Diminished bone formation during diabetic fracture healing is related to accelerated resorption of cartilage associated with high levels of tumor necrosis factor-alpha and increased osteoclast activity
McKenzie, Erin Heather
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Introduction: Diabetes interferes with fracture repair in human and animal models. Mechanisms of impaired fracture healing were investigated, specifically the transition from cartilage to bone, a midpoint in the fracture healing process. Tibial and femoral fractures were induced in mice rendered diabetic and compared to matching normoglycemic mice. Methods: Type I diabetes was induced using a low-dose treatment protocol of streptozotocin in CD-1 mice. After mice were hyperglycemic for three weeks, controlled closed simple transverse fractures of the tibia or femur were induced and fixed by intramedullary pin. Histomorphometric analysis of the tibias obtained 12, 16 and 22 days after fracture was performed across the fracture callus at 0.5 mm proximal and distal increments using computer assisted image analysis. Another study was performed on femur fractures. Similar histological analysis was performed 10, 16 and 22 days after fracture. Osteoclast numbers analyzed and callus size measured for each time point. Diabetic mice were treated with the TNF-specific inhibitor, pegsunercept, the number of osteoclasts, size of cartilage, and number of TNF-[alpha] and receptor activator for nuclear factor kB ligand positive chondrocytes were analyzed. Results: There was relatively little difference in the initial formation of the fracture callus on day 10. However, on day 16 the diabetic group had significantly smaller callus, greater loss of cartilage and enhanced osteoclastogenesis when assessed by histomorphometric analysis. Chondrocyte apoptosis was significantly higher in diabetic mice. On days 16 and 22 bone formation within the callus of diabetic mice was significantly less than the normoglycemic. The diabetic group on day 16, when cartilage is being replaced by bone, but not on days 12 or 22, showed elevated osteoclast numbers and accelerated removal of cartilage in the diabetic group (P[less than] 0.05), which was reflected by smaller callus size. When diabetic mice were treated with the TNF-specific inhibitor, pegsunercept, the number of osteoclasts, cartilage loss, and number of TNF-[alpha] and receptor activator for nuclear factor kB ligand positive chondrocytes were significantly reduced (P [less than] 0.05). Conclusion: These results suggest that a significant effect of diabetes on fracture healing is increased chondrocyte apoptosis and osteoclastogenesis that accelerates the loss of cartilage and reduces the anlage for endochondral bone formation during fracture repair. These results also suggest that diabetes-enhanced TNF-[alpha] increases the expression of resorptive factors in chondrocytes and that TNF-[alpha] dysregulation leads to enhanced osteoclast formation and accelerated loss of cartilage.
PLEASE NOTE: This work is protected by copyright. Downloading is restricted to the BU community: please click Download and log in with a valid BU account to access. If you are the author of this work and would like to make it publicly available, please contact email@example.com.Thesis (MSD) --Boston University, Goldman School of Dental Medicine, 2010 (Department of Endodontics).Includes bibliographic references: leaves 54-63.
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