Interstitial Fluid Flow in Bone Remodeling
The objective is to develop and characterize in vivo models of altered interstitial fluid flow (IFF) in bone, and to determine the role of IFF in bone remodeling.
The objective of this project is to develop and characterize in-vivo models of altered interstitial fluid flow (IFF) in bone, and to determine the role of IFF in bone remodeling. Our aims are to determine the remodeling patterns and significance of increased IFF in bone, and to develop an application based on altered IFF to prevent disuse osteopenia.
We will analyze the effect of increased venous pressure by femoral vein ligation in the rat by measuring femoral one dimensions, mechanical properties, mineral content, and mineral density.
The role of nitric oxide and prostaglandins in bone remodeling induced by venous ligation will be determined in murine models, utilizing NOS3-, and cyclooxygenase-knockout mice.
We will determine if temporary venous occlusion with an inflatable cuff leads to similar bone remodeling as seen with venous ligation.
The long-term goal is to determine the mechanisms of osteoporosis of disuse unduced by altered interstitial fluid flow. In addition, we will take a first step in the direction of a possible clinical application of our findings to develop a device to induce IFF-mediated bone remodeling.
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.
Principal Investigator: John A. Frangos, Ph.D.
Agency: NIH