The production of nitric oxide and prostaglandin E-2 by primary bone cellsis shear stress dependent

Loading-induced flow of interstitial fluid through the lacuno-canalicular n etwork is a likely signal for bone cell adaptive responses. However, the na ture of the stimulus that activates the cell is debated. Candidate stimuli include wall shear stress, streaming potentials, and chemotransport. We hav e addressed the nature of the flow-derived cell stimulus by comparing varia tions in fluid transport with variations in wall shear stress, using nitric oxide (NO) and prostaglandin E-2 (PGE(2)) production as a parameter of bon e cell activation. Adult mouse long bone cell cultures were treated for 15 min with or without pulsating fluid flow using the following regimes: Low P FF, mean flow rate 0.20 cm(3)/s, 3 Hz, shear stress 0.4 +/- 0.12 Pa; Medium PFF, 0.33 cm(3)/s, 5 Hz, 0.6 +/- 0.27 Pa; and High PFF, 0.63 cm(3)/s, 9 Hz , 1.2 +/- 0.37 Pa. In some Low PFF experiments, 2.8% neutral dextran (mol, wt. 4.98 x 10(4)) was added to the flow medium to increase the viscosity, t hereby increasing the wall shear stress 3-fold to a level similar of the Hi gh PFF stimulus, but without affecting streaming potentials or chemotranspo rt. NO and PGE(2) production were stimulated by Low, Medium, and High PFF i n a dose-dependent manner. Application of Low PFF using dextran-supplemente d medium, enhanced both the NO and PGE(2) response by 3-fold, to a level mi micking the response to High PFF at normal viscosity. These results show th at the production of NO and PGE(2) by bone cells can be enhanced in a dose- dependent manner by fluid flow of increasing wall shear stress. Therefore, the stimulus leading to NO and PGE(2) production is the flow-derived shear stress, and not streaming potentials or chemotransport. (C) 2001 Elsevier S cience Ltd. All rights reserved.