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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Marrow Cells / metabolism*
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Bone Marrow Cells / pathology
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Cell Differentiation
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Cell Division
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Cells, Cultured / drug effects
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Cells, Cultured / metabolism
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Coculture Techniques
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Endoribonucleases / deficiency
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Endoribonucleases / genetics
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Inflammation
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Interleukin-6 / biosynthesis
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Mice
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Mice, SCID
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Multiple Myeloma / metabolism
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Multiple Myeloma / pathology*
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Osteoclasts / pathology*
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / genetics
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RANK Ligand / biosynthesis
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RANK Ligand / genetics
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RANK Ligand / metabolism
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RNA Interference
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Recombinant Fusion Proteins / physiology
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Regulatory Factor X Transcription Factors
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Stromal Cells / metabolism*
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Stromal Cells / pathology
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Tumor Microenvironment
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Tumor Necrosis Factor-alpha / pharmacology
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Vascular Cell Adhesion Molecule-1 / biosynthesis
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Vascular Cell Adhesion Molecule-1 / genetics
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X-Box Binding Protein 1
Substances
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DNA-Binding Proteins
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IL6 protein, human
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Interleukin-6
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Neoplasm Proteins
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RANK Ligand
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Recombinant Fusion Proteins
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Regulatory Factor X Transcription Factors
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TNFSF11 protein, human
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Transcription Factors
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Tumor Necrosis Factor-alpha
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Vascular Cell Adhesion Molecule-1
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X-Box Binding Protein 1
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XBP1 protein, human
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Xbp1 protein, mouse
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Ern1 protein, mouse
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Protein Serine-Threonine Kinases
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Endoribonucleases