FGF-23 facilitates osteosarcoma metastasis by modulating the miR-4463/LOXL2 axis expression via the ERK, p38, and JNK signaling pathway
Journal
International Journal of Medical Sciences
Journal Volume
23
Journal Issue
1
Start Page
12-25
ISSN
1449-1907
Date Issued
2026-01-01
Author(s)
Lin, Chih-Yang
Abstract
Osteosarcoma is a highly malignant bone tumor affecting children and adolescents. Once metastasis occurs, the five-year survival rate drops to ~20%, emphasizing the need for new therapies. Fibroblast growth factor-23 (FGF-23), a bone-derived hormone, has been implicated in tumor progression, but its role in osteosarcoma remains unclear. Bioinformatics analysis using the R2 database revealed that elevated FGF-23 expression is associated with increased metastasis and reduced overall survival in osteosarcoma patients. Functional assays confirmed that FGF-23 enhances the migratory ability of osteosarcoma cells. Gene Expression Omnibus (GEO) analysis indicated that lysyl oxidase-like proteins-particularly LOXL1, LOXL2, and LOXL3-are overexpressed in osteosarcoma tissues compared to adjacent normal bone. In vitro experiments further showed that FGF-23 significantly upregulates LOXL2 expression in 143B and MG63 osteosarcoma cells, while LOXL2 knockdown via small interfering RNA (siRNA) markedly reduces cell migration. Moreover, pretreatment with ERK, p38, and JNK inhibitors or siRNAs targeting these pathways suppressed both FGF-23-induced LOXL2 expression and wound healing, indicating that FGF-23 promotes cell motility through ERK-, p38-, and JNK-dependent LOXL2 upregulation. FGF-23 stimulation also increased phosphorylation of ERK, p38, and JNK, and downregulated miR-4463. Inhibition of these pathways restored miR-4463 levels and suppressed LOXL2 expression. Taken together, these findings suggest that FGF-23 promotes osteosarcoma cell migration and may contribute to metastasis through coordinated regulation of the miR-4463/LOXL2 axis via ERK, p38, and JNK signaling. Targeting FGF-23 or its downstream signaling cascades may offer a promising therapeutic approach for metastatic osteosarcoma.
Subjects
FGF-23
LOXL2
metastasis
miR-4463
osteosarcoma
Publisher
Ivyspring International Publisher
Type
journal article