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J Biol Chem. 2001 Apr 20;276(16):13499-504. Epub 2000 Nov 28.

Oscillating fluid flow inhibits TNF-alpha -induced NF-kappa B activation via an Ikappa B kinase pathway in osteoblast-like UMR106 cells.

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  • 1Department of Orthopaedics and Rehabilitation and Cellular and Molecular Physiology, Musculoskeletal Research Laboratory, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.


Fluid flow plays an important role in load-induced bone remodeling. However, the molecular mechanism of flow-induced signal transduction in osteoblasts remains unclear. In endothelial cells, fluid flow alters activation of NF-kappaB resulting in changes in expression of cell adhesion molecules. To test the hypothesis that fluid flow alters NF-kappaB activation and expression of cell adhesion molecules in osteoblastic cells, we examined the effect of oscillating fluid flow (OFF) on tumor necrosis factor (TNF)-alpha-induced NF-kappaB activation in rat osteoblast-like UMR106 cells. We found that OFF inhibits NF-kappaB-DNA binding activities, especially TNF-alpha-induced p50-p65 heterodimer NF-kappaB activation and TNF-alpha-induced intercellular adhesion molecule-1 mRNA expression. The inhibitory effects of OFF on both TNF-alpha-induced NF-kappaB activation and intercellular adhesion molecule-1 mRNA expression were shear stress-dependent and also increased with OFF exposure duration, indicating that OFF has potent effects on mechanotransduction pathways. OFF also inhibited TNF-alpha-induced IkappaBalpha degradation and TNF-alpha-induced IkappaB kinase (IKK) activity in a shear stress-dependent manner. These results demonstrate that IKK is an initial target molecule for OFF effects on osteoblastic cells. Thus, OFF inhibits TNF-alpha-induced IKK activation, leading to a decrease in phosphorylation and degradation of inhibitory IkappaBalpha, which in turn results in the decrease of TNF-alpha-induced NF-kappaB activation and potentially the transcription of target genes.

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