-183"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1586\/ecp.12.35"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2010.08.056"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1998.8586"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2008.05.019"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.12.033"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.3719"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc867"},{"key":"e_1_2_9_49_1","first-page":"234","volume-title":"Nature","author":"Newton P. T.","year":"2019"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39835"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39837"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001139"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2005.08.021"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2702.2001.00506.x"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00586-015-4058-z"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1302\/0301-620X.95B9.31562"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2005.09.018"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.14348\/molcells.2014.0220"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.090217"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1100\/2012\/502781"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2018.00129"},{"issue":"4","key":"e_1_2_9_62_1","first-page":"3623","article-title":"Age\u2010dependent variations of cancellous bone in response to ovariectomy in C57BL\/6J mice","volume":"15","author":"Zhou S.","year":"2018","journal-title":"Experimental and Therapeutic Medicine"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbm.b.30872"}],"container-title":["European Journal of Pain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ejp.1662","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ejp.1662","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ejp.1662","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,3]],"date-time":"2023-09-03T11:13:19Z","timestamp":1693739599000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ejp.1662"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,12]]},"references-count":62,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,1]]}},"alternative-id":["10.1002\/ejp.1662"],"URL":"https:\/\/doi.org\/10.1002\/ejp.1662","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.738710194.793580740","asserted-by":"object"}]},"ISSN":["1090-3801","1532-2149"],"issn-type":[{"value":"1090-3801","type":"print"},{"value":"1532-2149","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,12]]},"assertion":[{"value":"2020-04-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-09-13","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-10-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}