Bone vascularization and trabecular bone formation are mediated by PKBalpha/Akt1 in a gene-dosage-dependent manner: In vivo and ex vivo MRI

摘要

PKBalpha/Akt1, a protein kinase, is a major mediator of angiogenic signaling. The purpose of this study was to determine the role of PKBalpha/Akt1 in bone vascularization and development. For that aim, macromolecular dynamic contrast enhanced MRI was applied to examine in vivo vascular changes in long bones of 40-day-old growing PKBalpha/Akt1-deficient, heterozygous, and wild-type mice. Ex vivo μMRI and μCT were applied to monitor the impact of PKBalpha/Akt1 gene dosage on trabecular bone formation during endochondral bone growth. PKBalpha/Akt1-deficient mice and, remarkably, also heterozygous mice showed significantly reduced blood volume fraction in the humerus compared to wild-type mice. Moreover, PKBalpha/Akt1-deficient mice showed a more severe vascular deficiency with reduced permeability. μCT and μMRI of trabeculae revealed impaired bone formation in both PKBalpha/Akt1-deficient and heterozygous mice, whereas cortical bone parameters were only reduced in PKBalpha/Akt1-deficient mice. Reduction of metaphyseal blood vessel invasion, concomitant with aberrant trabeculae and shorter long bones, demonstrates a gene-dose-dependent role for PKBalpha/Akt1 in regulation of overall size and endochondral bone growth. MRI proved to provide high sensitivity for in vivo detection of subtle gene dose effects leading to impaired bone vascularity and for uncovering changes in trabecular bone. Magn Reson Med, 2010. © 2010 Wiley-Liss, Inc.