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Deletion of FOXO1 in chondrocytes rescues the effect of diabetes on mechanical strength in fracture healing

机译:在软骨细胞中缺失FoxO1拯救糖尿病对骨折愈合中机械强度的影响

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摘要

Diabetes increases the risk of fracture, impairs fracture healing and causes rapid loss of the fracture callus cartilage, which was linked to increased FOXO1 expression in chondrocytes. We recently demonstrated that deletion of FOXO1 in chondrocytes blocked the premature removal of cartilage associated with endochondral bone formation during fracture healing. However, the ultimate impact of this deletion on mechanical strength was not investigated and remains unknown. Closed fractures were induced in Col2 alpha 1Cre(+).FOXO1(L/L) mice with lineage specific deletion of FOXO1 in chondrocytes compared to littermate controls. Type 1 diabetes was induced by multiple low dose streptozotocin treatment. Thirty-five days after fracture micro CT analysis showed that diabetes significantly reduced callus volume and bone volume (P < 0.05), both which were reversed by FOXO1 deletion in chondrocytes. Diabetes significantly reduced mechanical strength measured by maximum torque, stiffness, modulus of rigidity and toughness and FOXO1 deletion in diabetic mice rescued each parameter (P < 0.05). Diabetes also reduced both bone volume and mechanical strength in non-fractured femurs. However, FOXO1 deletion did not affect bone volume or strength in non-fractured bone. These results point to the important effect that diabetes has on chondrocytes and show for the first time that the premature removal of cartilage induced by FOXO1 in chondrocytes has a significant impact on the mechanical strength of the healing bone.
机译:糖尿病增加了骨折的风险,损害骨折愈合,并导致骨折愈伤组织的快速丧失,这与软骨细胞中的FoxO1表达增加有关。我们最近证明,在骨折愈合期间,软骨细胞中的FoxO1缺失阻碍了与内胆骨形成相关的软骨过早。然而,没有研究这种缺失对机械强度的最终影响并仍然未知。在Col2α1Cre(+)中诱导封闭的骨折。与偶体酸窝控制相比,在Col2α1cre(+)中诱导了血液图像特异性缺失FoxO1的小鼠。通过多剂量的低剂量链脲佐菌素处理诱导1型糖尿病。裂缝微型CT分析后三十五天显示,糖尿病显着降低愈伤组织体积和骨骼体积(P <0.05),两者通过FOXO1缺失在软骨细胞中逆转。糖尿病通过最大扭矩,刚度,刚度模量和韧性测量测量的机械强度显着降低,糖尿病小鼠的FoxO1缺失拯救了每种参数(P <0.05)。糖尿病还减少了非骨折股骨中的骨骼体积和机械强度。然而,FOXO1缺失不会影响非骨折骨骼的骨骼体积或强度。这些结果指出了糖尿病对软骨细胞的重要影响,并且首次表现出由软骨细胞中FoxO1诱导的软骨过早除去对愈合骨的机械强度的显着影响。

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