TNFα contributes to diabetes impaired angiogenesis in fracture healing.
TNFα contributes to diabetes impaired angiogenesis in fracture healing.
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DOI：
10.1016/j.bone.2017.02.014
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发表时间：
2017-06
期刊：
影响因子：
4.1
通讯作者：
Graves DT
中科院分区：
文献类型：
--
作者：
Lim JC;Ko KI;Mattos M;Fang M;Zhang C;Feinberg D;Sindi H;Li S;Alblowi J;Kayal RA;Einhorn TA;Gerstenfeld LC;Graves DT
糖尿病增加骨折的可能性，干扰骨折愈合，损害血管生成。后者可能是重要的，因为血管生成在骨折愈合中的关键性质。虽然已知糖尿病会干扰血管生成，但其机制仍不明确。我们检测了正常血糖和链脲佐菌素诱导的糖尿病小鼠的骨折愈合情况，并用针对三种不同血管标志物CD34、CD31和因子VIII的抗体量化了血管生成的程度。在骨折诱导后10天开始使用tnf α特异性抑制剂pegsunercept治疗，研究糖尿病增强炎症的作用。糖尿病降低血管生成和VEGFA的表达。体内TNF的特异性抑制可挽救糖尿病骨折中血管生成和VEGFA表达的减少。此外，TNF抑制剂挽救了糖尿病对内皮细胞增殖和内皮细胞凋亡的负面影响。高糖和晚期糖基化终产物可增强体外培养的TNFα抑制微血管细胞增殖和刺激细胞凋亡的作用。转录因子fox01介导TNF、高糖和AGE的作用，使p21和caspase-3的表达增加。这些研究表明，炎症通过对微血管内皮细胞和FOXO1的影响，在糖尿病诱导的软骨内骨形成血管生成中起重要作用。
Diabetes increases the likelihood of fracture, interferes with fracture healing and impairs angiogenesis. The latter may be significant due to the critical nature of angiogenesis in fracture healing. Although it is known that diabetes interferes with angiogenesis the mechanisms remain poorly defined. We examined fracture healing in normoglycemic and streptozotocin-induced diabetic mice and quantified the degree of angiogenesis with antibodies to three different vascular markers, CD34, CD31 and Factor VIII. The role of diabetes-enhanced inflammation was investigated by treatment of the TNFα-specific inhibitor, pegsunercept starting 10 days after induction of fractures. Diabetes decreased both angiogenesis and VEGFA expression. The reduced angiogenesis and VEGFA expression in diabetic fractures was rescued by specific inhibition of TNF in vivo. In addition, the TNF inhibitor rescued the negative effect of diabetes on endothelial cell proliferation and endothelial cell apoptosis. The effect of TNFα in vitro was enhanced by high glucose and an advanced glycation endproduct to impair microvascular cell proliferation and stimulate apoptosis. The effect of TNF, high glucose and an AGE was mediated by the transcription factor FOXO1, which increased expression of p21 and caspase-3. These studies indicate that inflammation plays a major role in diabetes-impaired angiogenesis in endochondral bone formation through its effect on microvascular endothelial cells and FOXO1.
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