Bone loss and impaired formation are associated with shared vascular changes in type 1 and type 2 diabetic mice with systemic microangiopathy

Abstract

Diabetes increases fracture risk, due to multifactorial bone fragility. Since bone vascularization is essential for bone health, we hypothesized that vascular alterations contribute to diabetic bone disease. We used two models of type 1 (T1D) and 2 (T2D) diabetes in C57Bl/6 male mice. For T1D, 8-week-old mice received saline (CTR1, n = 25) or streptozotocin (STZ, 185 mg/kg, n = 28). For T2D, 4-week-old mice were fed standard (CTR2, n = 23) or a high-fat (n = 24) diet, followed by STZ (60 and 40 mg/kg). Tibia bone parameters were assessed longitudinally at baseline, 6 (M6; both types) or 12 months (M12; T2D) by μCT. Bone perfusion, marrow flow cytometry, quantitative femoral histomorphometry and vascular immunohistochemistry of Endomucin⁺-endothelial cells and Leptin-Receptor⁺ pericytes, which include osteoblast progenitors, were performed. Retina and kidney microangiopathy were evaluated. By M6, T1D mice were hyperglycemic, lost 25 % of trabecular and cortical bone with markedly suppressed bone formation and a 30 % decreased bone perfusion, while exhibiting retinopathy. At M6, T2D mice were obese and hyperglycemic, with unchanged trabecular bone mass and osteoblastic formation but lower cortical mass, compared to CTR2. By M12, T2D displayed retinopathy together with trabecular and cortical bone loss, reduced perfusion and bone formation, while Endomucin⁺ marrow vessel density increased. In both models, vascular coverage by LepR⁺-pericytes increased at all time points. Overall, STZ-related T1D induced early and severe bone vascular dysfunction associated with systemic microangiopathy. In T2D, similar changes developed later. Diabetic bone fragility may involve altered microvascular remodeling and impaired pericyte mobilization.