Diabetes interferes with the bone formation by affecting the expression of transcription factors that regulate osteoblast differentiation

Abstract

Type 1 diabetes in humans has as one of its complications inadequate bone formation, resulting in osteopenia and delayed fracture healing. To investigate the mechanisms by which diabetes affects bone formation, experiments were performed in a marrow ablation model. Mice were made diabetic by multiple low dose streptozotocin treatment and controls were treated with vehicle alone. Sacrifice occurred 0, 2, 4, 6, 10 and 16 days following marrow ablation. Histologic analysis demonstrated that the amount of immature mesenchymal tissue was equivalent in both the experimental and control groups on day 4. On day 6 a burst of bone formation occurred in the control group that was significantly reduced in the diabetic group. This deficit was evident at the molecular level as shown by diminished expression of osteocalcin, collagen types 1. When transcription factors were examined, Cbfa1/Runx-2 and D1x5 expression were substantially reduced in the diabetic compared to control groups on days 4 and 6. C-fos but not c-jun expression was also suppressed in the diabetic group, but not closely linked to bone formation. Insulin treatment substantially reversed the effect of diabetes on the expression of bone matrix osteocalcin and collagen types 1, and transcription factors Runx2 and Dix 5. These results indicate that diabetic animals produce sufficient amounts of immature mesenchymal tissue but fail to adequately express genes that regulate osteoblast differentiation, Cbfal/Runx-2 and D1x5, which in turn, leads to decreased bone formation.