The cellular mechanisms of obesity and type 2 diabetes (T2D)- associated impaired fracture healing are poorly studied. In a murine model of T2D reflecting both hyperinsulinemia due to HFD and insulinopenia induced by streptozotocin (STZ:40mg/kg), we examined the cellular dynamics of bone fracture healing in a tibia cortical bone defect model. A delayed bone healing as evaluated by μCT-scanning, was observed in HFD compared to ND (Bone Volume BV: -31.6% at day (D)14 and -38.7% at D21). Defect area histomorphometric analysis revealed decreased newly formed bone (7.03%±1.6 vs 14.44%±2.8 HFD vs ND, pb 0.05), accumulation of adipocytes (13.04%±2.2 vs 5.82%±0.4 HFD vs ND, pb 0.05) and both parameters were inversely correlated (R 2 =0.49; pb 0.02). The number of osteoprogenitor cells Runx2+ and SCA1+ cells was unchanged or increased (189.5±26,0 vs 108.3 17.9 cells/mm 2 in HFD vs ND, pb 0.05), respectively. An accelerated senescence phenotype as shown by a 101.8% increase of ROS production and senescence gene expression was detected. Also, the number of senescent cells as evaluated by LAMIN B1 - was increased (11.02%±1.3 vs 3.39%±0.6 HFD vs ND, pb 0.0001). In HFD+STZ animals, a more pronounced delayed bone healing was observed (BV:-39.7% at D14) and inversely correlated with glucose tolerance (R 2 =0.48, pb 0.004) and marrow adiposity (R 2 =0.37,pb 0.01). Senescent phenotype presents in hyperinsulinemic condition was absent in insulinopenic condition. To test for the human relevance, we observed that sera from obese and T2D patients exerted inhibitory effects on osteoblastic differentiation of human marrow stromal MSC. Our data suggest that T2D exerts negative effects on bone healing through inhibitory effects of differentiation of osteoblastic stem cells and that the degree of hyperglycaemia and not insulin levels per se, are detrimental to bone healing.
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机译：肥胖症和2型糖尿病（T2D）相关的骨折愈合的细胞机制差异很差。在T2D的鼠模型中，反映了由于链脲佐菌素（STZ：40mg / kg）诱导的HFD和胰岛素血症的高胰岛素血症（STZ：40mg / kg），我们检查了胫骨皮质骨缺损模型中骨骨折愈合的细胞动态。与Nd（D）在D21的D）14和-38.7％的骨体积BV：-31.6％的Nd（骨体积BV：-31.6％）相比，在HFD中观察到延迟的骨愈合。缺陷区域组织形态分析显示新形成的骨骼下降（7.03％±1.6 Vs 14.44％±2.8 HFD Vs Nd，Pb 0.05），脂肪细胞的积累（13.04％±2.2与5.82％±0.4 Hfd Vs Nd，Pb 0.05）和两个参数同时相关（R 2 = 0.49; PB 0.02）。分别不变或增加骨催化剂细胞润滑细胞的数量，或增加（189.5±26,0 vs 108.317.9细胞/ mm 2，在HFD与Nd，pb 0.05中）。检测到ROS生产和衰老基因表达增加101.8％增加的加速衰老表型。而且，由Lamin B1评估的衰老细胞的数量增加（11.02％±1.3 Vs 3.39％±0.6 HFD Vs Nd，Pb 0.0001）。在HFD + STZ动物中，观察到更明显的延迟骨愈合（BV：-39.7％，D14）和与葡萄糖耐量相反（R 2 = 0.48，PB 0.004）和骨髓肥胖（R 2 = 0.37，PB 0.01） 。胰岛素血症病症中的衰老表型在胰岛素病症中不存在。为了测试人类的相关性，我们观察到肥胖和T2D患者的血清对人骨髓基质MSC的骨细胞分化施加抑制作用。我们的数据表明，T2D通过骨细胞干细胞分化的抑制作用对骨愈合产生负面影响，并且高血糖血症的程度而非胰岛素水平本身，对骨愈合有害。
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