Gallein increases the fibroblast growth factor 2-elicited osteoprotegerin synthesis in osteoblasts

• Published in: Biochimica et biophysica acta. General subjects Vol. 1868; no. 8; p. 130635
• Main Authors: Kuroyanagi, Gen, Hioki, Tomoyuki, Matsushima-Nishiwaki, Rie, Kozawa, Osamu, Tokuda, Haruhiko
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2024
• Subjects: 3T3 Cells; angiogenesis; Animals; bone resorption; Cell Line; Fibroblast growth factor; fibroblast growth factor 2; Fibroblast Growth Factor 2 - metabolism; fluorescein; Gallein; gene expression; ligands; Mice; mitogen-activated protein kinase; Osteoblast; osteoblasts; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteoprotegerin; Osteoprotegerin - biosynthesis; Osteoprotegerin - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; phosphorylation; Phosphorylation - drug effects; RANK Ligand - metabolism; Osteoblast; Fibroblast growth factor; Gallein; Osteoprotegerin
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2024.130635

Gallein is known as an inhibitor of Gβγ subunits, but roles of gallein in bone metabolism have not been reported. Fibroblast growth factor 2 (FGF-2) increases angiogenesis and promotes bone regeneration during the early stages of fracture healing. Osteoprotegerin (OPG) secreted by osteoblasts, binds to the receptor activator of nuclear factor-κB (RANK) ligand (RANKL) as a decoy receptor and prevents RANKL from binding to RANK, resulting in the suppression of bone resorption. Our previous report demonstrated that FGF-2 activates the phosphorylation of p38 mitogen-activated protein kinase (MAPK), stress-activated protein kinase/c-Jun N-terminal kinase (JNK), and p44/p42 MAPK in osteoblast-like MC3T3-E1 cells. Additionally, FGF-2-activated phosphorylation of p38 MAPK and JNK but not p44/p42 MAPK is positively involved in OPG synthesis in these cells. This work aimed to investigate the effects of gallein on the FGF-2-elicited OPG synthesis in osteoblast-like MC3T3-E1 cells and the mechanism. Our findings demonstrated that gallein significantly increased the FGF-2-elicited OPG synthesis in MC3T3-E1 cells. By contrast, fluorescein, gallein-like compound that does not bind Gβγ, did not affect the FGF-2-elicited OPG synthesis. Gallein significantly enhanced the FGF-2-induced OPG mRNA expression levels. Gallein did not affect the FGF-2-activated phosphorylation of p38 MAPK and p44/p42 MAPK, but significantly increased the FGF-2-activated phosphorylation of JNK, while fluorescein did not affect JNK phosphorylation. SP600125, a specific JNK inhibitor, strongly inhibited gallein-induced enhancement of FGF-2-induced OPG synthesis and mRNA expression levels. Our results indicated that gallein increases the FGF-2-induced OPG synthesis due to the JNK activation in the osteoblast. •FGF-2 up-regulates OPG release in osteoblasts.•The effect of gallein on the FGF-2-elicited OPG release was assessed.•Osteoblasts were treated with FGF-2, gallein or fluorescein, and JNK inhibitor.•Gallein but not fluorescein increases the FGF-2-elicited OPG release.•Gallein may provide new insights for promoting bone regeneration.