FOXO1 Deletion Reverses the Effect of Diabetic-Induced Impaired Fracture Healing

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DScD (Doctor of Science in Dentistry)
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Fracture healing
FOXO1
Diabetes
Chondrocytes.
Dentistry
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Objectives: Abstract Diabetes impairs fracture healing. Our laboratory previously suggested that a dominant mechanism was the premature loss of cartilage during endochondral bone formation. Based on these results we tested the hypothesis that chondrocytes regulate osteoclast formation in diabetes-impaired fracture healing and that it is controlled by the transcription factor FOXO1. Methods: Closed fracture of the femur was induced in mice with lineage-specific FOXO1 deletion in chondrocytes Col2α1Cre+/FOXO1L/L and Col2α1Cre-/ FOXO1L/L as control mice that had FOXO1 gene present. Mice were rendered diabetic by multiple streptozotocin injections. The normoglycemic group received vehicle alone. Specimens were collected at 10 days (cartilage formed), 16 days (transition from cartilage to bone formation) and 22 days (primary bone formed). The cartilage area was measured using safranin-O/fast green staining. Osteoclasts were counted as TRAP positive cells. The expression of cathepsin K and RANKL were determined by quantitative immunostaining with specific antibodies compared to control IgG. Micro CT was used to measure the callus volume and the mineralized bone. Statistical analysis was done using a one-way ANOVA test. Results with p iv Results: All the groups showed similar cartilage areas at day 10. At day16 the diabetic group had 77% less cartilage area than the normal (P Conclusion: Our data indicates that FOXO1 drives RANKL expression in chondrocytes and resorption of cartilage. FOXO1 deletion reverses diabetes-enhanced osteoclast formation and prevents the premature loss of cartilage, which results in a better bone healing.

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Dana Graves
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2017-06-19
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