Brain‐derived neurotrophic factor is a potential osteoclast stimulating factor in multiple myeloma

Abstract

Multiple myeloma (MM) is characterized by accumulation of monoclonal plasma cells in the bone marrow and progression of lytic bone lesions. The mechanisms of enhanced bone resorption in patients with myeloma are not fully defined. We have previously identified the role of brain-derived neurotrophic factor (BDNF) in proliferation and migration of MM cells. In our study, we investigated whether BDNF was possibly involved in MM cell-induced osteolysis. We showed that BDNF was elevated in MM patients and the bone marrow plasma levels of BDNF positively correlated with extent of bone disease. In osteoclast formation assay, bone marrow plasma from patients with MM increased osteoclast formation and the effect was significantly blocked by neutralizing antibody to BDNF, suggesting a critical role for BDNF in osteoclast activation. Furthermore, the direct effects of recombinant BDNF on osteoclast formation and bone resorption support the potential role of BDNF in the MM bone disease. BDNF receptor TrkB was expressed by human osteoclast precursors and a Trk inhibitor K252a markedly inhibited osteoclast formation stimulated with BDNF, demonstrating that BDNF used TrkB for its effects on osteoclast. Finally, bone marrow plasma BDNF level positively correlated with macrophage inflammatory protein-1a and receptor activator of nuclear factor-jB ligand, two major osteoclast stimulatory factors in MM. These results support an important role for BDNF in the development of myeloma bone disease.

Inhibition of BDNF in Multiple Myeloma Blocks Osteoclastogenesis via Down-Regulated Stroma-Derived RANKL Expression Both In Vitro and In Vivo

“…Basal levels of BDNF and RANKL in these marrow plasma were measured using Human BDNF Quantikine ELISA kit and Human RANKL Quantikine ELISA kit from R&D Systems (Minneapolis, MN). Human primary BMSCs and pre-osteoclasts were prepared and identified as previously described [22], [26]. Then a series of co- and triple- culture systems (MM-BMSCs, BMSCs-preOCs, MM-BMSCs-preOCs) were implemented and treated with various conditions.…”

“…The critical roles of BDNF in MM pathophysiology are evidenced by its over-expression in malignant plasma cells and myeloma cell lines, as well as its potential ability to promote the growth of MM cells in vitro [20], [21]. Recently, BDNF was identified as a potential osteoclastogenic factor in multiple myeloma, and its serum level correlated positively with that of soluble RANKL [22]. However, the mechanism by which osteoclastogenesis is promoted by BDNF in MM has not yet been clearly elucidated.…”

Neuronal Activity in Ontogeny and Oncology

“…In the BM niche, BDNF is expressed by osteoblasts, megakaryocytes, and endothelial cells [143], suggesting that non-neuronal cells may also contribute to MM through neurotrophin signaling. This reciprocal interaction between MM and the BM microenvironment may also lead to worsened bone disease by stimulating osteoclasts and enhancing bone resorption through the BDNF/TRKB axis [144]. …”

Upregulation of brain-derived neurotrophic factor in advanced gastric cancer contributes to bone metastatic osteolysis by inducing long pentraxin 3

“…Several studies have implicated BDNF and TrkB in the pathogenesis of various human malignancies, including not only neuronal tumors such as neuroblastoma [9] but also non-neuronal tumors such as lung cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic ductal carcinoma, prostate cancer, and multiple myeloma [10–14]. In addition, elevated expression of the BDNF/TrkB axis has been found to significantly correlate with disease progression and poor prognosis in gastric cancer in humans [15, 16].…”