Scavenging methylglyoxal improves bone quality and defect healing in diabetic mice.

Hyperglycemia in diabetes leads to the formation of methylglyoxal (MG) and accumulation of advanced glycation end-products (AGEs). We previously reported that exogenous MG exposure deteriorated osteoblastic differentiation in vitro and diabetic mice showed delayed bone defect healing along with elevated MG-derived AGE levels. However, whether endogenously formed MG is involved in impaired bone repair and remodeling in diabetes remains unclear. In this study, we investigated the effects of hyperglycemia-induced MG formation on bone quality and defect healing in mice. Using a synthetic MG probe [Ir(ppy)2(DA-phen)], we found that endogenous MG formation deteriorated osteoblastic and osteoclastic differentiation under hyperglycemic conditions in cultured cells. In the bone defect site of streptozotocin (STZ)-induced diabetic mice, along with impaired defect healing, we observed elevated endogenous MG levels and downregulation of alkaline phosphatase (ALP) compared with that in non-diabetic control mice; however, these alterations were alleviated by managing blood glucose levels through insulin supplementation. Furthermore, treatment with pyridoxamine (PM), an MG scavenger, ameliorated these impairments by suppressing MG elevation and upregulating the expression of osteocalcin, osteoprotegerin, and osteoclast-associated receptor genes without improving the diabetic status. These findings suggest that endogenously formed MG is detrimental to hyperglycemia-related delayed bone defect healing in type 1 diabetes mellitus (T1DM). Collectively, this study suggests that MG scavenging by PM and suppression of MG formation by glycemic control are potential therapeutic strategies for T1DM-associated bone disorders.