Contribution of methylglyoxal to delayed healing of bone injury in diabetes

Abstract

Abstract.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 µM) 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 ε -(carboxymethyl)-lysine and N δ -(5-hydro-5-methyl-4-imida zolone-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.

Non-standard AGE4 epitopes that predict polyneuropathy independently of obesity can be detected by slot dot-blot immunoassay

“…29 Similarly, MGO has been linked with diabetic complications, increasing risk of cardiovascular events and mortality, 31 as well as impairing bone regeneration in patients with diabetes. 32 Mechanistically, MGO has been shown to interfere with the platelet-derived growth factor B/platelet-derived growth factor receptor β (PDGFB/PDGFRβ) axis in smooth muscle cells and fibroblasts through formation of CML and CEL adducts on the PDGFB receptor. PDGFRβ inhibition, in turn, destabilizes the fibrous cap on atherosclerotic plaque, contributing to its rapture by inducing growth arrest and apoptosis of smooth muscle cells and fibroblasts.…”

Mass spectrometric quantitation of AGEs and enzymatic crosslinks in human cancellous bone

“…They analyzed several AGEs and early glycation products in body fluid and soft tissues such as organs and muscles, and sought their potentials as markers or even as causative substances of pathologies such as diabetic complications and chronic kidney disease. We also reported a liquid chromatography (LC)-triple quadrupole MS-based quantitation of CML 23 and N δ -(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine 1 (MG-H1) 24 in rodent bone. After technological and methodological improvements, we successfully established a system using LC-quadrupole time-of-flight (QqTOF)-MS to quantitate five AGEs and five enzymatic crosslinks in human bone collagen as depicted in Fig.…”

Systemically impaired fracture healing in small animal research: A review of fracture repair models

“…When administered to rats at birth, a single 100 mg/kg intraperitoneal dose of STZ results in an acute hyperglycemic state, which spontaneously improves by 8–10 weeks of age to more closely resemble T2DM 67 . In mice, intraperitoneal injections of 40–50 mg/kg/day STZ for 4–5 days result in hyperglycemia (13.9–16.6 mmol/L) within 4–7 days 68‐74 . STZ‐induced diabetic rodents consistently exhibit reductions in new bone formation of 20%–60% at the site of injury, when compared to healthy controls 54,58‐60,70,72‐75 .…”