{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T07:43:22Z","timestamp":1789371802890,"version":"build-2803163510"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2009,3,1]],"date-time":"2009-03-01T00:00:00Z","timestamp":1235865600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Multiple myeloma (MM) is associated with the development of osteolytic bone disease, mediated by increased osteoclastic bone resorption and impaired osteoblastic bone formation. Dickkopf-1 (Dkk1), a soluble inhibitor of wingless\/int (Wnt) signaling and osteoblastogenesis, is elevated in patients with MM and correlates with osteolytic bone disease. In this study, we investigated the effect of inhibiting Dkk1 on the development of osteolytic lesions in the 5T2MM murine model of myeloma. We showed that Dkk1 is expressed by murine 5T2MM myeloma cells. Injection of 5T2MM cells into C57BL\/KaLwRij mice resulted in the development of osteolytic bone lesions (p &amp;lt; 0.05), mediated by increased osteoclast numbers (p &amp;lt; 0.001) and a decrease in osteoblast numbers (p &amp;lt; 0.001) and mineralizing surface (p &amp;lt; 0.05). Mice bearing 5T2MM cells were treated with an anti-Dkk1 antibody (BHQ880, 10 mg\/kg, IV, twice weekly for 4 wk) from time of paraprotein detection. Anti-Dkk1 treatment prevented 5T2MM-induced suppression of osteoblast numbers (p &amp;lt; 0.001) and surface (p &amp;lt; 0.001). Treatment increased mineralizing surface by 28% and bone formation rate by 25%; however, there was no change in mineral apposition rate. Inhibiting Dkk1 had no effect on osteoclast numbers. \u03bcCT analysis showed that anti-Dkk1 treatment significantly protected against 5T2MM-induced trabecular bone loss (p &amp;lt; 0.05) and reduced the development of osteolytic bone lesions (p &amp;lt; 0.05). Treatment had no significant effect on tumor burden. These data suggest that inhibiting Dkk1 prevents the suppression of bone formation and in doing so is effective in preventing the development of osteolytic bone disease in myeloma, offering an effective therapeutic approach to treating this clinically important aspect of myeloma.<\/jats:p>","DOI":"10.1359\/jbmr.081104","type":"journal-article","created":{"date-parts":[[2008,11,18]],"date-time":"2008-11-18T09:32:29Z","timestamp":1227000749000},"page":"425-436","source":"Crossref","is-referenced-by-count":234,"title":["Inhibiting Dickkopf-1 (Dkk1) Removes Suppression of Bone Formation and Prevents the Development of Osteolytic Bone Disease in Multiple Myeloma"],"prefix":"10.1093","volume":"24","author":[{"given":"Deborah J","family":"Heath","sequence":"first","affiliation":[{"name":"These authors contributed equally to this work"},{"name":"Academic Unit of Bone Biology, Section of Musculoskeletal Sciences, University of Sheffield School of Medicine and Biomedical Sciences, Sheffield, Yorkshire, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew D","family":"Chantry","sequence":"additional","affiliation":[{"name":"These authors contributed equally to this work"},{"name":"Academic Unit of Bone Biology, Section of Musculoskeletal Sciences, University of Sheffield School of Medicine and Biomedical Sciences, Sheffield, Yorkshire, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clive H","family":"Buckle","sequence":"additional","affiliation":[{"name":"These authors contributed equally to this work"},{"name":"Academic Unit of Bone Biology, Section of Musculoskeletal Sciences, University of Sheffield School of Medicine and Biomedical Sciences, Sheffield, Yorkshire, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Les","family":"Coulton","sequence":"additional","affiliation":[{"name":"Academic Unit of Bone Biology, Section of Musculoskeletal Sciences, University of Sheffield School of Medicine and Biomedical Sciences, Sheffield, Yorkshire, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"John D","family":"Shaughnessy","sequence":"additional","affiliation":[{"name":"Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics, Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly R","family":"Evans","sequence":"additional","affiliation":[{"name":"Academic Unit of Bone Biology, Section of Musculoskeletal Sciences, University of Sheffield School of Medicine and Biomedical Sciences, Sheffield, Yorkshire, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A","family":"Snowden","sequence":"additional","affiliation":[{"name":"Department of Haematology, Royal Hallamshire Hospital, Sheffield, Yorkshire, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R","family":"Stover","sequence":"additional","affiliation":[{"name":"Novartis Institutes for Biomedical Research Incorporated, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Vanderkerken","sequence":"additional","affiliation":[{"name":"Department of Haematology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Peter I","family":"Croucher","sequence":"additional","affiliation":[{"name":"Academic Unit of Bone Biology, Section of Musculoskeletal Sciences, University of Sheffield School of Medicine and Biomedical Sciences, Sheffield, Yorkshire, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,12,4]]},"reference":[{"key":"2024020320035215800_bib1","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1111\/j.1365-2141.1982.tb03936.x","article-title":"Quantitative histology of myeloma-induced bone changes","volume":"52","author":"Valentin-Opran","year":"1982","journal-title":"Br J Haematol"},{"key":"2024020320035215800_bib2","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1172\/JCI115305","article-title":"Recruitment of new osteoblasts and osteoclasts is the earliest critical event in the pathogenesis of human multiple myeloma","volume":"88","author":"Bataille","year":"1991","journal-title":"J Clin Invest"},{"key":"2024020320035215800_bib3","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1111\/j.1600-0609.1992.tb00046.x","article-title":"Abnormal bone remodelling in patients with myelomatosis and normal biochemical indices of bone resorption","volume":"49","author":"Taube","year":"1992","journal-title":"Eur J Haematol"},{"key":"2024020320035215800_bib4","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/sj.cr.7290260","article-title":"Wnt signalling in disease and in development","volume":"15","author":"Nusse","year":"2005","journal-title":"Cell Res"},{"key":"2024020320035215800_bib5","doi-asserted-by":"crossref","first-page":"3324","DOI":"10.1073\/pnas.0408742102","article-title":"Regulation of osteoblastogenesis and bone mass by Wnt10b","volume":"102","author":"Bennett","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024020320035215800_bib6","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.devcel.2005.03.016","article-title":"Wnt\/beta catenin signalling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis","volume":"8","author":"Day","year":"2005","journal-title":"Dev Cell"},{"key":"2024020320035215800_bib7","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1016\/j.bone.2004.01.016","article-title":"Wnt signaling inhibits osteogenic differentiation of human mesenchymal stem cells","volume":"34","author":"de Boer","year":"2004","journal-title":"Bone"},{"key":"2024020320035215800_bib8","doi-asserted-by":"crossref","first-page":"33132","DOI":"10.1074\/jbc.M500608200","article-title":"Canonical Wnt signaling promotes osteogenesis by directly stimulating Runx2 gene expression","volume":"280","author":"Gaur","year":"2005","journal-title":"J Biol Chem"},{"key":"2024020320035215800_bib9","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.gene.2004.06.044","article-title":"Wnt signalling in osteoblasts and bone diseases","volume":"27","author":"Westendorf","year":"2004","journal-title":"Gene"},{"key":"2024020320035215800_bib10","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/S0092-8674(01)00571-2","article-title":"LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development","volume":"107","author":"Gong","year":"2001","journal-title":"Cell"},{"key":"2024020320035215800_bib11","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1056\/NEJMoa013444","article-title":"High bone density due to a mutation in LDL-receptor-related protein 5","volume":"346","author":"Boyden","year":"2002","journal-title":"N Engl J Med"},{"key":"2024020320035215800_bib12","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1086\/338450","article-title":"A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait","volume":"70","author":"Little","year":"2002","journal-title":"Am J Hum Genet"},{"key":"2024020320035215800_bib13","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1359\/jbmr.070211","article-title":"Novel LRP5 missense mutation in a patient with a high bone mass phenotype results in decreased DKK1-mediated inhibition of Wnt signaling","volume":"22","author":"Balemans","year":"2007","journal-title":"J Bone Miner Res"},{"key":"2024020320035215800_bib14","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1083\/jcb.200201089","article-title":"Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor","volume":"157","author":"Kato","year":"2002","journal-title":"J Cell Biol"},{"key":"2024020320035215800_bib15","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/35077108","article-title":"LDL-receptor-related protein 6 is a receptor for Dickkopf proteins","volume":"411","author":"Mao","year":"2001","journal-title":"Nature"},{"key":"2024020320035215800_bib16","doi-asserted-by":"crossref","first-page":"6100","DOI":"10.1128\/MCB.22.17.6100-6110.2002","article-title":"Regulation of Wnt\/LRP signaling by distinct domains of dickkopf proteins","volume":"22","author":"Brott","year":"2002","journal-title":"Mol Cell Biol"},{"key":"2024020320035215800_bib17","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":"2024020320035215800_bib18","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1359\/jbmr.2003.18.10.1842","article-title":"BMP-2 controls alkaline phosphatase and osteoblast mineralization by a Wnt autocrine loop","volume":"18","author":"Rawadi","year":"2003","journal-title":"J Bone Miner Res"},{"key":"2024020320035215800_bib19","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1634\/stemcells.2005-0220","article-title":"A crosstalk between myeloma cells and marrow stromal cells stimulates production of DKK1 and interleukin-6: A potential role in the development of lytic bone disease and tumor progression in multiple myeloma","volume":"24","author":"Gunn","year":"2006","journal-title":"Stem Cells"},{"key":"2024020320035215800_bib20","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/1476-4598-6-71","article-title":"Attenuation of WNT signaling by DKK1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF","volume":"6","author":"Fujita","year":"2007","journal-title":"Mol Cancer"},{"key":"2024020320035215800_bib21","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 inhibits osteoblast formation and differentiation","volume":"106","author":"Giuliani","year":"2005","journal-title":"Blood"},{"key":"2024020320035215800_bib22","doi-asserted-by":"crossref","first-page":"2309","DOI":"10.1074\/jbc.M406275200","article-title":"The Wnt signalling inhibitor dickkopf-1 is required for the re-entry into the cell cycle of human adult stem cells from bone marrow","volume":"280","author":"Gregory","year":"2005","journal-title":"J Biol Chem"},{"key":"2024020320035215800_bib23","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":"3","author":"MacDonald","year":"2007","journal-title":"Bone"},{"key":"2024020320035215800_bib24","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1359\/jbmr.060311","article-title":"Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass","volume":"21","author":"Morvan","year":"2006","journal-title":"J Bone Miner Res"},{"key":"2024020320035215800_bib25","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/S1534-5807(01)00041-7","article-title":"Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse","volume":"3","author":"Mukhopadhyay","year":"2001","journal-title":"Dev Cell"},{"key":"2024020320035215800_bib26","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1016\/j.bone.2006.03.017","article-title":"Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia","volume":"39","author":"Li","year":"2006","journal-title":"Bone"},{"key":"2024020320035215800_bib27","doi-asserted-by":"crossref","first-page":"7665","DOI":"10.1158\/0008-5472.CAN-06-4666","article-title":"Production of Wnt inhibitors by myeloma cells: Potential effects on canonical wnt pathway in the bone microenvironment","volume":"67","author":"Giuliani","year":"2007","journal-title":"Cancer Res"},{"key":"2024020320035215800_bib28","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":"19","author":"Politou","year":"2006","journal-title":"Int J Cancer"},{"key":"2024020320035215800_bib29","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1182\/blood-2007-03-082529","article-title":"Dickkopf-1 (DKK1) is widely expressed and a potent tumor-associated antigen in multiple myeloma","volume":"110","author":"Qian","year":"2007","journal-title":"Blood"},{"key":"2024020320035215800_bib30","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1111\/j.1365-2141.2007.06871.x","article-title":"Myeloma cell expression of 10 candidate genes for osteolytic bone disease. Only overexpression of DKK1 correlates with clinical bone involvement at diagnosis","volume":"140","author":"Haaber","year":"2007","journal-title":"Br J Haematol"},{"key":"2024020320035215800_bib31","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":"2024020320035215800_bib32","doi-asserted-by":"crossref","first-page":"609","DOI":"10.4049\/jimmunol.122.2.609","article-title":"Transplantation of the paraprotein-producing clone from old to young C57BL\/KaLwRij mice","volume":"122","author":"Radl","year":"1979","journal-title":"J Immunol"},{"key":"2024020320035215800_bib33","first-page":"177","article-title":"Animal model of human disease: Multiple myeloma","volume":"132","author":"Radl","year":"1988","journal-title":"Am J Pathol"},{"key":"2024020320035215800_bib34","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1038\/bjc.1996.277","article-title":"Follow-up of bone lesions in an experimental multiple myeloma mouse model: Description of an in vivo technique using radiography dedicated for mammography","volume":"12","author":"Vanderkerken","year":"1996","journal-title":"Br J Cancer"},{"key":"2024020320035215800_bib35","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":"2024020320035215800_bib36","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1182\/blood.V93.1.235","article-title":"Insulin like growth factor-1 acts as a chemo-attractant for 5T2 multiple myeloma cells","volume":"93","author":"Vanderkerken","year":"1999","journal-title":"Blood"},{"key":"2024020320035215800_bib37","first-page":"191","article-title":"The 5T2MM murine model of multiple myeloma: Maintenance and analysis","volume":"113","author":"Vanderkerken","year":"2005","journal-title":"Methods Mol Med"},{"key":"2024020320035215800_bib38","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/bjc.1997.409","article-title":"Organ involvement and phenotypic adhesion profile of 5T2 and 5T33MM cells in the C57BL\/KaLwRij mouse","volume":"76","author":"Vanderkerken","year":"1997","journal-title":"Br J Cancer"},{"key":"2024020320035215800_bib39","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1002\/jbmr.5650020617","article-title":"Bone histomorphometry: Standardization of nomenclature, symbols, and units","volume":"6","author":"Parfitt","year":"1987","journal-title":"Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res"},{"key":"2024020320035215800_bib40","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1359\/jbmr.060719","article-title":"Secreted frizzled-related protein 4 is a negative regulator of peak BMD in SAMP6 mice","volume":"21","author":"Nakanishi","year":"2006","journal-title":"J Bone Miner Res"},{"key":"2024020320035215800_bib41","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1359\/jbmr.060819","article-title":"Advanced molecular profiling in vivo detects novel function of dickkopf-3 in the regulation of bone formation","volume":"21","author":"Aslan","year":"2006","journal-title":"J Bone Miner Res"},{"key":"2024020320035215800_bib42","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":"2024020320035215800_bib43","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1242\/jcs.02883","article-title":"Wnt signalling in osteoblasts regulates expression of the receptor activator of NFkappaB ligand and inhibits osteoclastogenesis in vitro","volume":"119","author":"Spencer","year":"2006","journal-title":"J Cell Sci"},{"key":"2024020320035215800_bib44","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/j.devcel.2005.02.017","article-title":"Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation","volume":"8","author":"Glass","year":"2005","journal-title":"Dev Cell"},{"key":"2024020320035215800_bib45","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":"2024020320035215800_bib46","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.1182\/blood-2007-03-077685","article-title":"Increasing Wnt signaling in the bone marrow microenvironment inhibits the development of myeloma bone disease and reduces tumour burden in bone in vivo","volume":"111","author":"Edwards","year":"2008","journal-title":"Blood"},{"key":"2024020320035215800_bib47","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":"2024020320035215800_bib48","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1359\/jbmr.2003.18.3.482","article-title":"Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: Evidence for decreases osteolysis, tumour burden and angiogenesis, and increased survival","volume":"18","author":"Croucher","year":"2003","journal-title":"J Bone Miner Res"},{"key":"2024020320035215800_bib49","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"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1359%2Fjbmr.081104","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/24\/3\/425\/56574965\/5650240306.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/24\/3\/425\/56574965\/5650240306.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T10:51:40Z","timestamp":1710327100000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/24\/3\/425-436\/7599896"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,3,1]]},"references-count":49,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2009,12,4]]},"published-print":{"date-parts":[[2009,3,1]]}},"URL":"https:\/\/doi.org\/10.1359\/jbmr.081104","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2009,3,1]]},"published":{"date-parts":[[2009,3,1]]}}}