RRC ID 65021
Author Tsubaki M, Seki S, Takeda T, Chihara A, Arai Y, Morii Y, Imano M, Satou T, Shimomura K, Nishida S.
Title The HGF/Met/NF-κB Pathway Regulates RANKL Expression in Osteoblasts and Bone Marrow Stromal Cells.
Journal Int J Mol Sci
Abstract 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.
Volume 21(21)
Published 2020-10-24
DOI 10.3390/ijms21217905
PII ijms21217905
PMID 33114380
PMC PMC7663721
MeSH 3T3 Cells Animals Bone Marrow Cells / cytology Bone Marrow Cells / metabolism* Cell Differentiation Cells, Cultured Hepatocyte Growth Factor / genetics* Hepatocyte Growth Factor / pharmacology Humans Mice Multiple Myeloma / complications Multiple Myeloma / genetics* Multiple Myeloma / metabolism NF-kappa B / metabolism Osteoblasts / cytology Osteoblasts / metabolism* Osteolysis / etiology Osteolysis / genetics* Osteolysis / metabolism Phosphorylation / drug effects Proto-Oncogene Proteins c-met / metabolism RANK Ligand / metabolism* Signal Transduction / drug effects Up-Regulation*
IF 4.556
Human and Animal Cells ST2(RCB0224) MC3T3-E1(RCB1126)