Activation of Akt leading to NF-κB up-regulation in chondrocytes stimulated with fibronectin fragment.

Increased fibronectin fragments are thought to contribute to joint destruction in osteoarthritis (OA). However, the mechanism whereby fibronectin fragments cause catabolic activities is not totally understood. While COOH-terminal heparin-binding fibronectin fragment (HBFN-f) has been shown to activate nuclear factor (NF)-κB pathway, intracellular upstream events that cause NF-κB up-regulation in response to HBFN-f remain unclear. Thus, this study was aimed to elucidate the involvement of phosphoinositide-3-OH kinase (PI3K)/Akt pathway in NF-κB activation by HBFN-f in OA chondrocytes. In chondrocyte monolayer cultures, HBFN-f stimulated nitric oxide (NO) production in association with phosphorylation of NF-κB and Akt. Inhibition studies using LY294002 revealed the requirement of PI3K/Akt pathway for NO production and NF-κB activation by HBFN-f. Anti-CD44 treatment with anti-CD44 antibody and hyaluronan resulted in significant inhibition of HBFN-f actions on NO, NF-κB, and Akt. Herein, we provided the first evidence that HBFN-f activates PI3K/Akt pathway leading to up-regulation of NF-κB through interaction with CD44.