PMID- 23420490 OWN - NLM STAT- MEDLINE DCOM- 20131023 LR - 20160303 IS - 1097-0215 (Electronic) IS - 0020-7136 (Linking) VI - 133 IP - 5 DP - 2013 Sep 1 TI - Gene silencing of the BDNF/TrkB axis in multiple myeloma blocks bone destruction and tumor burden in vitro and in vivo. PG - 1074-84 LID - 10.1002/ijc.28116 [doi] AB - Osteolytic bone diseases are a prominent feature of multiple myeloma (MM), resulting from aberrant osteoclastic bone resorption that is uncoupled from osteoblastic bone formation. Myeloma stimulates osteoclastogenesis, which is largely dependent on an increase in receptor activator of NF-kappaB ligand (RANKL) and a decrease in osteoprotegerin (OPG) within the bone marrow milieu. Recently, brain-derived neurotrophic factor (BDNF) was identified as a MM-derived factor that correlates with increased RANKL levels and contributes to osteolytic bone destruction in myeloma patients. Because tyrosine receptor kinase B (TrkB), the receptor of BDNF, is abundantly expressed in osteoblasts, we sought to evaluate the role of BDNF/TrkB in myeloma-osteoblast interactions and the effect of this pathway on the RANKL/OPG ratio and osteoclastogenesis. Coculture systems constructed with noncontact transwells revealed that, in vitro, MM-derived BDNF increased RANKL and decreased OPG production in osteoblasts in a time- and dose-dependent manner. These effects were completely abolished by a specific small interfering RNA for TrkB. BDNF regulates RANKL/OPG expression in osteoblasts through the TrkB/ERK pathway. To investigate the biological effects of BDNF on myeloma in vivo, a SCID-RPMI8226 mice model was constructed using lentiviral short hairpin RNA-transfected RPMI8226 cells. In this system, stable knockdown of BDNF in MM cells significantly restored the RANKL/OPG homostasis, inhibited osteolytic bone destruction and reduced angiogenesis and tumor burden. Our studies provide further support for the potential osteoclastogenic effects of BDNF, which mediates stroma-myeloma interactions to disrupt the balance of RANKL/OPG expression, ultimately increasing osteoclastogenesis in MM. CI - Copyright (c) 2013 UICC. FAU - Ai, Li-Sha AU - Ai LS AD - Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. FAU - Sun, Chun-Yan AU - Sun CY FAU - Wang, Ya-Dan AU - Wang YD FAU - Zhang, Lu AU - Zhang L FAU - Chu, Zhang-Bo AU - Chu ZB FAU - Qin, You AU - Qin Y FAU - Gao, Fei AU - Gao F 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 - 20130308 PL - United States TA - Int J Cancer JT - International journal of cancer JID - 0042124 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Osteoprotegerin) RN - 0 (RANK Ligand) RN - 0 (RNA, Small Interfering) RN - EC 2.7.10.1 (Receptor, trkB) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/antagonists & inhibitors/genetics/*physiology MH - Cell Line, Tumor MH - Female MH - Gene Silencing MH - Humans MH - MAP Kinase Signaling System MH - Mice MH - Multiple Myeloma/*therapy MH - Osteoclasts/physiology MH - Osteolysis MH - Osteoprotegerin/genetics MH - RANK Ligand/genetics MH - RNA, Small Interfering/genetics MH - Receptor, trkB/antagonists & inhibitors/genetics/*physiology MH - Tumor Burden OTO - NOTNLM OT - brain-derived neurotrophic factor OT - multiple myeloma bone disease OT - osteoclastogenesis OT - osteoprotegerin OT - receptor activator of nuclear factor kappa B ligand EDAT- 2013/02/20 06:00 MHDA- 2013/10/24 06:00 CRDT- 2013/02/20 06:00 PHST- 2012/09/13 00:00 [received] PHST- 2013/02/08 00:00 [accepted] PHST- 2013/02/20 06:00 [entrez] PHST- 2013/02/20 06:00 [pubmed] PHST- 2013/10/24 06:00 [medline] AID - 10.1002/ijc.28116 [doi] PST - ppublish SO - Int J Cancer. 2013 Sep 1;133(5):1074-84. doi: 10.1002/ijc.28116. Epub 2013 Mar 8.