INTERSTITIAL FLUID FLOW IN BONE REMODELING

据推测，由间质液流动引起的流体剪切应力介导了骨对载荷的反应，并介导了骨的建模/重塑。体外研究表明，骨细胞受到流体剪切应力的刺激，并释放一氧化氮（NO）和前列腺素。然而，间质液流动（IFF）的体内相关性尚未确定，该研究旨在描述在没有机械应变的情况下IFF改变的三种模型，并确定一氧化氮和前列腺素在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引起的IFF改变对后肢悬吊小鼠和大鼠的组织形态学、股骨尺寸、力学性能、矿物质含量和矿物质密度的影响；(2)我们将利用缺乏一氧化氮合酶2 （NOS2）、一氧化氮合酶3 （NOS3）和环氧合酶2 （COX2）的基因工程小鼠，确定一氧化氮和前列腺素在iff介导的建模/重塑中的作用；(3)作为临床应用的第一步，我们将开发一种外用袖带来改变骨中的IFF。我们将寻求优化袖带压力应用方案和治疗时间以增加骨骼；(4)为了进一步验证我们的大鼠模型中IFF的改变，将通过磁共振成像直接测量IFF。长期目标是发展非药物方法来对抗废弃的骨质减少。

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.