PMID- 23077504 OWN - NLM STAT- MEDLINE DCOM- 20130320 LR - 20211021 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 7 IP - 10 DP - 2012 TI - Inhibition of BDNF in multiple myeloma blocks osteoclastogenesis via down-regulated stroma-derived RANKL expression both in vitro and in vivo. PG - e46287 LID - 10.1371/journal.pone.0046287 [doi] LID - e46287 AB - Brain-derived neurotrophic factor (BDNF) was recently identified as a factor produced by multiple myeloma (MM) cells, which may contribute to bone resorption and disease progression in MM, though the molecular mechanism of this process is not well understood. The purpose of this study was to test the effect of BDNF on bone disease and growth of MM cells both in vitro and in vivo. Co- and triple-culture systems were implemented. The in vitro results demonstrate that BDNF augmented receptor activator of nuclear factor kappa B ligand (RANKL) expression in human bone marrow stromal cells, thus contributing to osteoclast formation. To further clarify the effect of BDNF on myeloma bone disease in vivo, ARH-77 cells were stably transfected with an antisense construct to BDNF (AS-ARH) or empty vector (EV-ARH) to test their capacity to induce MM bone disease in SCID-rab mice. Mice treated with AS-ARH cells were preserved, exhibited no radiologically identifiable lytic lesions and, unlike the controls treated with EV-ARH cells, lived longer and showed reduced tumor burden. Consistently, bones harboring AS-ARH cells showed marked reductions of RANKL expression and osteoclast density compared to the controls harboring EV-ARH cells. These results provide further support for the potential osteoclastogenic effects of BDNF, which may mediate stromal-MM cell interactions to upregulate RANKL secretion, in myeloma bone diseases. FAU - Ai, Li-Sha AU - Ai LS AD - Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Sun, Chun-Yan AU - Sun CY FAU - Zhang, Lu AU - Zhang L FAU - Zhou, Shun-Chang AU - Zhou SC FAU - Chu, Zhang-Bo AU - Chu ZB FAU - Qin, You AU - Qin Y FAU - Wang, Ya-Dan AU - Wang YD FAU - Zeng, Wei AU - Zeng W FAU - Yan, Han AU - Yan H FAU - Guo, Tao AU - Guo T FAU - Chen, Lei AU - Chen L FAU - Yang, Di AU - Yang D FAU - Hu, Yu AU - Hu Y LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20121015 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (RANK Ligand) RN - 0 (TNFSF11 protein, human) RN - 63231-63-0 (RNA) RN - EC 2.7.- (Protein Kinases) SB - IM MH - Animals MH - Base Sequence MH - Brain-Derived Neurotrophic Factor/*antagonists & inhibitors MH - Cell Line, Tumor MH - *Down-Regulation MH - Fluorescent Antibody Technique MH - Humans MH - In Vitro Techniques MH - Male MH - Mice MH - Mice, Inbred NOD MH - Mice, SCID MH - Multiple Myeloma/*pathology MH - Osteoclasts/*pathology MH - Protein Kinases/metabolism MH - RANK Ligand/*metabolism MH - RNA MH - Real-Time Polymerase Chain Reaction MH - Signal Transduction MH - Stromal Cells/*pathology PMC - PMC3471864 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2012/10/19 06:00 MHDA- 2013/03/21 06:00 PMCR- 2012/10/15 CRDT- 2012/10/19 06:00 PHST- 2012/05/29 00:00 [received] PHST- 2012/08/28 00:00 [accepted] PHST- 2012/10/19 06:00 [entrez] PHST- 2012/10/19 06:00 [pubmed] PHST- 2013/03/21 06:00 [medline] PHST- 2012/10/15 00:00 [pmc-release] AID - PONE-D-12-15548 [pii] AID - 10.1371/journal.pone.0046287 [doi] PST - ppublish SO - PLoS One. 2012;7(10):e46287. doi: 10.1371/journal.pone.0046287. Epub 2012 Oct 15.