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-jB 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 RNAtransfected 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.Multiple myeloma (MM) is a B-cell neoplasm characterized by clonal expansion of plasma cells within the bone marrow (BM). Bone destruction is the most common feature of MM, which results from the deregulation of osteoclast and osteoblast activities adjacent to myeloma cells.1 Signs of skeleton involvement in MM include osteolytic bone lesions, spine compression and fractures, which significantly impact morbidity and mortality. A variety of MM-derived factors that stimulate osteoclast formation and activity, either directly or indirectly, has been identified. These osteoclast-activating factors (OAFs) include interleukin-1b (IL-1b), interleukin-11 (IL-11), tumor necrosis factor-1b (TNF-1b), hepatocyte growth factor (HGF), stromal-derived factor-1a (SDF-1a), RANKL and the more recently identified macrophage inflammatory protein-1a (MIP-1a).2-6 Among all these factors, RANKL plays a predominate role. 7 Osteoclasts are activated by binding of RANKL to its cognate receptor, RANK, whereas osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor family, acts as a nonfunctional decoy receptor to compete with RANK and inhibits the terminal stages of osteoclast differentiation and activation.
8Mice deficient in OPG showed severe osteoporosis, 9,10 where...