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首页> 外文期刊>Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research >TNF-alpha mediates diabetes-enhanced chondrocyte apoptosis during fracture healing and stimulates chondrocyte apoptosis through FOXO1.
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TNF-alpha mediates diabetes-enhanced chondrocyte apoptosis during fracture healing and stimulates chondrocyte apoptosis through FOXO1.

机译：TNF-α在骨折愈合过程中介导糖尿病增强的软骨细胞凋亡，并通过FOXO1刺激软骨细胞凋亡。

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To gain insight into the effect of diabetes on fracture healing, experiments were carried out focusing on chondrocyte apoptosis during the transition from cartilage to bone. Type 1 diabetes was induced in mice by multiple low-dose streptozotocin injections, and simple transverse fractures of the tibia or femur was carried out. Large-scale transcriptional profiling and gene set enrichment analysis were performed to examine apoptotic pathways on total RNA isolated from fracture calluses on days 12, 16, and 22, a period of endochondral bone formation when cartilage is resorbed and chondrocyte numbers decrease. Tumor necrosis factor alpha (TNF-alpha) protein levels were assessed by ELISA and caspase-3 by bioactivity assay. The role of TNF was examined by treating mice with the TNF-specific inhibitor pegsunercept. In vitro studies investigated the proapoptotic transcription factor FOXO1 in regulating TNF-induced apoptosis of chondrogenic ATDC5 and C3H10T1/2 cells as representative of differentiated chondrocytes, which are important during endochondral ossification. mRNA profiling revealed an upregulation of gene sets related to apoptosis in the diabetic group on day 16 when cartilage resorption is active but not day 12 or day 22. This coincided with elevated TNF-alpha protein levels, chondrocyte apoptosis, enhanced caspase-3 activity, and increased FOXO1 nuclear translocation (p < .05). Inhibition of TNF significantly reduced these parameters in the diabetic mice but not in normoglycemic control mice (p < .05). Silencing FOXO1 using siRNA in vitro significantly reduced TNF-induced apoptosis and caspase activity in differentiated chondrocytes. The mRNA levels of the proapoptotic genes caspase-3, caspase-8, caspase-9, and TRAIL were significantly reduced with silencing of FOXO1 in chondrocytic cells. Inhibiting caspase-8 and caspase-9 significantly reduced TNF-induced apoptosis in chondrogenic cells. These results suggest that diabetes causes an upregulation of proapoptotic genes during the transition from cartilage to bone in fracture healing. Diabetes increased chondrocyte apoptosis through a mechanism that involved enhanced production of TNF-alpha, which stimulates chondrocyte apoptosis and upregulates mRNA levels of apoptotic genes through FOXO1 activation.
机译：为了深入了解糖尿病对骨折愈合的影响，进行了针对软骨从骨过渡到骨软骨细胞凋亡的实验。多次低剂量链脲佐菌素注射在小鼠中诱发1型糖尿病，并进行了胫骨或股骨的简单横向骨折。进行了大规模的转录谱分析和基因集富集分析，以检查在第12、16和22天从骨折老茧分离出的总RNA的凋亡途径，这是软骨吸收后软骨内骨形成的时期，软骨细胞数量减少。通过ELISA和生物活性测定评估肿瘤坏死因子α（TNF-α）蛋白水平。通过用TNF特异性抑制剂pegsunercept治疗小鼠来检查TNF的作用。体外研究调查了促凋亡转录因子FOXO1在调节TNF诱导的软骨生成ATDC5和C3H10T1 / 2细胞凋亡方面的作用，这些细胞是分化软骨细胞的代表，这在软骨内骨化过程中很重要。 mRNA谱分析显示，在软骨吸收活跃的第16天，糖尿病组中与凋亡相关的基因组上调，但在第12天或第22天不活跃。这与TNF-α蛋白水平升高，软骨细胞凋亡，caspase-3活性增强，并增加FOXO1核易位（p <.05）。 TNF的抑制在糖尿病小鼠中显着降低了这些参数，但在正常血糖对照小鼠中却没有降低（p <.05）。在体外使用siRNA沉默FOXO1可以显着降低TNF诱导的分化软骨细胞凋亡和caspase活性。随着软骨细胞中FOXO1的沉默，促凋亡基因caspase-3，caspase-8，caspase-9和TRAIL的mRNA水平显着降低。抑制caspase-8和caspase-9可以显着降低TNF诱导的软骨细胞凋亡。这些结果表明，糖尿病在骨折愈合中从软骨过渡到骨骼的过程中会引起凋亡基因的上调。糖尿病通过增加TNF-α产生的机制增加了软骨细胞凋亡，该机制可刺激软骨细胞凋亡并通过FOXO1激活上调凋亡基因的mRNA水平。

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