INTERSTITIAL FLUID FLOW IN BONE REMODELING

假设由间质液流动引起的流体剪切应力介导骨对载荷的响应并介导建模/重塑。 体外研究表明，骨细胞受到流体切应力的刺激，并以释放一氧化氮（NO）和三尖杉酯碱作为反应。 然而，组织间液流（IFF）的体内相关性尚未确定，拟议的研究是在没有机械应变的情况下表征三种改变IFF的模型，并确定一氧化氮和野牡丹素在IFF诱导的骨建模/重塑中的作用。 具体而言，（1）我们将描述股静脉结扎诱导的IFF改变对后肢悬吊小鼠和大鼠的组织形态计量学、股骨尺寸、机械性能、矿物质含量和矿物质密度的影响;（2）我们将通过使用缺乏一氧化氮合酶2（NOS 2）的基因工程小鼠来确定NO和洋地黄素在IF介导的建模/重塑中的作用，一氧化氮合酶3（NOS 3）和环氧合酶2（COX 2）;（3）我们将开发一种外部应用的袖带来改变骨中的IFF，作为临床应用的第一步。 我们将寻求优化袖带压力应用的方案和治疗持续时间以增加骨;（4）为了进一步验证IFF在我们的大鼠模型中改变，将通过磁共振成像直接测量IFF。 长期目标是开发非药物方法来对抗废用性骨质减少。

It has been hypothesized that fluid shear stress, induced by the flow of interstitial fluid, mediates the response of bone to loading and mediates modeling/remodeling. In vitro studies have demonstrated that bone cells are stimulated by fluid shear stress, and respond with the release of nitric oxide (NO) and prostaglandins. The in-vivo relevance of interstitial fluid flow (IFF), however, has yet to be established of the proposed research is to characterize three models of altered IFF in the absence of mechanical strain, and determine the role of nitric oxide and prostaglandins in IFF induced bone modeling/remodeling. Specifically, (1) we will characterize the effects of altered IFF induced by femoral vein ligation on histomorphometry, femoral dimensions, mechanical properties, mineral content, and mineral density in hindlimb suspended mice and rats; (2) we will determine the role of NO and prostaglandins if IFF-mediated modeling/remodeling by using genetically engineered mice lacking nitric oxide synthase 2 (NOS2), nitric oxide synthase 3 (NOS3), and cyclooxygenase 2 (COX2); (3) We will develop an externally applied cuff to alter IFF in bone as the first step in the clinical application of the findings. We will seek to optimize the regime of cuff pressure application and the duration of treatment to increase bone; (4) to further validate that IFF is altered in our rat models, direct measurements of IFF by magnetic resonance imaging will be performed. The long-term goal is the development of non- pharmacological methods to counter osteopenia of disuse.