Lim Jason C, Ko Kang I, Mattos Marcelo, Fang Miao, Zhang Citong, Feinberg Daniel, Sindi Hisham, Li Shuai, Alblowi Jazia, Kayal Rayyan A, Einhorn Thomas A, Gerstenfeld Louis C, Graves Dana T
Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Endocrinology, Shanxi Province People's Hospital, Shanxi Province, China.
Bone. 2017 Jun;99:26-38. doi: 10.1016/j.bone.2017.02.014. Epub 2017 Mar 8.
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 10days after induction of fractures. Diabetes decreased both angiogenesis and VEGFA expression by chondrocytes. 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 endothelial cell proliferation and tube formation and to 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.
糖尿病会增加骨折的可能性，干扰骨折愈合并损害血管生成。由于血管生成在骨折愈合中至关重要，所以后者可能具有重要意义。尽管已知糖尿病会干扰血管生成，但其机制仍不清楚。我们研究了血糖正常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记物CD34、CD31和因子VIII的抗体对血管生成程度进行了量化。通过在骨折诱导10天后使用TNFα特异性抑制剂培格司亭进行治疗，研究了糖尿病增强炎症的作用。糖尿病降低了软骨细胞的血管生成和VEGFA表达。通过体内特异性抑制TNF，可挽救糖尿病骨折中血管生成和VEGFA表达的降低。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。高葡萄糖和晚期糖基化终产物增强了TNFα在体外的作用，损害微血管内皮细胞增殖和管腔形成并刺激凋亡。TNF、高葡萄糖和晚期糖基化终产物的作用是由转录因子FOXO1介导的，FOXO1增加了p21和caspase-3的表达。这些研究表明，炎症通过对微血管内皮细胞和FOXO1的作用，在软骨内骨形成中糖尿病损害的血管生成中起主要作用。
