Abstract
Metabolic diseases like diabetes mellitus cause bone healing deficiencies. We found significant impairment of bone regeneration, osteogenic differentiation and proliferation in diabetic bone. Moreover recent studies suggest a highly underestimated importance of GDF8 (Myostatin) in bone metabolism. Our goal was to analyze the role of GDF8 as a regulator of osteogenic differentiation, proliferation and bone regeneration. We used a murine tibial defect model in diabetic (Leprdb−/−) mice. Myostatin-Inhibitor Follistatin was administered in tibial bony defects of diabetic mice. By means of histology, immunohistochemistry and QRT-PC osteogenesis, differentiation and proliferation were analyzed. Application of Myostatin-inhibitor showed a significant improvement in diabetic bone regeneration compared to the control group (6.5 fold, p < 0.001). Immunohistochemistry revealed a significantly higher proliferation (7.7 fold, p = 0.009), osteogenic differentiation (Runx-2: 3.7 fold, p = 0.011, ALP: 9.3 fold, p < 0.001) and calcification (4.9 fold, p = 0.024) in Follistatin treated diabetic animals. Therapeutical application of Follistatin, known for the importance in muscle diseases, plays an important role in bone metabolism. Diabetic bone revealed an overexpression of the catabolic protein Myostatin. Antagonization of Myostatin in diabetic animals leads to a restoration of the impaired bone regeneration and represents a promising therapeutic option.
Highlights
Bone regeneration is usually an efficient process without scarring
Local substitution of Fibroblast Growth Factor 9 (FGF-9) and Vascular Endothelial Growth Factor (VEGF) in a diabetic murine unicortical tibial defect model revealed a significant enhancement of bone regeneration, angiogenesis, proliferation and osteogenic differentiation compared to diabetic control animals[10]
A 9.4 fold increase of Myostatin expression was observed in uninjured diabetic bone (p < 0.0001), while a 2.1 fold increase of Activin A (p = 0.03) was detected
Summary
Bone regeneration is usually an efficient process without scarring Diseases such as diabetes mellitus can cause higher fracture rates accompanied by non-unions and a detrimentally diminished healing capacity[1,2,3]. Most studies, analyzing diabetes associated impairment of bone healing were generated in diabetes mellitus type 1 animal models. Expression of runt-related transcription factor-2 (Runx-2), a master gene of osteogenesis was shown to be significantly decreased in an intramembranous bone healing type 1 diabetes mellitus model. A deficiency of osteoprogenitor cells in diabetes type 1 was revealed[5, 6] The reasons for this are largely unknown, it was hypothesized that the expression of crucial growth factors is decreased by systemic diabetes mellitus[7,8,9]. Systemic effects of Myostatin knockout on parameters of the metabolic syndrome such as reduced blood glucose-, insulin-, and triglyceride values and a normalization of hyperphagia were confirmed in an additional study[11]
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