Soluble rank ligand produced by myeloma cells causes generalised bone loss in multiple myeloma
Patients with multiple myeloma commonly develop focal osteolytic bone disease, as well as generalised osteoporosis. The mechanisms underlying the development of osteoporosis in patients with myeloma are poorly understood. Although disruption of the RANKL/OPG pathway has been shown to underlie format...
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| description | Patients with multiple myeloma commonly develop focal osteolytic bone disease, as well as generalised osteoporosis. The mechanisms underlying the development of osteoporosis in patients with myeloma are poorly understood. Although disruption of the RANKL/OPG pathway has been shown to underlie formation of focal osteolytic lesions, its role in the development of osteoporosis in myeloma remains unclear. Increased soluble RANKL in serum from patients with myeloma raises the possibility that this molecule plays a key role. The aim of the present study was to establish whether sRANKL produced by myeloma cells contributes directly to osteoporosis. C57BL/KaLwRij mice were injected with either 5T2MM or 5T33MM murine myeloma cells. 5T2MM-bearing mice developed osteolytic bone lesions (p |
| doi_str_mv | 10.1371/journal.pone.0041127 |
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The mechanisms underlying the development of osteoporosis in patients with myeloma are poorly understood. Although disruption of the RANKL/OPG pathway has been shown to underlie formation of focal osteolytic lesions, its role in the development of osteoporosis in myeloma remains unclear. Increased soluble RANKL in serum from patients with myeloma raises the possibility that this molecule plays a key role. The aim of the present study was to establish whether sRANKL produced by myeloma cells contributes directly to osteoporosis. C57BL/KaLwRij mice were injected with either 5T2MM or 5T33MM murine myeloma cells. 5T2MM-bearing mice developed osteolytic bone lesions (p<0.05) with increased osteoclast surface (p<0.01) and reduced trabecular bone volume (p<0.05). Bone volume was also reduced at sites where 5T2MM cells were not present (p<0.05). In 5T2MM-bearing mice soluble mRANKL was increased (p<0.05), whereas OPG was not altered. In contrast, 5T33MM-bearing mice had no changes in osteoclast surface or trabecular bone volume and did not develop osteolytic lesions. Soluble mRANKL was undetectable in serum from 5T33MM-bearing mice. In separate experiments, RPMI-8226 human myeloma cells were transduced with an human RANKL/eGFP construct, or eGFP alone. RPMI-8226/hRANKL/eGFP cells, but not RPMI-8226/eGFP cells, stimulated osteoclastic bone resorption (p<0.05) in vitro. Sub-cutaneous injection of NOD/SCID mice with RPMI-8226/hRANKL/eGFP or RPMI-8226/eGFP cells resulted in tumour development in all mice. RPMI-8226/hRANKL/eGFP-bearing mice exhibited increased serum soluble hRANKL (p<0.05) and a three-fold increase in osteoclast number (p<0.05) compared to RPMI-8226/eGFP-bearing mice. This was associated with reduced trabecular bone volume (27%, p<0.05), decreased trabecular number (29%, p<0.05) and increased trabecular thickness (8%, p<0.05). Our findings demonstrate that soluble RANKL produced by myeloma cells causes generalised bone loss, suggesting that targeting RANKL may prevent osteoporosis in patients with myeloma.]]></description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0041127</identifier><identifier>PMID: 22952578</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Bearing ; Biocompatibility ; Biology ; Biomedical materials ; Bone and Bones - metabolism ; Bone diseases ; Bone lesions ; Bone loss ; Bone marrow ; Bone resorption ; Cancellous bone ; Cancer ; Cell Line, Tumor ; Complications and side effects ; Dentistry ; DNA, Complementary - metabolism ; Green Fluorescent Proteins - metabolism ; Health aspects ; Hematology ; Humans ; Lesions ; Ligands ; Ligands (Chemistry) ; Lumbar Vertebrae - metabolism ; Medical research ; Medicine ; Metabolism ; Metastasis ; Mice ; Mice, Inbred C57BL ; Mice, SCID ; Multiple myeloma ; Multiple Myeloma - metabolism ; Neoplasm Transplantation ; Osteoclasts ; Osteoclasts - cytology ; Osteolysis ; Osteoporosis ; Osteoporosis - genetics ; Osteoporosis - physiopathology ; Osteoprotegerin ; Osteoprotegerin - metabolism ; Patients ; Prevention ; RANK Ligand - metabolism ; Risk factors ; Rodents ; TRANCE protein ; Tumor necrosis factor-TNF ; Tumors</subject><ispartof>PloS one, 2012-08, Vol.7 (8), p.e41127-e41127</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>Buckle et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2012 Buckle et al 2012 Buckle et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-46381a33ce621243586e4baf3c0aa6abf84db31793d90019888cf3108cbfa8d33</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3430669/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3430669/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22952578$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>de Carvalho, Denise Pires</contributor><creatorcontrib>Buckle, Clive Henry</creatorcontrib><creatorcontrib>De Leenheer, Evy</creatorcontrib><creatorcontrib>Lawson, Michelle Anne</creatorcontrib><creatorcontrib>Yong, Kwee</creatorcontrib><creatorcontrib>Rabin, Neil</creatorcontrib><creatorcontrib>Perry, Mark</creatorcontrib><creatorcontrib>Vanderkerken, Karen</creatorcontrib><creatorcontrib>Croucher, Peter Ian</creatorcontrib><title>Soluble rank ligand produced by myeloma cells causes generalised bone loss in multiple myeloma</title><title>PloS one</title><addtitle>PLoS One</addtitle><description><![CDATA[Patients with multiple myeloma commonly develop focal osteolytic bone disease, as well as generalised osteoporosis. The mechanisms underlying the development of osteoporosis in patients with myeloma are poorly understood. Although disruption of the RANKL/OPG pathway has been shown to underlie formation of focal osteolytic lesions, its role in the development of osteoporosis in myeloma remains unclear. Increased soluble RANKL in serum from patients with myeloma raises the possibility that this molecule plays a key role. The aim of the present study was to establish whether sRANKL produced by myeloma cells contributes directly to osteoporosis. C57BL/KaLwRij mice were injected with either 5T2MM or 5T33MM murine myeloma cells. 5T2MM-bearing mice developed osteolytic bone lesions (p<0.05) with increased osteoclast surface (p<0.01) and reduced trabecular bone volume (p<0.05). Bone volume was also reduced at sites where 5T2MM cells were not present (p<0.05). In 5T2MM-bearing mice soluble mRANKL was increased (p<0.05), whereas OPG was not altered. In contrast, 5T33MM-bearing mice had no changes in osteoclast surface or trabecular bone volume and did not develop osteolytic lesions. Soluble mRANKL was undetectable in serum from 5T33MM-bearing mice. In separate experiments, RPMI-8226 human myeloma cells were transduced with an human RANKL/eGFP construct, or eGFP alone. RPMI-8226/hRANKL/eGFP cells, but not RPMI-8226/eGFP cells, stimulated osteoclastic bone resorption (p<0.05) in vitro. Sub-cutaneous injection of NOD/SCID mice with RPMI-8226/hRANKL/eGFP or RPMI-8226/eGFP cells resulted in tumour development in all mice. RPMI-8226/hRANKL/eGFP-bearing mice exhibited increased serum soluble hRANKL (p<0.05) and a three-fold increase in osteoclast number (p<0.05) compared to RPMI-8226/eGFP-bearing mice. This was associated with reduced trabecular bone volume (27%, p<0.05), decreased trabecular number (29%, p<0.05) and increased trabecular thickness (8%, p<0.05). Our findings demonstrate that soluble RANKL produced by myeloma cells causes generalised bone loss, suggesting that targeting RANKL may prevent osteoporosis in patients with myeloma.]]></description><subject>Animals</subject><subject>Bearing</subject><subject>Biocompatibility</subject><subject>Biology</subject><subject>Biomedical materials</subject><subject>Bone and Bones - metabolism</subject><subject>Bone diseases</subject><subject>Bone lesions</subject><subject>Bone loss</subject><subject>Bone marrow</subject><subject>Bone resorption</subject><subject>Cancellous bone</subject><subject>Cancer</subject><subject>Cell Line, Tumor</subject><subject>Complications and side effects</subject><subject>Dentistry</subject><subject>DNA, Complementary - metabolism</subject><subject>Green Fluorescent Proteins - metabolism</subject><subject>Health aspects</subject><subject>Hematology</subject><subject>Humans</subject><subject>Lesions</subject><subject>Ligands</subject><subject>Ligands (Chemistry)</subject><subject>Lumbar Vertebrae - metabolism</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Metabolism</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, SCID</subject><subject>Multiple myeloma</subject><subject>Multiple Myeloma - metabolism</subject><subject>Neoplasm Transplantation</subject><subject>Osteoclasts</subject><subject>Osteoclasts - cytology</subject><subject>Osteolysis</subject><subject>Osteoporosis</subject><subject>Osteoporosis - genetics</subject><subject>Osteoporosis - physiopathology</subject><subject>Osteoprotegerin</subject><subject>Osteoprotegerin - metabolism</subject><subject>Patients</subject><subject>Prevention</subject><subject>RANK Ligand - metabolism</subject><subject>Risk factors</subject><subject>Rodents</subject><subject>TRANCE protein</subject><subject>Tumor necrosis factor-TNF</subject><subject>Tumors</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk12L1DAUhoso7rr6D0QLgujFjPlqmt4Iy-LHwMKCq14aTtPTTsa0mW1acf69Gae7TGUvpIGG5Hnfk5yckyTPKVlSntN3Gz_2Hbjl1ne4JERQyvIHySktOFtIRvjDo_lJ8iSEDSEZV1I-Tk4YKzKW5eo0-XHt3Vg6THvofqbONtBV6bb31WiwSstd2u7Q-RZSg86F1MAYMKQNdtiDs2HPxPip8yGktkvb0Q12G-0m2dPkUQ0u4LPpf5Z8-_jh68XnxeXVp9XF-eXCyIINCyG5osC5QckoEzxTEkUJNTcEQEJZK1GVnOYFrwpCaKGUMjWnRJmyBlVxfpa8PPhu40n0lJqgKWdSZEQoFonVgag8bPS2ty30O-3B6r8Lvm809IM1DrWUJWJO44hqqA1gUVQUsxIY1lhW0ev9FG0sW6wMdkPMxsx0vtPZtW78L80FJ1IW0eDNZND7mxHDoFsb9hmGDv0Yz024ygqaSxnRV_-g999uohqIF7Bd7WNcszfV56JQTAhBaKSW91Dxq7C1Jr5jbeP6TPB2JojMgL-HJlZB0KvrL__PXn2fs6-P2DWCG9YhFuJgfRfmoDiApo8V1mN9l2RK9L4NbrOh922gpzaIshfHD3Qnuq17_gemAANC</recordid><startdate>20120829</startdate><enddate>20120829</enddate><creator>Buckle, Clive Henry</creator><creator>De Leenheer, Evy</creator><creator>Lawson, Michelle Anne</creator><creator>Yong, Kwee</creator><creator>Rabin, Neil</creator><creator>Perry, Mark</creator><creator>Vanderkerken, Karen</creator><creator>Croucher, Peter Ian</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20120829</creationdate><title>Soluble rank ligand produced by myeloma cells causes generalised bone loss in multiple myeloma</title><author>Buckle, Clive Henry ; De Leenheer, Evy ; Lawson, Michelle Anne ; Yong, Kwee ; Rabin, Neil ; Perry, Mark ; Vanderkerken, Karen ; Croucher, Peter Ian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-46381a33ce621243586e4baf3c0aa6abf84db31793d90019888cf3108cbfa8d33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Bearing</topic><topic>Biocompatibility</topic><topic>Biology</topic><topic>Biomedical materials</topic><topic>Bone and Bones - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Buckle, Clive Henry</au><au>De Leenheer, Evy</au><au>Lawson, Michelle Anne</au><au>Yong, Kwee</au><au>Rabin, Neil</au><au>Perry, Mark</au><au>Vanderkerken, Karen</au><au>Croucher, Peter Ian</au><au>de Carvalho, Denise Pires</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Soluble rank ligand produced by myeloma cells causes generalised bone loss in multiple myeloma</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-08-29</date><risdate>2012</risdate><volume>7</volume><issue>8</issue><spage>e41127</spage><epage>e41127</epage><pages>e41127-e41127</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract><![CDATA[Patients with multiple myeloma commonly develop focal osteolytic bone disease, as well as generalised osteoporosis. The mechanisms underlying the development of osteoporosis in patients with myeloma are poorly understood. Although disruption of the RANKL/OPG pathway has been shown to underlie formation of focal osteolytic lesions, its role in the development of osteoporosis in myeloma remains unclear. Increased soluble RANKL in serum from patients with myeloma raises the possibility that this molecule plays a key role. The aim of the present study was to establish whether sRANKL produced by myeloma cells contributes directly to osteoporosis. C57BL/KaLwRij mice were injected with either 5T2MM or 5T33MM murine myeloma cells. 5T2MM-bearing mice developed osteolytic bone lesions (p<0.05) with increased osteoclast surface (p<0.01) and reduced trabecular bone volume (p<0.05). Bone volume was also reduced at sites where 5T2MM cells were not present (p<0.05). In 5T2MM-bearing mice soluble mRANKL was increased (p<0.05), whereas OPG was not altered. In contrast, 5T33MM-bearing mice had no changes in osteoclast surface or trabecular bone volume and did not develop osteolytic lesions. Soluble mRANKL was undetectable in serum from 5T33MM-bearing mice. In separate experiments, RPMI-8226 human myeloma cells were transduced with an human RANKL/eGFP construct, or eGFP alone. RPMI-8226/hRANKL/eGFP cells, but not RPMI-8226/eGFP cells, stimulated osteoclastic bone resorption (p<0.05) in vitro. Sub-cutaneous injection of NOD/SCID mice with RPMI-8226/hRANKL/eGFP or RPMI-8226/eGFP cells resulted in tumour development in all mice. RPMI-8226/hRANKL/eGFP-bearing mice exhibited increased serum soluble hRANKL (p<0.05) and a three-fold increase in osteoclast number (p<0.05) compared to RPMI-8226/eGFP-bearing mice. This was associated with reduced trabecular bone volume (27%, p<0.05), decreased trabecular number (29%, p<0.05) and increased trabecular thickness (8%, p<0.05). Our findings demonstrate that soluble RANKL produced by myeloma cells causes generalised bone loss, suggesting that targeting RANKL may prevent osteoporosis in patients with myeloma.]]></abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22952578</pmid><doi>10.1371/journal.pone.0041127</doi><tpages>e41127</tpages><oa>free_for_read</oa></addata></record> |
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| language | eng |
| recordid | cdi_plos_journals_1326450482 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Animals Bearing Biocompatibility Biology Biomedical materials Bone and Bones - metabolism Bone diseases Bone lesions Bone loss Bone marrow Bone resorption Cancellous bone Cancer Cell Line, Tumor Complications and side effects Dentistry DNA, Complementary - metabolism Green Fluorescent Proteins - metabolism Health aspects Hematology Humans Lesions Ligands Ligands (Chemistry) Lumbar Vertebrae - metabolism Medical research Medicine Metabolism Metastasis Mice Mice, Inbred C57BL Mice, SCID Multiple myeloma Multiple Myeloma - metabolism Neoplasm Transplantation Osteoclasts Osteoclasts - cytology Osteolysis Osteoporosis Osteoporosis - genetics Osteoporosis - physiopathology Osteoprotegerin Osteoprotegerin - metabolism Patients Prevention RANK Ligand - metabolism Risk factors Rodents TRANCE protein Tumor necrosis factor-TNF Tumors |
| title | Soluble rank ligand produced by myeloma cells causes generalised bone loss in multiple myeloma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-21T19%3A39%3A16IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Soluble%20rank%20ligand%20produced%20by%20myeloma%20cells%20causes%20generalised%20bone%20loss%20in%20multiple%20myeloma&rft.jtitle=PloS%20one&rft.au=Buckle,%20Clive%20Henry&rft.date=2012-08-29&rft.volume=7&rft.issue=8&rft.spage=e41127&rft.epage=e41127&rft.pages=e41127-e41127&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0041127&rft_dat=%3Cgale_plos_%3EA498244401%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1326450482&rft_id=info:pmid/22952578&rft_galeid=A498244401&rft_doaj_id=oai_doaj_org_article_66bee71e71264afcae99d1e5ba2efebd&rfr_iscdi=true |