title: Bone vascularization and trabecular bone formation are mediated by PKB alpha/Akt1 in a gene-dosage-dependent manner: in vivo and ex vivo MRI.
abstract: PKBalpha/Akt1, a protein kinase, is a major mediator of angiogenic signaling. The purpose of this study was to determine the role of PKB alpha/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 PKB alpha/Akt1-deficient, heterozygous, and wild-type mice. Ex vivo microMRI and microCT were applied to monitor the impact of PKB alpha/Akt1 gene dosage on trabecular bone formation during endochondral bone growth. PKB alpha/Akt1-deficient mice and, remarkably, also heterozygous mice showed significantly reduced blood volume fraction in the humerus compared to wild-type mice. Moreover, PKB alpha/Akt1-deficient mice showed a more severe vascular deficiency with reduced permeability. microCT and microMRI of trabeculae revealed impaired bone formation in both PKB alpha/Akt1-deficient and heterozygous mice, whereas cortical bone parameters were only reduced in PKB alpha/Akt1-deficient mice. Reduction of metaphyseal blood vessel invasion, concomitant with aberrant trabeculae and shorter long bones, demonstrates a gene-dose-dependent role for PKB alpha/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.
authors.affiliation: Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Katrien
authors.initials: K
authors.lastname: Vandoorne
authors.forename: Jeremy
authors.initials: J
authors.lastname: Magland
authors.forename: Vicki
authors.initials: V
authors.lastname: Plaks
authors.forename: Amnon
authors.initials: A
authors.lastname: Sharir
authors.forename: Elazar
authors.initials: E
authors.lastname: Zelzer
authors.forename: Felix
authors.initials: F
authors.lastname: Wehrli
authors.forename: Brian A
authors.initials: BA
authors.lastname: Hemmings
authors.forename: Alon
authors.initials: A
authors.lastname: Harmelin
authors.forename: Michal
authors.initials: M
authors.lastname: Neeman
mesh_terms: D000818:Animals; D015519:Bone Density; D018628:Gene Dosage; D006811:Humerus / Q000098:blood supply / Q000000981:diagnostic imaging / Q000254:growth & development; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D011859:Radiography
chemical_list: D051057:Proto-Oncogene Proteins c-akt