title: Gene silencing of the BDNF/TrkB axis in multiple myeloma blocks bone destruction and tumor burden in vitro and in vivo.
abstract: 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-κB 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.
authors: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors: Li-Sha
authors: LS
authors: Ai
authors: Chun-Yan
authors: CY
authors: Sun
authors: Ya-Dan
authors: YD
authors: Wang
authors: Lu
authors: L
authors: Zhang
authors: Zhang-Bo
authors: ZB
authors: Chu
authors: You
authors: Y
authors: Qin
authors: Fei
authors: F
authors: Gao
authors: Han
authors: H
authors: Yan
authors: Tao
authors: T
authors: Guo
authors: Lei
authors: L
authors: Chen
authors: Di
authors: D
authors: Yang
authors: Yu
authors: Y
authors: Hu
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D005260:Female; D020868:Gene Silencing; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D009101:Multiple Myeloma / Q000628:therapy*; D010010:Osteoclasts / Q000502:physiology; D010014:Osteolysis; D053244:Osteoprotegerin / Q000235:genetics; D053245:RANK Ligand / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D047368:Tumor Burden
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D053244:Osteoprotegerin; D053245:RANK Ligand; D034741:RNA, Small Interfering; D020813:Receptor, trkB
keywords: brain-derived neurotrophic factor; multiple myeloma bone disease; osteoclastogenesis; osteoprotegerin; receptor activator of nuclear factor kappa B ligand