Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka 577-8502, Japan.
Department of Pharmacy, Municipal Ikeda Hospital, Ikeda 563-0025, Japan.
Int J Mol Sci. 2020 Oct 24;21(21):7905. doi: 10.3390/ijms21217905.
Multiple myeloma (MM)-induced bone disease occurs through hyperactivation of osteoclasts by several factors secreted by MM cells. MM cell-secreted factors induce osteoclast differentiation and activation via direct and indirect actions including enhanced expression of receptor activator of nuclear factor κB ligand (RANKL) in osteoblasts and bone marrow stromal cells (BMSCs). Hepatocyte growth factor (HGF) is elevated in MM patients and is associated with MM-induced bone disease, although the mechanism by which HGF promotes bone disease remains unclear. In the present study, we demonstrated that HGF induces RANKL expression in osteoblasts and BMSCs, and investigated the mechanism of induction. We found that HGF and MM cell supernatants induced RANKL expression in ST2 cells, MC3T3-E1 cells, and mouse BMSCs. In addition, HGF increased phosphorylation of Met and nuclear factor κB (NF-κB) in ST2 cells, MC3T3-E1 cells, or mouse BMSCs. Moreover, Met and NF-κB inhibitors suppressed HGF-induced RANKL expression in ST2 cells, MC3T3-E1 cells, and mouse BMSCs. These results indicated that HGF promotes RANKL expression in osteoblasts and BMSCs via the Met/NF-κB signaling pathway, and Met and NF-κB inhibitors suppressed HGF-induced RANKL expression. Our findings suggest that Met and NF-κB inhibitors are potentially useful in mitigating MM-induced bone disease in patients expressing high levels of HGF.
多发性骨髓瘤（MM）诱导的骨病是通过 MM 细胞分泌的多种因子激活破骨细胞引起的。MM 细胞分泌的因子通过直接和间接作用诱导破骨细胞分化和激活，包括增强核因子κB 配体（RANKL）在成骨细胞和骨髓基质细胞（BMSCs）中的表达。肝细胞生长因子（HGF）在 MM 患者中升高，与 MM 诱导的骨病相关，尽管 HGF 促进骨病的机制尚不清楚。在本研究中，我们证明 HGF 诱导成骨细胞和 BMSCs 中 RANKL 的表达，并研究了诱导机制。我们发现 HGF 和 MM 细胞上清液诱导 ST2 细胞、MC3T3-E1 细胞和小鼠 BMSCs 中 RANKL 的表达。此外，HGF 增加了 ST2 细胞、MC3T3-E1 细胞或小鼠 BMSCs 中 Met 和核因子κB（NF-κB）的磷酸化。此外，Met 和 NF-κB 抑制剂抑制了 ST2 细胞、MC3T3-E1 细胞和小鼠 BMSCs 中 HGF 诱导的 RANKL 表达。这些结果表明，HGF 通过 Met/NF-κB 信号通路促进成骨细胞和 BMSCs 中 RANKL 的表达，而 Met 和 NF-κB 抑制剂抑制了 HGF 诱导的 RANKL 表达。我们的研究结果表明，在表达高水平 HGF 的患者中，Met 和 NF-κB 抑制剂可能有助于减轻 MM 诱导的骨病。
