Yasuda Tadashi
Department of Sports Medicine, Tenri University.
Biomed Res. 2011 Jun;32(3):209-15. doi: 10.2220/biomedres.32.209.
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.
纤连蛋白片段增加被认为与骨关节炎（OA）中的关节破坏有关。然而，纤连蛋白片段引起分解代谢活动的机制尚未完全明确。虽然已证明羧基末端肝素结合纤连蛋白片段（HBFN-f）可激活核因子（NF）-κB通路，但响应HBFN-f导致NF-κB上调的细胞内上游事件仍不清楚。因此，本研究旨在阐明磷酸肌醇-3-羟基激酶（PI3K）/Akt通路在OA软骨细胞中HBFN-f激活NF-κB过程中的作用。在软骨细胞单层培养中，HBFN-f刺激一氧化氮（NO）产生，并伴有NF-κB和Akt的磷酸化。使用LY294002的抑制研究表明，PI3K/Akt通路是HBFN-f产生NO和激活NF-κB所必需的。用抗CD44抗体和透明质酸进行抗CD44处理可显著抑制HBFN-f对NO、NF-κB和Akt的作用。在此，我们首次提供证据表明，HBFN-f通过与CD44相互作用激活PI3K/Akt通路，导致NF-κB上调。
