{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:36:23Z","timestamp":1787027783474,"version":"build-2736575974"},"reference-count":59,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,8,4]],"date-time":"2020-08-04T00:00:00Z","timestamp":1596499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["grant n\u00b018783"],"award-info":[{"award-number":["grant n\u00b018783"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Bone disease severely affects the quality of life of over 70% of multiple myeloma (MM) patients, which daily experience pain, pathological fractures, mobility issues and an increased mortality. Recent data have highlighted the crucial role of the endoplasmic reticulum-associated unfolded protein response (UPR) in malignant transformation and tumor progression; therefore, targeting of UPR-related molecules may open novel therapeutic avenues. Endoplasmic reticulum (ER) stress and UPR pathways are constitutively activated in MM cells, which are characterized by an increased protein turnover as a consequence of high production of immunoglobulins and high rates of protein synthesis. A great deal of scientific data also evidenced that a mild activation of UPR pathway can regulate cellular differentiation. Our previous studies revealed that MM cell-derived small extracellular vesicle (MM-EV) modulated osteoclasts (OCs) function and induced OCs differentiation. Here, we investigated the role of the UPR pathway, and in particular of the IRE1\u03b1\/XBP1 axis, in osteoclastogenesis induced by MM-EVs. By proteomic analysis, we identified UPR signaling molecules as novel MM-EV cargo, prompting us to evaluate the effects of the MM-EVs on osteoclastogenesis through UPR pathway. MM-EVs administration in a murine macrophage cell line rapidly induced activation of IRE1\u03b1 by phosphorylation in S724; accordingly, Xbp1 mRNA splicing was increased and the transcription of NFATc1, a master transcription factor for OCs differentiation, was activated. Some of these results were also validated using both human primary OC cultures and MM-EVs from MM patients. Notably, a chemical inhibitor of IRE1\u03b1 (GSK2850163) counteracted MM-EV-triggered OC differentiation, hampering the terminal stages of OCs differentiation and reducing bone resorption.<\/jats:p>","DOI":"10.3390\/cancers12082167","type":"journal-article","created":{"date-parts":[[2020,8,4]],"date-time":"2020-08-04T10:45:17Z","timestamp":1596537917000},"page":"2167","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Multiple Myeloma-Derived Extracellular Vesicles Induce Osteoclastogenesis through the Activation of the XBP1\/IRE1\u03b1 Axis"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9394-2002","authenticated-orcid":false,"given":"Lavinia","family":"Raimondi","sequence":"first","affiliation":[{"name":"IRCSS Istituto Ortopedico Rizzoli, SC Scienze e Tecnologie Chirurgiche\u2013SS Piattaforma Scienze Omiche per Ortopedia Personalizzata, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5493-9441","authenticated-orcid":false,"given":"Angela","family":"De Luca","sequence":"additional","affiliation":[{"name":"IRCSS Istituto Ortopedico Rizzoli, SC Scienze e Tecnologie Chirurgiche\u2013SS Piattaforma Scienze Omiche per Ortopedia Personalizzata, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4681-2170","authenticated-orcid":false,"given":"Simona","family":"Fontana","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Section of Biology and Genetics, University of Palermo, 90134 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Amodio","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2425-6460","authenticated-orcid":false,"given":"Viviana","family":"Costa","sequence":"additional","affiliation":[{"name":"IRCSS Istituto Ortopedico Rizzoli, SC Scienze e Tecnologie Chirurgiche\u2013SS Piattaforma Scienze Omiche per Ortopedia Personalizzata, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7323-8023","authenticated-orcid":false,"given":"Valeria","family":"Carina","sequence":"additional","affiliation":[{"name":"IRCSS Istituto Ortopedico Rizzoli, SC Scienze e Tecnologie Chirurgiche\u2013SS Piattaforma Scienze Omiche per Ortopedia Personalizzata, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3308-9112","authenticated-orcid":false,"given":"Daniele","family":"Bellavia","sequence":"additional","affiliation":[{"name":"IRCSS Istituto Ortopedico Rizzoli, SC Scienze e Tecnologie Chirurgiche\u2013SS Piattaforma Scienze Omiche per Ortopedia Personalizzata, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Raimondo","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Section of Biology and Genetics, University of Palermo, 90134 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Siragusa","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Haematology Unit, University of Palermo, 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Monteleone","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Section of Biology and Genetics, University of Palermo, 90134 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9935-1040","authenticated-orcid":false,"given":"Riccardo","family":"Alessandro","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Section of Biology and Genetics, University of Palermo, 90134 Palermo, Italy"},{"name":"Institute for Biomedical Research and Innovation-National Research Council (IRIB-CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena","family":"Fini","sequence":"additional","affiliation":[{"name":"IRCSS Istituto Ortopedico Rizzoli, SC Scienze e Tecnologie Chirurgiche\u2013SS Piattaforma Scienze Omiche per Ortopedia Personalizzata, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7843-5969","authenticated-orcid":false,"given":"Gianluca","family":"Giavaresi","sequence":"additional","affiliation":[{"name":"IRCSS Istituto Ortopedico Rizzoli, SC Scienze e Tecnologie Chirurgiche\u2013SS Piattaforma Scienze Omiche per Ortopedia Personalizzata, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1158\/1078-0432.CCR-10-1804","article-title":"Advances in the biology and treatment of bone disease in multiple myeloma","volume":"17","author":"Raje","year":"2011","journal-title":"Clin. 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