Journal
BLOOD
Volume 119, Issue 18, Pages 4205-4214Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-05-353300
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Funding
- Multiple Myeloma Research Foundation
- National Institutes of Health/National Institute of Dental and Craniofacial Research [DE017439]
- VA Merit Review
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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-boxbinding 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-kappa B 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 BM-SCs greatly compromised their increased VCAM-1 protein expression and IL-6 and RANKL secretion in response to TNF alpha 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. (Blood. 2012;119(18):4205-4214)
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