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The underlying mechanisms of the pain are unknown and understudied, and there is a need for immunocompetent preclinical models of myeloma\u2010induced bone pain. The aim of this study was to provide the first in\u2010depth behavioral characterization of an immunocompetent mouse model of MM presenting the clinical disease features: osteolytic bone disease and bone pain. We hypothesized that a widely used syngeneic model of MM, established by systemic inoculation of green fluorescent protein\u2010tagged myeloma cells (5TGM1\u2010GFP) in immunocompetent C57Bl\/KaLwRijHsd (BKAL) mice, would present pain\u2010related behaviors. Disease phenotype was confirmed by splenomegaly, high serum paraprotein, and tumor infiltration in the bone marrow of the hind limbs; however, myeloma\u2010bearing mice did not present pain\u2010related behaviors or substantial bone disease. Thus, we investigated an alternative model in which 5TGM1\u2010GFP cells were directly inoculated into the intrafemoral medullary cavity. This localized myeloma model presented the hallmarks of the disease, including high serum paraprotein, tumor growth, and osteolytic bone lesions. Compared with control mice, myeloma\u2010bearing mice presented myeloma\u2010induced pain\u2010related behaviors, a phenotype that was reversed by systemic morphine treatment. Micro\u2010computed tomography analyses of the myeloma\u2010inoculated femurs showed bone disease in cortical and trabecular bone. Repeated systemic bisphosphonate treatment induced an amelioration of the nociceptive phenotype, but did not completely reverse it. Furthermore, intrafemorally injected mice presented a profound denervation of the myeloma\u2010bearing bones, a previously unknown feature of the disease. This study reports the intrafemoral inoculation of 5TGM1\u2010GFP cells as a robust immunocompetent model of myeloma\u2010induced bone pain, with consistent bone loss. Moreover, the data suggest that myeloma\u2010induced bone pain is caused by a combinatorial mechanism including osteolysis and bone marrow denervation. \u00a9 2019 The Authors. <jats:italic>JBMR Plus<\/jats:italic> published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.<\/jats:p>","DOI":"10.1002\/jbm4.10252","type":"journal-article","created":{"date-parts":[[2019,11,11]],"date-time":"2019-11-11T22:00:30Z","timestamp":1573509630000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Differential Pain\u2010Related Behaviors and Bone Disease in Immunocompetent Mouse Models of Myeloma"],"prefix":"10.1093","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7719-6839","authenticated-orcid":false,"given":"Marta","family":"Diaz\u2010delCastillo","sequence":"first","affiliation":[{"name":"Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danna","family":"Kamstrup","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rikke Brix","family":"Olsen","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rie Bager","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Pembridge","sequence":"additional","affiliation":[{"name":"Department of Oncology &amp; Metabolism University of Sheffield  Sheffield UK"},{"name":"Mellanby Centre for Bone Research University of Sheffield  Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brigita","family":"Simanskaite","sequence":"additional","affiliation":[{"name":"Department of Oncology &amp; Metabolism University of Sheffield  Sheffield UK"},{"name":"Mellanby Centre for Bone Research University of Sheffield  Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan Miguel","family":"Jimenez\u2010Andrade","sequence":"additional","affiliation":[{"name":"Department of Unidad Acad\u00e9mica Multidisciplinaria Reynosa Aztlan Universidad Aut\u00f3noma de Tamaulipas  Reynosa, Tamaulipas Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5446-923X","authenticated-orcid":false,"given":"Michelle A","family":"Lawson","sequence":"additional","affiliation":[{"name":"Department of Oncology &amp; Metabolism University of Sheffield  Sheffield UK"},{"name":"Mellanby Centre for Bone Research University of Sheffield  Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2754-0800","authenticated-orcid":false,"given":"Anne\u2010Marie","family":"Heegaard","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,12,30]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdq370"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/bmb\/ldu016"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar2168"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1359\/JBMR.041131"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(05)70022-X"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.22991"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/qjmed\/hcm077"},{"issue":"1","key":"e_1_2_7_9_1","first-page":"29","article-title":"Multiple myeloma: review of 869 cases","volume":"50","author":"Kyle RA","year":"1975","journal-title":"Mayo Clin Proc"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2007.03.024"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejh.12790"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-007-0296-4"},{"issue":"7","key":"e_1_2_7_13_1","first-page":"1163","article-title":"Pain, mood disturbance, and quality of life in patients with multiple myeloma","volume":"28","author":"Poulos AR","year":"2001","journal-title":"Oncol Nurs Forum."},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2016.380"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-3545"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2010.11.010"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20021650"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V100.1.230"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-05-283895"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S8756-3282(97)00056-2"},{"issue":"2","key":"e_1_2_7_21_1","first-page":"609","article-title":"Idiopathic paraproteinemia. 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