Novel CCL3-HMGB1 signaling axis regulating osteocyte RANKL expression in multiple myeloma
Multiple myeloma (MM) is a clonal plasma cell proliferative malignancy characterized by a debilitating bone disease. Osteolytic destruction, a hallmark of MM, is driven by increased osteoclast number and exacerbated bone resorption, primarily fueled by the excessive production of RANKL, the master...
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| Format: | Article |
| Language: | English |
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Ferrata Storti Foundation
2024-11-01
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| Series: | Haematologica |
| Online Access: | https://haematologica.org/article/view/11852 |
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| author | Aric Anloague Hayley M. Sabol Japneet Kaur Sharmin Khan Cody Ashby Carolina Schinke C. Lowry Barnes Farah Alturkmani Elena Ambrogini Michael Tveden Gundesen Thomas Lund Anne Kristine Amstrup Thomas Levin Andersen Marta Diaz-delCastillo G. David Roodman Teresita Bellido Jesus Delgado-Calle |
| author_facet | Aric Anloague Hayley M. Sabol Japneet Kaur Sharmin Khan Cody Ashby Carolina Schinke C. Lowry Barnes Farah Alturkmani Elena Ambrogini Michael Tveden Gundesen Thomas Lund Anne Kristine Amstrup Thomas Levin Andersen Marta Diaz-delCastillo G. David Roodman Teresita Bellido Jesus Delgado-Calle |
| author_sort | Aric Anloague |
| collection | DOAJ |
| description |
Multiple myeloma (MM) is a clonal plasma cell proliferative malignancy characterized by a debilitating bone disease. Osteolytic destruction, a hallmark of MM, is driven by increased osteoclast number and exacerbated bone resorption, primarily fueled by the excessive production of RANKL, the master regulator of osteoclast formation, within the tumor niche. We previously reported that osteocytes, the most abundant cells in the bone niche, promote tumor progression and support MM bone disease by overproducing RANKL. However, the molecular mechanisms underlying RANKL dysregulation in osteocytes in the context of MM bone disease are not entirely understood. Here, we present evidence that MM-derived CCL3 induces upregulation of RANKL expression in both human and murine osteocytes. Through a combination of in vitro, ex vivo, and in vivo models and clinical data, we demonstrate that genetic or pharmacologic inhibition of CCL3 prevents RANKL upregulation in osteocytes and attenuates the bone loss induced by MM cells. Mechanistic studies revealed that MM-derived CCL3 triggers the secretion of HMGB1 by osteocytes, a process required for osteocytic RANKL upregulation by MM cells. These findings identify a previously unknown CCL3-HMGB1 signaling axis in the MM tumor niche that drives bone resorption by promoting RANKL overproduction in osteocytes.
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| format | Article |
| id | doaj-art-2cc6d4c16ea547a48e641d7a171fc618 |
| institution | Kabale University |
| issn | 0390-6078 1592-8721 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Ferrata Storti Foundation |
| record_format | Article |
| series | Haematologica |
| spelling | doaj-art-2cc6d4c16ea547a48e641d7a171fc6182024-11-28T19:42:36ZengFerrata Storti FoundationHaematologica0390-60781592-87212024-11-01999110.3324/haematol.2024.286484Novel CCL3-HMGB1 signaling axis regulating osteocyte RANKL expression in multiple myelomaAric Anloague0Hayley M. Sabol1Japneet Kaur2Sharmin Khan3Cody Ashby4Carolina Schinke5C. Lowry Barnes6Farah Alturkmani7Elena Ambrogini8Michael Tveden Gundesen9Thomas Lund10Anne Kristine Amstrup11Thomas Levin Andersen12Marta Diaz-delCastillo13G. David Roodman14Teresita Bellido15Jesus Delgado-Calle16Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, ARPhysiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, ARPhysiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, US; Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little RockPhysiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, ARWinthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, US; Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, ARWinthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, US; Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, ARDepartment of Orthopedic Surgery; University of Arkansas for Medical Sciences, Little Rock, ARDivision of Endocrinology and Metabolism, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, US; Center for Musculoskeletal Disease Research, University of Arkansas for Medical Sciences Little Rock, ARDivision of Endocrinology and Metabolism, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, US; Center for Musculoskeletal Disease Research, University of Arkansas for Medical Sciences Little Rock, AR, US; Central Arkansas Veterans Healthcare System, Little Rock, ARDepartment of Hematology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, DenmarkDepartment of Hematology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark; Centre for Innovative Medical Technology, Odense University Hospital, Odense, DenmarkDepartment of Endocrinology and Internal Medicine (MEA), THG, Aarhus University Hospital, Aarhus, DenmarkDepartment of Clinical Research, University of Southern Denmark, Odense, Denmark; Department of Pathology, Odense University Hospital, Odense, Denmark; Department of Forensic Medicine, University of Aarhus, Aarhus, DenmarkDepartment of Hematology, Odense University Hospital, Odense, DenmarkDivision of Hematology and Oncology, Department of Medicine, Indiana University, Indianapolis, INPhysiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, US; Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, US; Department of Orthopedic Surgery; University of Arkansas for Medical Sciences, Little Rock, AR, US; Center for Musculoskeletal Disease Research, University of Arkansas for Medical Sciences Little Rock, AR, US; Central Arkansas Veterans Healthcare System, Little Rock, ARPhysiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, US; Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, US; Department of Orthopedic Surgery; University of Arkansas for Medical Sciences, Little Rock, AR, US; Center for Musculoskeletal Disease Research, University of Arkansas for Medical Sciences Little Rock, AR Multiple myeloma (MM) is a clonal plasma cell proliferative malignancy characterized by a debilitating bone disease. Osteolytic destruction, a hallmark of MM, is driven by increased osteoclast number and exacerbated bone resorption, primarily fueled by the excessive production of RANKL, the master regulator of osteoclast formation, within the tumor niche. We previously reported that osteocytes, the most abundant cells in the bone niche, promote tumor progression and support MM bone disease by overproducing RANKL. However, the molecular mechanisms underlying RANKL dysregulation in osteocytes in the context of MM bone disease are not entirely understood. Here, we present evidence that MM-derived CCL3 induces upregulation of RANKL expression in both human and murine osteocytes. Through a combination of in vitro, ex vivo, and in vivo models and clinical data, we demonstrate that genetic or pharmacologic inhibition of CCL3 prevents RANKL upregulation in osteocytes and attenuates the bone loss induced by MM cells. Mechanistic studies revealed that MM-derived CCL3 triggers the secretion of HMGB1 by osteocytes, a process required for osteocytic RANKL upregulation by MM cells. These findings identify a previously unknown CCL3-HMGB1 signaling axis in the MM tumor niche that drives bone resorption by promoting RANKL overproduction in osteocytes. https://haematologica.org/article/view/11852 |
| spellingShingle | Aric Anloague Hayley M. Sabol Japneet Kaur Sharmin Khan Cody Ashby Carolina Schinke C. Lowry Barnes Farah Alturkmani Elena Ambrogini Michael Tveden Gundesen Thomas Lund Anne Kristine Amstrup Thomas Levin Andersen Marta Diaz-delCastillo G. David Roodman Teresita Bellido Jesus Delgado-Calle Novel CCL3-HMGB1 signaling axis regulating osteocyte RANKL expression in multiple myeloma Haematologica |
| title | Novel CCL3-HMGB1 signaling axis regulating osteocyte RANKL expression in multiple myeloma |
| title_full | Novel CCL3-HMGB1 signaling axis regulating osteocyte RANKL expression in multiple myeloma |
| title_fullStr | Novel CCL3-HMGB1 signaling axis regulating osteocyte RANKL expression in multiple myeloma |
| title_full_unstemmed | Novel CCL3-HMGB1 signaling axis regulating osteocyte RANKL expression in multiple myeloma |
| title_short | Novel CCL3-HMGB1 signaling axis regulating osteocyte RANKL expression in multiple myeloma |
| title_sort | novel ccl3 hmgb1 signaling axis regulating osteocyte rankl expression in multiple myeloma |
| url | https://haematologica.org/article/view/11852 |
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