Fibroblast growth factor 8 (FGF8) induces mitochondrial remodeling in chondrocytes via ERK/AMPK signaling pathway.

Osteoarthritis (OA) is a disease characterized by articular cartilage degeneration, and its pathogenic mechanisms are associated with mitochondrial homeostasis disorders. Fibroblast growth factor 8 (FGF8) is a multipotent protein ligand which is upregulated in OA cartilage. However, the molecular mechanisms by which FGF8 regulates mitochondria in chondrocytes are not yet fully understood. Here, we treated chondrocytes with FGF8 and detected the effects of FGF8 on mitochondrial morphology in the cytoplasm using transmission electron and confocal laser scanning microscopy. ATP levels were measured to determine the cellular energy status. Western blotting and immunofluorescence staining experiments were employed to detect the fusion-fission proteins mitofusin 1 (MFN1), mitofusin 2 (MFN2), optic atrophy 1 (OPA1), dynamin-related protein 1 (DRP1), mitochondrial fission 1 protein (FIS1), and related signaling pathways. The FGF receptor (FGFR) inhibitor, AZD4547, and the ERK inhibitor, U0126, were used to verify the specific effects of the FGFR and ERK pathways. We found that FGF8 regulated mitochondrial morphology and dynamics in chondrocytes by inducing mitochondrial elongation. While it upregulated fusion proteins MFN1, MFN2, and OPA1, FGF8 downregulated fission proteins DRP1 and FIS1. ERK and AMPK pathways were activated in chondrocytes after FGF8 treatment. In contrast, both AZD4547 and U0126 inhibitors abolished mitochondrial elongation as well as the alteration of fusion-fission proteins induced by FGF8, and U0126 also inhibited the FGF8-triggered activation of AMPK. This study is the first to reveal that FGF8 remodels mitochondria through ERK/AMPK signaling in chondrocytes, offering novel insights into the potential role of FGF8 in OA.