title: Role for beta1 integrins in cortical osteocytes during acute musculoskeletal disuse.
abstract: The mammalian skeleton adjusts bone structure and strength in response to changes in mechanical loading, however the molecular and cellular mechanisms governing this process in vivo are unknown. Terminally differentiated osteoblasts, the osteocytes, are presumptive mechanosensory cells for bone, and cell culture studies demonstrate that beta1 integrins participate in mechanical signaling. To determine the role of beta1 integrins in osteoblasts in vivo, we used the Cre-lox system to delete beta1 integrin from cells committed to the osteoblast lineage. While pCol2.3 Cre-mediated recombination was widespread in bones from Colalpha1(I)-Cre+/beta1fl/fl conditional knockout mice (cKO), beta1 integrin protein was depleted from cortical osteocytes, but not from cancellous osteocytes or cells lining bone surfaces in adults. Bones from cKO mice that were normally loaded were similar in structure to WT littermates. However, hindlimb unloading of adult cKO mice for one week intended to cause bone loss (disuse osteopenia), resulted in unexpected, rapid changes in the geometry of cortical bone; hindlimb unloading increased the cross-sectional area, marrow area, and moments of inertia in cKO, but not WT mice. Furthermore, these hindlimb unloading-induced geometric changes in cortical bone of cKO mice resulted in increased whole bone bending stiffness and strength of the femur. Together, these results confirmed the concept that osteocytes are mechanosensory cells and showed beta1 integrins in cortical osteocytes limited changes in cortical geometry in response to disuse, thus providing the first in vivo evidence that beta1 integrins on osteocytes mediate specific aspects of mechanotransduction.
authors.affiliation: Bone and Signaling Laboratory, Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Phillips
authors.forename: Eduardo A C
authors.initials: EA
authors.lastname: Almeida
authors.forename: Esther L
authors.initials: EL
authors.lastname: Hill
authors.forename: J Ignacio
authors.initials: JI
authors.lastname: Aguirre
authors.forename: Mercedes F
authors.initials: MF
authors.lastname: Rivera
authors.forename: Inaam
authors.initials: I
authors.lastname: Nachbandi
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wronski
authors.forename: Marjolein C H
authors.initials: MC
authors.lastname: van der Meulen
authors.forename: Ruth K
authors.initials: RK
authors.lastname: Globus
mesh_terms: D000208:Acute Disease; D000818:Animals; D001851:Bone Diseases, Metabolic; D005260:Female; D017353:Gene Deletion; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D008957:Models, Genetic; D010006:Osteoblasts / Q000378:metabolism; D010011:Osteocytes / Q000378:metabolism*; D015398:Signal Transduction; D013718:Tensile Strength; D014018:Tissue Distribution
chemical_list: D019012:Integrin beta1