PT  - JOURNAL ARTICLE
AU  - T. Yasuda
TI  - AB0107 AKT activation by fibronectin fragment leads to NF-KB up-regulation in rheumatoid arthritic chondrocytes
AID  - 10.1136/annrheumdis-2012-eular.107
DP  - 2013 Jun 01
TA  - Annals of the Rheumatic Diseases
PG  - 643--643
VI  - 71
IP  - Suppl 3
4099  - http://ard.bmj.com/content/71/Suppl_3/643.15.short
4100  - http://ard.bmj.com/content/71/Suppl_3/643.15.full
SO  - Ann Rheum Dis2013 Jun 01; 71
AB  - Background Increased fibronectin fragments are thought to contribute to joint destruction in rheumatoid arthritis (RA). 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. Objectives This study was aimed to elucidate the involvement of phosphoinositide-3-OH kinase (PI3K)/Akt pathwayin NF-κB activation by HBFN-f in RA chondrocytes. Methods Chondrocytes isolated from articular cartilage from RA knee joints were cultured in monolayer with HBFN-f. Secreted levels of nitric oxide (NO) in conditioned media were determined. Activation of NF-κB and Akt pathways was assessed with enzyme-linked immunosorbent assay (ELISA). Involvement of CD44 in HBFN-f action was evaluated using anti-CD44 antibody and high molecular weight hyaluronan (HA). Results In chondrocyte monolayer cultures, HBFN-f stimulated NO production in association with up-regulation of NF-κB and Akt. Inhibition studies using BAY11-7085 confirmed that NO production by HBFN-f was dependent on NF-κB pathway. Inhibition studies using LY294002 revealed the requirement of PI3K/Akt pathway for NF-κB activation by HBFN-f. Anti-CD44 treatment with anti-CD44 antibody and HA resulted in significant inhibition of HBFN-f actions on activation of Akt and NF-κB, and on NO production. Conclusions This is the first study demonstrating that HBFN-f activates PI3K/Akt pathway leading to up-regulation of NF-κB through interaction with CD44. Elucidation of intracellular pathways activated by fibronectin fragments may be helpful to understand the pathological process in RA cartilage destruction. Disclosure of Interest None Declared