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Fibroblast growth factor‐2 promotes catabolism via FGFR1‐Ras‐Raf‐MEK1/2‐ERK1/2 axis that coordinates with the PKCδ pathway in human articular chondrocytes

Fibroblast growth factor 2 (FGF‐2) has been found to play an anti‐anabolic and/or a catabolic role in adult human articular cartilage via regulation of multiple signaling pathways. Upon FGF‐2 stimulation, a molecular crosstalk between the mitogen activated protein kinase (MAPK) and protein kinase C δ (PKCδ) pathways are initiated, where PKCδ positively regulates downstream MAPK signaling. In this study, we explored the relationship between fibroblast growth factor receptor 1 (FGFR1), Ras, and PKCδ in FGF‐2 signaling in human articular chondrocytes. Pathway‐specific inhibition using both chemical inhibitors and siRNA targeting FGFR1 demonstrated that, upon FGF‐2 stimulation, FGFR1 controlled both Ras and PKCδ activation, which converged on the Raf‐MEK1/2‐ERK1/2 axis. No crosstalk was observed between Ras and PKCδ. Quantitative PCR analyses revealed that both Ras and PKCδ contributed to FGF‐2‐mediated upregulation of MMP‐13, ADAMTS5, and repression of aggrecan gene. Correspondingly, FGF‐2‐mediated proteoglycan loss was effectively reversed by individual pathway‐specific inhibitor of Ras, PKCδ, and ERK1/2 in both 3‐dimensional alginate bead culture and cartilage organ culture systems. Our findings suggest that FGFR1 interacts with FGF‐2 and then activates Ras and PKCδ, which concertedly drive MAPK signaling to mediate biological effects of FGF‐2. Such an integration of dual inputs constitutes a novel mechanism of FGF‐2 signaling cascade in human articular chondrocytes. J. Cell. Biochem. 113: 2856–2865, 2012. © 2012 Wiley Periodicals, Inc.