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. Killing occurred 0, 2, 4, 6, 10, and 16 d following marrow ablation. Histologic analysis demonstrated that the amount of immature mesenchymal tissue was equivalent in both the experimental and control groups on d 4. On d 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 I. When transcription factors were examined, core-binding factor alpha1 (Cbfa1)/runt domain factor-2 (Runx-2) and human homolog of the drosophila distal-less gene (Dlx5) expression were substantially reduced in the diabetic, compared with control, groups on d 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 type I and transcription factors Cbfa1/Runx2 and Dlx5. These results indicate that diabetic animals produce sufficient amounts of immature mesenchymal tissue but fail to adequately express genes that regulate osteoblast differentiation, Cbfa1/Runx-2 and Dlx5, which in turn, leads to decreased bone formation.

Determining the Role of Sost and Sostdc1 During Fracture Healing

“…In another report, STZ mice had the same amount of immature mesenchymal tissue but decreased osteoblast differentiation. This was associated with decreased collagen type 1, and Runx2 mRNA expression in an intramembranous bone repair model [156], similar to our findings. Song et al (2012) [157] demonstrated that loss of b-catenin in osteoblast precursors results in a switch from osteogenesis to adipogenesis that causes low bone mass.…”

Diabetes and Oral Implant Failure

“…The effects of a hyperglycemic state have been shown to include inhibition of osteoblastic cell proliferation and collagen production during the early stages of callus development, resulting in reduced bone formation as well as diminished mechanical properties of the newly formed bone (Lu et al, 2003). Reduced BIC may indicate a poorer healing response and may predict a reduced ability of the implant to withstand bacterial and load challenges.…”

Recombinant human platelet‐derived growth factor BB (rhPDGF‐BB) and beta‐tricalcium phosphate/collagen matrix enhance fracture healing in a diabetic rat model

“…For example, in a model of intramembranous bone formation, diabetes impaired expression of Runx2 and Dlx5, which are osteoblast differentiation regulators. 34 In turn, bone formation and Type I collagen and osteocalcin expression were reduced. Other studies have shown that diabetes leads to reduced fracture callus biomechanical properties consistent with impaired healing.…”