{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T15:58:20Z","timestamp":1792425500454,"version":"4.5.0"},"reference-count":64,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T00:00:00Z","timestamp":1766016000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004622","name":"Dutch Cancer Society","doi-asserted-by":"publisher","award":["VU2011-5127"],"award-info":[{"award-number":["VU2011-5127"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004622","name":"Dutch Cancer Society","doi-asserted-by":"publisher","award":["13923"],"award-info":[{"award-number":["13923"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Multiple myeloma (MM) is a plasma cell malignancy that disrupts bone homeostasis by suppressing osteogenesis and promoting osteoclast activity. While most therapeutic interventions to date have focused on targeting tumor cells and reducing osteolysis, we investigate whether osteoinductive strategies can restore bone formation and counteract disease progression. Using a human bone marrow-like scaffold model that enables direct in vivo evaluation of tumor\u2013stroma interactions and human bone formation, we demonstrate that MM-derived mesenchymal stromal cells (MSCs) retain osteogenic potential but are functionally suppressed by MM cells. Transcriptomic profiling of MM-primed MSCs revealed the downregulation of small leucine-rich proteoglycans (SLRPs), ASPN, OGN, and OMD, key mediators of bone morphogenetic protein (BMP) signaling, which governs osteoblast differentiation. Among the BMPs analyzed, BMP6 emerged as a potent inducer of osteogenesis and regulator of the expression of these SLRPs. Notably, BMP6 selectively promoted bone formation without enhancing osteoclastogenesis and attenuated inflammatory and tumor-supportive MSC phenotypes. BMP6 also directly inhibited MM cell proliferation and suppressed IL6-induced growth. These findings highlight BMP6 as a distinct multifunctional regulator warranting further investigation as a potential therapeutic approach, while establishing the humanized model as a valuable platform for dissecting tumor\u2013bone interactions in MM.<\/jats:p>","DOI":"10.3390\/biom15121747","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T09:15:21Z","timestamp":1766049321000},"page":"1747","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Humanized Bone Model Identifies BMP6 as a Multifunctional Regulator in Myeloma Bone Disease"],"prefix":"10.3390","volume":"15","author":[{"given":"Jiaxian","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Hematology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1500-6688","authenticated-orcid":false,"given":"Thomas","family":"Baardemans","sequence":"additional","affiliation":[{"name":"Department of Hematology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"de Matos Simoes","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willy","family":"Noort","sequence":"additional","affiliation":[{"name":"Department of Hematology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruud W. J.","family":"Ruiter","sequence":"additional","affiliation":[{"name":"Department of Hematology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henk-Jan","family":"Prins","sequence":"additional","affiliation":[{"name":"Department of Hematology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan E.","family":"van Hal-van Veen","sequence":"additional","affiliation":[{"name":"Department of Hematology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huipin","family":"Yuan","sequence":"additional","affiliation":[{"name":"Kuros Biosciences BV, 3723 MB Bilthoven, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost D.","family":"de Bruijn","sequence":"additional","affiliation":[{"name":"Kuros Biosciences BV, 3723 MB Bilthoven, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton C. M.","family":"Martens","sequence":"additional","affiliation":[{"name":"Department of Hematology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantine S.","family":"Mitsiades","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Zweegman","sequence":"additional","affiliation":[{"name":"Department of Hematology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Themeli","sequence":"additional","affiliation":[{"name":"Department of Hematology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5010-4604","authenticated-orcid":false,"given":"Richard W. J.","family":"Groen","sequence":"additional","affiliation":[{"name":"Department of Hematology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/leu.2008.336","article-title":"Pathogenesis of myeloma bone disease","volume":"23","author":"Roodman","year":"2009","journal-title":"Leukemia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1056\/NEJMra1011442","article-title":"Multiple Myeloma","volume":"364","author":"Palumbo","year":"2011","journal-title":"New Engl. J. 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