title: Expression of XBP1s in bone marrow stromal cells is critical for myeloma cell growth and osteoclast formation.
abstract: BM stromal cells (BMSCs) are key players in the microenvironmental support of multiple myeloma (MM) cell growth and bone destruction. A spliced form of the X-box-binding protein-1 (XBP1s), a major proximal effector of unfolded protein response signaling, is highly expressed in MM cells and plays an indispensable role in MM pathogenesis. In the present study, we found that XBP1s is induced in the BMSCs of the MM microenvironment. XBP1s overexpression in healthy human BMSCs enhanced gene and/or protein expression of VCAM-1, IL-6, and receptor activator of NF-κB ligand (RANKL), enhancing BMSC support of MM cell growth and osteoclast formation in vitro and in vivo. Conversely, deficiency of XBP1 in healthy donor BMSCs displayed a range of effects on BMSCs that were opposite to those cells with overexpression of XBP1s. Knock-down of XBP1 in MM patient BMSCs greatly compromised their increased VCAM-1 protein expression and IL-6 and RANKL secretion in response to TNFα and reversed their enhanced support of MM-cell growth and osteoclast formation. Our results demonstrate that XBP1s is a pathogenic factor underlying BMSC support of MM cell growth and osteoclast formation and therefore represents a therapeutic target for MM bone disease.
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15240, USA.
authors.forename: Guoshuang
authors.initials: G
authors.lastname: Xu
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.forename: Judy
authors.initials: J
authors.lastname: Anderson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Patrene
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lentzsch
authors.forename: G David
authors.initials: GD
authors.lastname: Roodman
authors.forename: Hongjiao
authors.initials: H
authors.lastname: Ouyang
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004722:Endoribonucleases / Q000172:deficiency / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010010:Osteoclasts / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D053245:RANK Ligand / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000502:physiology; D000071701:Regulatory Factor X Transcription Factors; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D059016:Tumor Microenvironment; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D009363:Neoplasm Proteins; D053245:RANK Ligand; D011993:Recombinant Fusion Proteins; D000071701:Regulatory Factor X Transcription Factors; C505688:TNFSF11 protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases