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dc.contributor.authorVallet, Soniaen_US
dc.contributor.authorPozzi, Samanthaen_US
dc.contributor.authorPatel, Kishanen_US
dc.contributor.authorVaghela, Nileshwarien_US
dc.contributor.authorFulciniti, MariaTeresaen_US
dc.contributor.authorVeiby, Petteren_US
dc.contributor.authorHideshima, Teruen_US
dc.contributor.authorSanto, Loredanaen_US
dc.contributor.authorCirstea, Dianaen_US
dc.contributor.authorScadden, David Ten_US
dc.contributor.authorAnderson, Kenneth Cen_US
dc.contributor.authorRaje, Noopuren_US
dc.date.accessioned2014-09-08T15:35:36Z
dc.date.issued2014en_US
dc.identifier.citationVallet, S., S. Pozzi, K. Patel, N. Vaghela, M. Fulciniti, P. Veiby, T. Hideshima, et al. 2014. “A Novel Role for CCL3 (MIP-1α) in Myeloma-induced Bone Disease via Osteocalcin Downregulation and Inhibition of Osteoblast Function.” Leukemia 25 (7): 1174-1181. doi:10.1038/leu.2011.43. http://dx.doi.org/10.1038/leu.2011.43.en
dc.identifier.issn0887-6924en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:12785791
dc.description.abstractUpregulation of cytokines and chemokines is a frequent finding in multiple myeloma (MM). CCL3 (also known as MIP-1α) is a pro-inflammatory chemokine whose levels in the MM microenvironment correlate with osteolytic lesions and tumor burden. CCL3 and its receptors, CCR1 and CCR5, contribute to the development of bone disease in MM by supporting tumor growth and regulating osteoclast (OC) differentiation. Here, we identify inhibition of osteoblast (OB) function as an additional pathogenic mechanism in CCL3-induced bone disease. MM-derived and exogenous CCL3 represses mineralization and osteocalcin production by primary human bone marrow stromal cells and HS27A cells. Our results suggest that CCL3 effects on OBs are mediated by ERK activation and subsequent downregulation of the osteogenic transcription factor osterix. CCR1 inhibition reduced ERK phosphorylation and restored both osterix and osteocalcin expression in the presence of CCL3. Finally, treating SCID-hu mice with a small molecule CCR1 inhibitor suggests an upregulation of osteocalcin expression along with OC downregulation. Our results show that CCL3, in addition to its known catabolic activity, reduces bone formation by inhibiting OB function and therefore contributes to OB/OC uncoupling in MM.en
dc.language.isoen_USen
dc.relation.isversionofdoi:10.1038/leu.2011.43en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142423/pdf/en
dash.licenseLAAen_US
dc.subjectMyelomaen
dc.subjectCCL3en
dc.subjectOsteoblasten
dc.subjectOsteocalcinen
dc.subjectERKen
dc.subjectOsterixen
dc.titleA Novel Role for CCL3 (MIP-1α) in Myeloma-induced Bone Disease via Osteocalcin Downregulation and Inhibition of Osteoblast Functionen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalLeukemiaen
dash.depositing.authorFulciniti, MariaTeresaen_US
dc.date.available2014-09-08T15:35:36Z
dc.identifier.doi10.1038/leu.2011.43*
dash.authorsorderedfalse
dash.contributor.affiliatedSanto, Loredana
dash.contributor.affiliatedRaje, Noopur
dash.contributor.affiliatedFulciniti, Mariateresa
dash.contributor.affiliatedHideshima, Teru
dash.contributor.affiliatedScadden, David
dash.contributor.affiliatedAnderson, Kenneth


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