Contribution of methylglyoxal to delayed healing of bone injury in diabetes

Patients with diabetes are vulnerable to delayed bone fracture healing or pseudoarthrosis. Chronic sustained hyperglycemia, reactive intermediate derivatives of glucose metabolism, such as methylglyoxal (MGO), and advanced glycation end-products (AGEs) are implicated in diabetic complications. In the present study, it was examined whether MGO is able to cause disturbed bone healing in diabetes. Diabetes was induced in male mice by injection of streptozotocin (50 mg/ kg) for 5 days. A bone defect (1.0-mm diameter) was created in the left distal femur, and bone repair was assessed from an examination of computed tomography scans. ST2 cells were exposed to MGO (0-400 mu M) to investigate osteoblastic differentiation, cell viability, and damage. Consequently, blood glucose and hemoglobin A1c levels in diabetic mice were determined to be 493 +/- 14.1 mg/dl and 8.0 +/- 0.05%, respectively. Compared with non-diabetic control mice, diabetic mice exhibited markedly delayed bone healing, with increased levels of the MGO-derived AGEs, N-delta-(carboxymethyl)-lysine and N-delta-(5-hydro-5-methyl-4-imidazolone-2-yl)-ornithine, in the sera and femurs. MGO inhibited the osteoblastic differentiation of ST2 cells in a dose-dependent manner, and markedly decreased cell proliferation through cytotoxicity. In conclusion, MGO has been demonstrated to cause impaired osteoblastic differentiation and delayed bone repair in diabetes. Therefore, detoxification of MGO may be a potentially useful strategy against bone problems in patients with diabetes.