title: Deletion of FoxO1, 3, and 4 in Osteoblast Progenitors Attenuates the Loss of Cancellous Bone Mass in a Mouse Model of Type 1 Diabetes.
abstract: Type 1 diabetes is associated with osteopenia and increased fragility fractures, attributed to reduced bone formation. However, the molecular mechanisms mediating these effects remain unknown. Insulin promotes osteoblast formation and inhibits the activity of the FoxO transcription factors. FoxOs, on the other hand, inhibit osteoprogenitor proliferation and bone formation. Here, we investigated whether FoxOs play a role in the low bone mass associated with type 1 diabetes, using mice lacking FoxO1, 3, and 4 in osteoprogenitor cells (FoxO1,3,4ΔOsx1-Cre). Streptozotocin-induced diabetes caused a reduction in bone mass and strength in FoxO-intact mice. In contrast, cancellous bone was unaffected in diabetic FoxO1,3,4ΔOsx1-Cremice. The low bone mass in the FoxO-intact diabetic mice was associated with decreased osteoblast number and bone formation, as well as decreased expression of the anti-osteoclastogenic cytokine osteoprotegerin (OPG) and increased osteoclast number. FoxO deficiency did not alter the effects of diabetes on bone formation; however, it did prevent the decrease in OPG and the increase in osteoclast number. Addition of high glucose to osteoblastic cell cultures decreased OPG mRNA, indicating that hyperglycemia in and of itself contributes to diabetic bone loss. Taken together, these results suggest that FoxOs exacerbate the loss of cancellous bone mass associated with type 1 diabetes and that inactivation of FoxOs might ameliorate the adverse effects of insulin deficiency. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Srividhya
authors.initials: S
authors.lastname: Iyer
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Han
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Ambrogini
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Yavropoulou
authors.affiliation: Barnstable Brown Diabetes and Obesity Center, Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: John
authors.initials: J
authors.lastname: Fowlkes
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Stavros C
authors.initials: SC
authors.lastname: Manolagas
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Almeida
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology; D000071556:Cancellous Bone / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D019070:Cell Lineage; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000473:pathology*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D053244:Osteoprotegerin / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*; D055114:X-Ray Microtomography
chemical_list: D051858:Forkhead Transcription Factors; D053244:Osteoprotegerin; C045073:Cre recombinase; D019426:Integrases; D005947:Glucose
keywords: BONE HISTOMORPHOMETRY; DISEASES AND DISORDERS OF/RELATED TO BONE; GENETIC ANIMAL MODELS; STROMAL/STEM CELLS; TRANSCRIPTION FACTORS