{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T15:45:33Z","timestamp":1784130333228,"version":"3.55.0"},"reference-count":114,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2021,9,2]],"date-time":"2021-09-02T00:00:00Z","timestamp":1630540800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Lytic bone disease remains a life-altering complication of multiple myeloma, with up to 90% of sufferers experiencing skeletal events at some point in their cancer journey. This tumour-induced bone disease is driven by an upregulation of bone resorption (via increased osteoclast (OC) activity) and a downregulation of bone formation (via reduced osteoblast (OB) activity), leading to phenotypic osteolysis. Treatments are limited, and currently exclusively target OCs. Despite existing bone targeting therapies, patients successfully achieving remission from their cancer can still be left with chronic pain, poor mobility, and reduced quality of life as a result of bone disease. As such, the field is desperately in need of new and improved bone-modulating therapeutic agents. One such option is the use of bone anabolics, drugs that are gaining traction in the osteoporosis field following successful clinical trials. The prospect of using these therapies in relation to myeloma is an attractive option, as they aim to stimulate OBs, as opposed to existing therapeutics that do little to orchestrate new bone formation. The preclinical application of bone anabolics in myeloma mouse models has demonstrated positive outcomes for bone repair and fracture resistance. Here, we review the role of the OB in the pathophysiology of myeloma-induced bone disease and explore whether novel OB targeted therapies could improve outcomes for patients.<\/jats:p>","DOI":"10.3390\/jcm10173973","type":"journal-article","created":{"date-parts":[[2021,9,2]],"date-time":"2021-09-02T21:13:36Z","timestamp":1630617216000},"page":"3973","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Myeloma Bone Disease: The Osteoblast in the Spotlight"],"prefix":"10.3390","volume":"10","author":[{"given":"Rebecca E.","family":"Andrews","sequence":"first","affiliation":[{"name":"Department of Oncology and Metabolism, The Medical School, The University of Sheffield, Sheffield S10 2RX, UK"},{"name":"Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield S10 2JF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet E.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Oncology and Metabolism, The Medical School, The University of Sheffield, Sheffield S10 2RX, UK"},{"name":"Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield S10 2JF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5446-923X","authenticated-orcid":false,"given":"Michelle A.","family":"Lawson","sequence":"additional","affiliation":[{"name":"Department of Oncology and Metabolism, The Medical School, The University of Sheffield, Sheffield S10 2RX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew D.","family":"Chantry","sequence":"additional","affiliation":[{"name":"Department of Oncology and Metabolism, The Medical School, The University of Sheffield, Sheffield S10 2RX, UK"},{"name":"Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield S10 2JF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1053\/j.seminoncol.2016.11.004","article-title":"Multiple myeloma epidemiology and survival: A unique malignancy","volume":"43","author":"Kazandjian","year":"2016","journal-title":"Semin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21332","article-title":"Cancer statistics, 2016","volume":"66","author":"Siegel","year":"2016","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1136\/pgmj.2006.054627","article-title":"Management of paraproteinaemia","volume":"83","author":"Cook","year":"2007","journal-title":"Postgrad. Med. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1001\/jamaoncol.2018.2128","article-title":"Global Burden of Multiple Myeloma: A Systematic Analysis for the Global Burden of Disease Study 2016","volume":"4","author":"Cowan","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1038\/bjc.2016.304","article-title":"Cancer incidence and mortality projections in the UK until 2035","volume":"115","author":"Smittenaar","year":"2016","journal-title":"Br. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"21","DOI":"10.4065\/78.1.21","article-title":"Review of 1027 patients with newly diagnosed multiple myeloma","volume":"78","author":"Kyle","year":"2003","journal-title":"Mayo Clin. Proc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1002\/(SICI)1097-0142(19971015)80:8+<1588::AID-CNCR9>3.0.CO;2-G","article-title":"Skeletal complications of malignancy","volume":"80","author":"Coleman","year":"1997","journal-title":"Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1359\/JBMR.041131","article-title":"Fracture risk with multiple myeloma: A population-based study","volume":"20","author":"Melton","year":"2005","journal-title":"J. Bone Miner. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1002\/cncr.22991","article-title":"Pathologic fractures correlate with reduced survival in patients with malignant bone disease","volume":"110","author":"Saad","year":"2007","journal-title":"Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Novack, D.V., and Mbalaviele, G. (2016). Osteoclasts-Key Players in Skeletal Health and Disease. Microbiol Spectr., 4.","DOI":"10.1128\/microbiolspec.MCHD-0011-2015"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2681","DOI":"10.1093\/annonc\/mds068","article-title":"Circulating activin-A is elevated in patients with advanced multiple myeloma and correlates with extensive bone involvement and inferior survival; no alterations post-lenalidomide and dexamethasone therapy","volume":"23","author":"Terpos","year":"2012","journal-title":"Ann. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2633","DOI":"10.1002\/jbmr.142","article-title":"Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo","volume":"25","author":"Chantry","year":"2010","journal-title":"J. Bone Miner. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5124","DOI":"10.1073\/pnas.0911929107","article-title":"Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease","volume":"107","author":"Vallet","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3452","DOI":"10.1182\/blood-2017-03-773341","article-title":"Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma","volume":"129","author":"McDonald","year":"2017","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2483","DOI":"10.1056\/NEJMoa030847","article-title":"The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma","volume":"349","author":"Tian","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1002\/ijc.22033","article-title":"Serum concentrations of Dickkopf-1 protein are increased in patients with multiple myeloma and reduced after autologous stem cell transplantation","volume":"119","author":"Politou","year":"2006","journal-title":"Int. J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6871","DOI":"10.1182\/blood-2011-04-346775","article-title":"Gfi1 expressed in bone marrow stromal cells is a novel osteoblast suppressor in patients with multiple myeloma bone disease","volume":"118","author":"Jin","year":"2011","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3024","DOI":"10.1182\/blood-2006-07-034884","article-title":"HGF inhibits BMP-induced osteoblastogenesis: Possible implications for the bone disease of multiple myeloma","volume":"109","author":"Standal","year":"2007","journal-title":"Blood"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1111\/bjh.12270","article-title":"Hepatocyte growth factor pathway upregulation in the bone marrow microenvironment in multiple myeloma is associated with lytic bone disease","volume":"161","author":"Kristensen","year":"2013","journal-title":"Br. J. Haematol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.bone.2013.07.024","article-title":"Heparanase inhibits osteoblastogenesis and shifts bone marrow progenitor cell fate in myeloma bone disease","volume":"57","author":"Ruan","year":"2013","journal-title":"Bone"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2308","DOI":"10.1182\/blood-2003-06-1992","article-title":"IL-3 expression by myeloma cells increases both osteoclast formation and growth of myeloma cells","volume":"103","author":"Lee","year":"2004","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1182\/blood-2005-03-1080","article-title":"IL-3 is a potential inhibitor of osteoblast differentiation in multiple myeloma","volume":"106","author":"Ehrlich","year":"2005","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.1182\/blood-2004-12-4986","article-title":"Myeloma cells block RUNX2\/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation","volume":"106","author":"Giuliani","year":"2005","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1172\/JCI0215687","article-title":"Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency","volume":"110","author":"Weitzmann","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.1080\/10428190701648281","article-title":"Myeloma cells and bone marrow osteoblast interactions: Role in the development of osteolytic lesions in multiple myeloma","volume":"48","author":"Giuliani","year":"2007","journal-title":"Leuk. Lymphoma"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3883","DOI":"10.1182\/blood.V94.11.3883","article-title":"Hepatocyte growth factor (HGF) induces interleukin-11 secretion from osteoblasts: A possible role for HGF in myeloma-associated osteolytic bone disease","volume":"94","author":"Hjertner","year":"1999","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1038\/leu.2011.43","article-title":"A novel role for CCL3 (MIP-1alpha) in myeloma-induced bone disease via osteocalcin downregulation and inhibition of osteoblast function","volume":"25","author":"Vallet","year":"2011","journal-title":"Leukemia"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1186\/s12935-014-0132-6","article-title":"Osteoblast inhibition by chemokine cytokine ligand3 in myeloma-induced bone disease","volume":"14","author":"Fu","year":"2014","journal-title":"Cancer Cell Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.3324\/haematol.2010.038133","article-title":"N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation","volume":"96","author":"Groen","year":"2011","journal-title":"Haematologica"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/leu.2014.147","article-title":"Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma","volume":"29","author":"Hiasa","year":"2015","journal-title":"Leukemia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1111\/j.1749-6632.2011.06196.x","article-title":"Sclerostin is overexpressed by plasma cells from multiple myeloma patients","volume":"1237","author":"Brunetti","year":"2011","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1002\/ijc.27342","article-title":"Elevated circulating sclerostin correlates with advanced disease features and abnormal bone remodeling in symptomatic myeloma: Reduction post-bortezomib monotherapy","volume":"131","author":"Terpos","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3160","DOI":"10.1182\/blood-2004-12-4940","article-title":"Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2","volume":"106","author":"Oshima","year":"2005","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1016\/j.bbrc.2007.03.099","article-title":"TNF-alpha inhibits BMP-induced osteoblast differentiation through activating SAPK\/JNK signaling","volume":"356","author":"Mukai","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1158\/1541-7786.MCR-16-0242-T","article-title":"EZH2 or HDAC1 Inhibition Reverses Multiple Myeloma-Induced Epigenetic Suppression of Osteoblast Differentiation","volume":"15","author":"Adamik","year":"2017","journal-title":"Mol. Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Takeuchi, K., Abe, M., Hiasa, M., Oda, A., Amou, H., Kido, S., Harada, T., Tanaka, O., Miki, H., and Nakamura, S. (2010). Tgf-Beta inhibition restores terminal osteoblast differentiation to suppress myeloma growth. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009870"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s10585-007-9125-3","article-title":"Syndecan-1: A dynamic regulator of the myeloma microenvironment","volume":"25","author":"Sanderson","year":"2008","journal-title":"Clin. Exp. Metastasis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.semcancer.2010.04.003","article-title":"Adhesion molecules--The lifelines of multiple myeloma cells","volume":"20","author":"Katz","year":"2010","journal-title":"Semin. Cancer Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/s41408-017-0037-4","article-title":"Pathogenesis of bone disease in multiple myeloma: From bench to bedside","volume":"8","author":"Terpos","year":"2018","journal-title":"Blood Cancer J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e217","DOI":"10.1038\/bcj.2014.37","article-title":"Notch pathway inhibition controls myeloma bone disease in the murine MOPC315.BM model","volume":"4","author":"Schwarzer","year":"2014","journal-title":"Blood Cancer J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e119","DOI":"10.1016\/S1470-2045(20)30559-3","article-title":"Treatment of multiple myeloma-related bone disease: Recommendations from the Bone Working Group of the International Myeloma Working Group","volume":"22","author":"Terpos","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1158\/0008-5472.CAN-19-0284","article-title":"Runx2 Deficiency in Osteoblasts Promotes Myeloma Progression by Altering the Bone Microenvironment at New Bone Sites","volume":"80","author":"Xu","year":"2020","journal-title":"Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3598","DOI":"10.1182\/blood-2014-12-613968","article-title":"Myeloma cell-derived Runx2 promotes myeloma progression in bone","volume":"125","author":"Trotter","year":"2015","journal-title":"Blood"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1136\/jim-2019-001010","article-title":"Multiple myeloma-derived exosomes inhibit osteoblastic differentiation and improve IL-6 secretion of BMSCs from multiple myeloma","volume":"68","author":"Liu","year":"2020","journal-title":"J. Investig. Med."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Liu, Z., Liu, H., He, J., Lin, P., Tong, Q., and Yang, J. (2020). Myeloma cells shift osteoblastogenesis to adipogenesis by inhibiting the ubiquitin ligase MURF1 in mesenchymal stem cells. Sci. Signal., 13.","DOI":"10.1126\/scisignal.aay8203"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e10183","DOI":"10.1002\/jbm4.10183","article-title":"Epigenetic-Based Mechanisms of Osteoblast Suppression in Multiple Myeloma Bone Disease","volume":"3","author":"Adamik","year":"2019","journal-title":"JBMR Plus."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.jbo.2018.09.001","article-title":"Osteoblast suppression in multiple myeloma bone disease","volume":"13","author":"Adamik","year":"2018","journal-title":"J. Bone Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1046\/j.1365-2141.2003.04374.x","article-title":"Upregulation of osteoblast apoptosis by malignant plasma cells: A role in myeloma bone disease","volume":"122","author":"Silvestris","year":"2003","journal-title":"Br. J. Haematol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3534","DOI":"10.1182\/blood.V98.13.3534","article-title":"Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma","volume":"98","author":"Croucher","year":"2001","journal-title":"Blood"},{"key":"ref_50","first-page":"287","article-title":"Recombinant osteoprotegerin decreases tumor burden and increases survival in a murine model of multiple myeloma","volume":"63","author":"Vanderkerken","year":"2003","journal-title":"Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2269","DOI":"10.1182\/blood.V98.7.2269","article-title":"Serum osteoprotegerin levels are reduced in patients with multiple myeloma with lytic bone disease","volume":"98","author":"Seidel","year":"2001","journal-title":"Blood"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1083\/jcb.201207142","article-title":"Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin","volume":"200","author":"Albers","year":"2013","journal-title":"J. Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s13045-018-0615-3","article-title":"Wnt signaling in multiple myeloma: A central player in disease with therapeutic potential","volume":"11","author":"Spaan","year":"2018","journal-title":"J. Hematol. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1038\/s41375-019-0404-1","article-title":"Aberrant Wnt signaling in multiple myeloma: Molecular mechanisms and targeting options","volume":"33","author":"Kocemba","year":"2019","journal-title":"Leukemia"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/leu.2012.190","article-title":"Myeloma cells inhibit non-canonical wnt co-receptor ror2 expression in human bone marrow osteoprogenitor cells: Effect of wnt5a\/ror2 pathway activation on the osteogenic differentiation impairment induced by myeloma cells","volume":"27","author":"Bolzoni","year":"2013","journal-title":"Leukemia"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nm.3074","article-title":"WNT signaling in bone homeostasis and disease: From human mutations to treatments","volume":"19","author":"Baron","year":"2013","journal-title":"Nat. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1177\/0004563218759371","article-title":"The bone remodelling cycle","volume":"55","author":"Kenkre","year":"2018","journal-title":"Ann. Clin. Biochem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.gene.2004.06.044","article-title":"Wnt signaling in osteoblasts and bone diseases","volume":"341","author":"Westendorf","year":"2004","journal-title":"Gene"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2627","DOI":"10.1242\/jcs.00623","article-title":"Secreted antagonists of the Wnt signalling pathway","volume":"116 Pt 13","author":"Kawano","year":"2003","journal-title":"J. Cell Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"4295","DOI":"10.1242\/dev.00674","article-title":"Wise, a context-dependent activator and inhibitor of Wnt signalling","volume":"130","author":"Itasaki","year":"2003","journal-title":"Development"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.blre.2013.08.002","article-title":"Dickkopf-1 is a key regulator of myeloma bone disease: Opportunities and challenges for therapeutic intervention","volume":"27","author":"Zhou","year":"2013","journal-title":"Blood Rev."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1038\/nature756","article-title":"Kremen proteins are Dickkopf receptors that regulate Wnt\/beta-catenin signalling","volume":"417","author":"Mao","year":"2002","journal-title":"Nature"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.bone.2007.05.009","article-title":"Bone mass is inversely proportional to Dkk1 levels in mice","volume":"41","author":"MacDonald","year":"2007","journal-title":"Bone"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1056\/NEJM200407083510223","article-title":"Bone lesions in molecular subtypes of multiple myeloma","volume":"351","author":"Robbiani","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1182\/blood-2008-01-132134","article-title":"Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: A potential mechanism underlying osteolytic bone lesions in multiple myeloma","volume":"112","author":"Qiang","year":"2008","journal-title":"Blood"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2106","DOI":"10.1182\/blood-2006-09-047712","article-title":"Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo","volume":"109","author":"Yaccoby","year":"2007","journal-title":"Blood"},{"key":"ref_67","first-page":"192","article-title":"Inhibitory effects of osteoblasts and increased bone formation on myeloma in novel culture systems and a myelomatous mouse model","volume":"91","author":"Yaccoby","year":"2006","journal-title":"Haematologica"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1359\/jbmr.081104","article-title":"Inhibiting Dickkopf-1 (Dkk1) removes suppression of bone formation and prevents the development of osteolytic bone disease in multiple myeloma","volume":"24","author":"Heath","year":"2009","journal-title":"J. Bone Miner. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1182\/blood-2008-11-191577","article-title":"Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma","volume":"114","author":"Fulciniti","year":"2009","journal-title":"Blood"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1111\/bjh.13056","article-title":"A Phase IB multicentre dose-determination study of BHQ880 in combination with anti-myeloma therapy and zoledronic acid in patients with relapsed or refractory multiple myeloma and prior skeletal-related events","volume":"167","author":"Iyer","year":"2014","journal-title":"Br. J. Haematol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1182\/blood.V120.21.331.331","article-title":"Early Evidence of Anabolic Bone Activity of BHQ880, a Fully Human Anti-DKK1 Neutralizing Antibody: Results of a Phase 2 Study in Previously Untreated Patients with Smoldering Multiple Myeloma At Risk for Progression","volume":"120","author":"Munshi","year":"2012","journal-title":"Blood"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1007\/s00223-017-0351-7","article-title":"New agents in the Treatment of Myeloma Bone Disease","volume":"102","author":"Ring","year":"2018","journal-title":"Calcif. Tissue Int."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e482","DOI":"10.1038\/bcj.2016.90","article-title":"High levels of periostin correlate with increased fracture rate, diffuse MRI pattern, abnormal bone remodeling and advanced disease stage in patients with newly diagnosed symptomatic multiple myeloma","volume":"6","author":"Terpos","year":"2016","journal-title":"Blood Cancer J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"16744","DOI":"10.1074\/jbc.M114.628313","article-title":"The Wnt Inhibitor Sclerostin Is Up-regulated by Mechanical Unloading in Osteocytes in Vitro","volume":"290","author":"Spatz","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"6267","DOI":"10.1093\/emboj\/cdg599","article-title":"Osteocyte control of bone formation via sclerostin, a novel BMP antagonist","volume":"22","author":"Winkler","year":"2003","journal-title":"EMBO J."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e27","DOI":"10.1038\/bcj.2011.22","article-title":"Myeloma cells suppress osteoblasts through sclerostin secretion","volume":"1","author":"Colucci","year":"2011","journal-title":"Blood Cancer J."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1056\/NEJMoa1305224","article-title":"Romosozumab in postmenopausal women with low bone mineral density","volume":"370","author":"McClung","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1016\/S0140-6736(17)31613-6","article-title":"Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: A randomised, open-label, phase 3 trial","volume":"390","author":"Langdahl","year":"2017","journal-title":"Lancet"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3183","DOI":"10.1210\/jc.2017-02163","article-title":"A Phase 3 Randomized Placebo-controlled Trial to Evaluate Efficacy and Safety of Romosozumab in Men with Osteoporosis","volume":"103","author":"Lewiecki","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1056\/NEJMoa1708322","article-title":"Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis","volume":"377","author":"Saag","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1002\/jbmr.2092","article-title":"Single- and multiple-dose randomized studies of blosozumab, a monoclonal antibody against sclerostin, in healthy postmenopausal women","volume":"29","author":"McColm","year":"2014","journal-title":"J. Bone Miner. Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.bone.2010.05.036","article-title":"TGF-beta-related mechanisms of bone destruction in multiple myeloma","volume":"48","author":"Matsumoto","year":"2011","journal-title":"Bone"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1182\/blood.V87.5.1928.1928","article-title":"Transforming growth factor-beta1: Differential effects on multiple myeloma versus normal B cells","volume":"87","author":"Urashima","year":"1996","journal-title":"Blood"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2620","DOI":"10.1182\/blood-2011-04-347484","article-title":"Multiple myeloma-related deregulation of bone marrow-derived CD34(+) hematopoietic stem and progenitor cells","volume":"120","author":"Bruns","year":"2012","journal-title":"Blood"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S8756-3282(98)00078-7","article-title":"Decreased bone mass and bone elasticity in mice lacking the transforming growth factor-beta1 gene","volume":"23","author":"Geiser","year":"1998","journal-title":"Bone"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1002\/jbmr.3606","article-title":"Preventing and Repairing Myeloma Bone Disease by Combining Conventional Antiresorptive Treatment with a Bone Anabolic Agent in Murine Models","volume":"34","author":"Tazzyman","year":"2019","journal-title":"J. Bone Miner. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.bone.2016.07.007","article-title":"Combined treatment with a transforming growth factor beta inhibitor (1D11) and bortezomib improves bone architecture in a mouse model of myeloma-induced bone disease","volume":"91","author":"Nyman","year":"2016","journal-title":"Bone"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Mohammad, K.S., Chen, C.G., Balooch, G., Stebbins, E., McKenna, C.R., Davis, H., Niewolna, M., Peng, X.H., Nguyen, D.H.N., and Ionova-Martin, S.S. (2009). Pharmacologic inhibition of the TGF-beta type I receptor kinase has anabolic and anti-catabolic effects on bone. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005275"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2311","DOI":"10.1002\/jbmr.3859","article-title":"TGFbeta Inhibition Stimulates Collagen Maturation to Enhance Bone Repair and Fracture Resistance in a Murine Myeloma Model","volume":"34","author":"Green","year":"2019","journal-title":"J. Bone Miner. Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/j.ajpath.2015.11.003","article-title":"Inhibition of Transforming Growth Factor-beta Activation Diminishes Tumor Progression and Osteolytic Bone Disease in Mouse Models of Multiple Myeloma","volume":"186","author":"Lu","year":"2016","journal-title":"Am. J. Pathol."},{"key":"ref_91","first-page":"586","article-title":"Sotatercept, a soluble activin receptor type 2A IgG-Fc fusion protein for the treatment of anemia and bone loss","volume":"12","author":"Raje","year":"2010","journal-title":"Curr. Opin. Mol. Ther."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e63","DOI":"10.1016\/S2352-3026(18)30002-4","article-title":"Sotatercept with long-term extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: A phase 2, dose-ranging trial","volume":"5","author":"Komrokji","year":"2018","journal-title":"Lancet Haematol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1111\/bjh.12835","article-title":"Sotatercept in patients with osteolytic lesions of multiple myeloma","volume":"165","author":"Abdulkadyrov","year":"2014","journal-title":"Br. J. Haematol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1080\/10428190290012182","article-title":"Bone morphogenetic protein (BMP)-2 induces apoptosis in human myeloma cells","volume":"43","author":"Kawamura","year":"2002","journal-title":"Leuk. Lymphoma."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Seher, A., Lagler, C., Stuhmer, T., Muller-Richter, U.D.A., Kubler, A.C., Sebald, W., M\u00fcller, T.D., and Nickel, J. (2017). Utilizing BMP-2 muteins for treatment of multiple myeloma. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174884"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"4533","DOI":"10.1038\/s41467-019-12296-1","article-title":"Transcriptomic profiling of the myeloma bone-lining niche reveals BMP signalling inhibition to improve bone disease","volume":"10","author":"Gooding","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1158\/1078-0432.CCR-16-0230","article-title":"The Novel Pan-PIM Kinase Inhibitor, PIM447, Displays Dual Antimyeloma and Bone-Protective Effects, and Potently Synergizes with Current Standards of Care","volume":"23","author":"Paino","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2924","DOI":"10.1038\/s41375-019-0482-0","article-title":"The first-in-human study of the pan-PIM kinase inhibitor PIM447 in patients with relapsed and\/or refractory multiple myeloma","volume":"33","author":"Raab","year":"2019","journal-title":"Leukemia"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1182\/blood.V89.5.1560","article-title":"Hepatocyte growth factor is constitutively produced by human bone marrow stromal cells and indirectly promotes hematopoiesis","volume":"89","author":"Takai","year":"1997","journal-title":"Blood"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"7644","DOI":"10.1073\/pnas.93.15.7644","article-title":"Hepatocyte growth factor is a coupling factor for osteoclasts and osteoblasts in vitro","volume":"93","author":"Grano","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_101","first-page":"806","article-title":"Elevated serum concentrations of hepatocyte growth factor in patients with multiple myeloma","volume":"91","author":"Seidel","year":"1998","journal-title":"Nord. Myeloma Study Group Blood"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1038\/sj.leu.2402875","article-title":"The hepatocyte growth factor\/Met pathway controls proliferation and apoptosis in multiple myeloma","volume":"17","author":"Derksen","year":"2003","journal-title":"Leukemia"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"3597","DOI":"10.1073\/pnas.95.7.3597","article-title":"Osteoclast differentiation factor is a ligand for osteoprotegerin\/osteoclastogenesis-inhibitory factor and is identical to TRANCE\/RANKL","volume":"95","author":"Yasuda","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S8756-3282(02)00915-8","article-title":"Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism","volume":"32","author":"Kudo","year":"2003","journal-title":"Bone"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"4615","DOI":"10.1182\/blood-2002-04-1121","article-title":"Human myeloma cells stimulate the receptor activator of nuclear factor-kappa B ligand (RANKL) in T lymphocytes: A potential role in multiple myeloma bone disease","volume":"100","author":"Giuliani","year":"2002","journal-title":"Blood"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Alkharabsheh, O., and Frankel, A.E. (2019). Clinical Activity and Tolerability of SL-401 (Tagraxofusp): Recombinant Diphtheria Toxin and Interleukin-3 in Hematologic Malignancies. Biomedicines, 7.","DOI":"10.3390\/biomedicines7010006"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2652","DOI":"10.1038\/leu.2017.135","article-title":"A novel agent SL-401 induces anti-myeloma activity by targeting plasmacytoid dendritic cells, osteoclastogenesis and cancer stem-like cells","volume":"31","author":"Ray","year":"2017","journal-title":"Leukemia"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1007\/BF01351844","article-title":"Interleukin-11 inhibits bone formation in vitro","volume":"53","author":"Hughes","year":"1993","journal-title":"Calcif. Tissue Int."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"111490","DOI":"10.1016\/j.yexcr.2019.07.003","article-title":"Myeloma-derived extracellular vesicles mediate HGF\/c-Met signaling in osteoblast-like cells","volume":"383","author":"Stromme","year":"2019","journal-title":"Exp. Cell Res."},{"key":"ref_110","first-page":"73","article-title":"Dkk-1 and IL-7 in plasma of patients with multiple myeloma prevent differentiation of mesenchymal stem cells into osteoblasts","volume":"4","author":"Nierste","year":"2014","journal-title":"Am. J. Blood Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1111\/j.1749-6632.2009.05304.x","article-title":"The formation of osteoclasts in multiple myeloma bone disease patients involves the secretion of soluble decoy receptor 3","volume":"1192","author":"Brunetti","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1172\/JCI11176","article-title":"TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand","volume":"106","author":"Lam","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"12950","DOI":"10.18632\/oncotarget.2633","article-title":"LIGHT\/TNFSF14 increases osteoclastogenesis and decreases osteoblastogenesis in multiple myeloma-bone disease","volume":"5","author":"Brunetti","year":"2014","journal-title":"Oncotarget"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"e12761","DOI":"10.1111\/ecc.12761","article-title":"Mechanisms of bone destruction in multiple myeloma","volume":"26","author":"Terpos","year":"2017","journal-title":"Eur. J. Cancer Care"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/17\/3973\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:54:55Z","timestamp":1760165695000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/17\/3973"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,2]]},"references-count":114,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["jcm10173973"],"URL":"https:\/\/doi.org\/10.3390\/jcm10173973","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,2]]}}}