Oscillating fluid flow inhibits TNF-alpha -induced NF-kappa B activation via an Ikappa B kinase pathway in osteoblast-like UMR106 cells.
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.
Kurokouchi
K
K
Department of Orthopaedics and Rehabilitation and Cellular and Molecular Physiology, Musculoskeletal Research Laboratory, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Jacobs
C R
CR
Donahue
H J
HJ
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D051550:I-kappa B Kinase; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism*; D009991:Oscillometry; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase