Femoral vein ligation increases bone mass in the hindlimb suspended rat

Abstract

Bone remodeling in response to changing mechanical demands is well recognized. It has been hypothesized that alterations in interstitial fluid flow (IFF), due to intraosseous pressure changes, influence bone remodeling. The goal of this study was to investigate the role of IFF in bone in the absence of mechanical strain using an in vivo model, the hindlimb suspended rat. Bone remodeling was assessed by direct measurements of weight, dimensions, bone mineral content (BMC) and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DEXA), and trabecular density using peripheral computed tomography (pQCT). Ligation of one femoral vein was performed as a means to alter the IFF within the ipsilateral femur; the contralateral limb was sham-operated as control. Animals were suspended for a period of 19 days. Intramedullary pressure in the venous-ligated femurs increased relative to the sham-operated control femurs (27.8 mmHg vs. 16.4 mmHg, p < 0.05), suggesting venous ligation increased IFF proportional to the pressure drop across the bone. Bone mineral content (BMC), when normalized to body weight, increased significantly in the venous-ligated femurs relative to control limbs (115.9 ± 15.6% vs. 103.8 ± 13.2%, p < 0.001); similarly, gains in length (106.2 ± 2.4% vs. 104.5 ± 2.1%, p < 0.05) and distal width (110.8 ± 10.3% vs. 106.2 ± 8.2%, p < 0.05) for the femurs with venous ligation were significantly greater relative to sham control. Furthermore, trabecular density was significantly higher in the femurs with venous ligation (351 ± 12 g/cm3 vs. 329 ± 11 g/cm3, p < 0.05). Daily administration of the cyclooxygenase inhibitor, indomethacin, via drinking water, suppressed the length increases observed for the venous ligated femur, suggesting a role for prostaglandins in IFF-mediated remodeling. These results suggest that IFF can directly influence bone adaptation independent of mechanical loading, and supports the hypothesis that fluid flow modulates bone remodeling.