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AB0107 AKT activation by fibronectin fragment leads to NF-KB up-regulation in rheumatoid arthritic chondrocytes
  1. T. Yasuda
  1. Department of Sports Medicine, Tenri University, Tenri, Japan

Abstract

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

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