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J. Biol. Chem., Vol. 276, Issue 16, 13499-13504, April 20, 2001

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Oscillating Fluid Flow Inhibits TNF--induced NF-B Activation via an IB Kinase Pathway in Osteoblast-like UMR106 Cells^*

Kazutoshi Kurokouchi^§, Christopher R. Jacobs, and Henry J. Donahue^¶

From the  Departments of Orthopaedics and Rehabilitation and Cellular and Molecular Physiology, Musculoskeletal Research Laboratory, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033 and the ^§ Department of Orthopaedics, Nagoya University School of Medicine, Nagoya 466-8550, Japan

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-B resulting in changes in expression of cell adhesion molecules. To test the hypothesis that fluid flow alters NF-B activation and expression of cell adhesion molecules in osteoblastic cells, we examined the effect of oscillating fluid flow (OFF) on tumor necrosis factor (TNF)--induced NF-B activation in rat osteoblast-like UMR106 cells. We found that OFF inhibits NF-B-DNA binding activities, especially TNF--induced p50-p65 heterodimer NF-B activation and TNF--induced intercellular adhesion molecule-1 mRNA expression. The inhibitory effects of OFF on both TNF--induced NF-B 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--induced IB degradation and TNF--induced IB 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--induced IKK activation, leading to a decrease in phosphorylation and degradation of inhibitory IB, which in turn results in the decrease of TNF--induced NF-B activation and potentially the transcription of target genes.

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