Abstract
Background: Diabetes is a world-wide health problem. Among the diabetes related comorbidities, low-energy-trauma fracture is one of the major causes of morbidity and mortality of patients, due to the increased fracture risk in comparison with normal group and the impaired healing procedure after fracture. Bone morphogenetic proteins are well-known for their osteoinductive functions. BMP-6, which is a newly-discovered member to the BMP family, has been reported to show potent bone-forming effects and take active part in glucose metabolism. Although the mechanisms are barely understood, the properties of BMP-6 make it a promising promoter of fracture healing in the diabetic. It was hypothesised that if a reasonable BMP was selected for the treatment of bone fracture, the healing procedure could be improved and the diabetic condition could also be relieved.Aim: Find an efficient way to enhance fracture healing by applying gene therapy to a diabetic rat model.
Stages & objectives: 1) Build a closed femoral transverse fracture rat model and investigate the role of BMP-6 in normal fracture healing. A self-designed guillotine system was employed to induce transverse fracture. Before in vivo experiment, cadavers were used to calibrate the system so that it was able to produce stable and repeatable transverse fracture in rats’ femurs. The role of BMP-6 in normal fracture healing was studied. 2) Build a fracture model in diabetic rats and investigate the relation between BMP-6 and impaired fracture healing. Type 1 diabetes was induced by streptozotocin intraperitoneal injection. Radiological, histological and biomechanical comparison was made between fracture healing in diabetic and non-diabetic rats. The association between BMP-6 and fracture healing in the diabetic was investigated. 3) Carry out local BMP-6 gene delivery to fractured rats with diabetes and investigate effects of gene therapy on fracture and diabetic metabolic disorders.
Outcomes: 1) Fracture model building was successful. BMP-6 was significantly increased during normal fracture healing. 2) Stable hyperglycaemic symptoms were achieved after STZ injection. A significant inhibition in the expression of endogenic BMP-6 was found related to the impaired fracture healing in diabetic rats. 3) After BMP6 gene delivery, polyphagia, polydipsia and polyuria was improved. Blood glucose was lowered significantly (p<0.05). The size, calcification ratio and mechanical endurance of calluses increased significantly (p<0.05).
Achievements & Benefits: A stable and repeatable fracture model in diabetic rats was built and optimized during this study. Impaired fracture healing was found in diabetic rats. This rat model could be valuable to researchers who are interested in the interaction between endocrine system and skeleton system.
To our knowledge, it was the first time that the negative effect of diabetes on the expression of endogenic BMP-6 was reported. It was the first time that BMP-6 gene therapy was applied to a fracture model in diabetic rats. It was also the first time that fracture healing and diabetic metabolic disorders were improved by only one single gene therapy. The results of this study brought new understandings of the endocrine and skeleton system. They could bring new prospect to the treatment of fracture and diabetic metabolic disorders.
| Date of Award | 2015 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Weijie Wang (Supervisor) & Rami Abboud (Supervisor) |