title: Loss of insulin receptor in osteoprogenitor cells impairs structural strength of bone.
abstract: Type 1 diabetes mellitus (T1D) is associated with decreased bone mineral density, a deficit in bone structure, and subsequently an increased risk of fragility fracture. These clinical observations, paralleled by animal models of T1D, suggest that the insulinopenia of T1D has a deleterious effect on bone. To further examine the action of insulin signaling on bone development, we generated mice with an osteoprogenitor-selective (osterix-Cre) ablation of the insulin receptor (IR), designated OIRKO. OIRKO mice exhibited an 80% decrease in IR in osteoblasts. Prenatal elimination of IR did not affect fetal survival or gross morphology. However, loss of IR in mouse osteoblasts resulted in a postnatal growth-constricted phenotype. By 10-12 weeks of age, femurs of OIRKO mice were more slender, with a thinner diaphyseal cortex and, consequently, a decrease in whole bone strength when subjected to bending. In male mice alone, decreased metaphyseal trabecular bone, with thinner and more rodlike trabeculae, was also observed. OIRKO mice did not, however, exhibit abnormal glucose tolerance. The skeletal phenotype of the OIRKO mouse appeared more severe than that of previously reported bone-specific IR knockdown models, and confirms that insulin receptor expression in osteoblasts is critically important for proper bone development and maintenance of structural integrity.
authors: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA ; Arkansas Children's Hospital, 1 Children's Way, Slot 512-6, Little Rock, AR 72202, USA.
authors: Kathryn
authors: K
authors: Thrailkill
authors: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors: R Clay
authors: RC
authors: Bunn
authors: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA ; Arkansas Children's Hospital Research Institute, Little Rock, AR, USA.
authors: Charles
authors: C
authors: Lumpkin
authors: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA ; Arkansas Children's Hospital Research Institute, Little Rock, AR, USA.
authors: Elizabeth
authors: 0000-0002-0147-0421
authors: E
authors: Wahl
authors: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors: Gael
authors: G
authors: Cockrell
authors: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA ; Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: Lindsey
authors: 0000-0003-1546-8581
authors: L
authors: Morris
authors: Joslin Diabetes Center and Harvard Medical School, Boston, MA, USA.
authors: C Ronald
authors: CR
authors: Kahn
authors: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors: John
authors: J
authors: Fowlkes
authors: VA Tennessee Valley Health Care System, Vanderbilt University Medical Center, Nashville, TN, USA ; Department of Orthopaedic Surgery & Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, USA ; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Jeffry S
authors: JS
authors: Nyman
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D049628:Body Size; D001842:Bone and Bones / Q000473:pathology*; D005260:Female; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis; D010641:Phenotype; D011972:Receptor, Insulin / Q000235:genetics / Q000502:physiology*
chemical_list: D007328:Insulin; D011972:Receptor, Insulin; D005947:Glucose