Inhibition of BDNF in multiple myeloma blocks osteoclastogenesis via down-regulated stroma-derived RANKL expression both in vitro and in vivo.
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.
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Li-Sha
LS
Ai
Chun-Yan
CY
Sun
Lu
L
Zhang
Shun-Chang
SC
Zhou
Zhang-Bo
ZB
Chu
You
Y
Qin
Ya-Dan
YD
Wang
Wei
W
Zeng
Han
H
Yan
Tao
T
Guo
Lei
L
Chen
Di
D
Yang
Yu
Y
Hu
D000818:Animals; D001483:Base Sequence; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005455:Fluorescent Antibody Technique; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000473:pathology*; D010010:Osteoclasts / Q000473:pathology*; D011494:Protein Kinases / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism*; D012313:RNA; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D017154:Stromal Cells / Q000473:pathology*
D019208:Brain-Derived Neurotrophic Factor; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D012313:RNA; D011494:Protein Kinases