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原花青素对兔激素性股骨头坏死的改善作用及机制研究
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| 篇名： | 原花青素对兔激素性股骨头坏死的改善作用及机制研究 |
| TITLE： | Study on the improvement effects and mechanism of proanthocyanidins on steroid-induced osteonecrosis of the femoral head in rabbits |
| 摘要： | 目的 基于受体相互作用蛋白激酶1（RIPK1）/RIPK3/混合谱系激酶结构域样蛋白（MLKL）信号通路，研究原花青素（PACs）对兔激素性股骨头坏死（SONFH）的改善作用及机制。方法采用注射大肠杆菌内毒素+甲泼尼龙的方法复制SONFH模型兔。将造模成功的兔随机分为模型组（Model组，生理盐水）、PACs低剂量组（PACs-L组，11mg/kg）、PACs高剂量组（PACs-H组，22mg/kg）、PACs高剂量+RIPK1激活剂（RIPK1重组蛋白，简称“rRIPK1”）组（PACs-H+rRIPK1组，22mg/kgPACs+4μg/kgrRIPK1），另设置对照组（Control组，生理盐水），每组6只。各药物组兔每天灌胃/注射相应药液1次，持续干预4周。末次给药后，检测兔血清中肿瘤坏死因子α（TNF-α）、白细胞介素6（IL-6）含量；检测兔股骨微结构[骨密度（BMD）、骨小梁厚度（Tb.Th）、骨小梁数（Tb.N）和骨小梁分离度（Tb.Sp）]变化；观察兔股骨组织的病理学形态；检测兔股骨组织细胞凋亡情况；检测兔股骨组织中血管内皮生长因子（VEGF）、骨形态发生蛋白2（BMP2）mRNA的表达水平；检测兔股骨组织中RIPK1/RIPK3/MLKL信号通路相关蛋白的表达水平。结果与Control组比较，Model组兔血清中TNF-α、IL-6含量和Tb.Sp、空骨陷窝率、细胞凋亡率以及股骨组织中RIPK1、RIPK3、MLKL蛋白的磷酸化水平均显著升高（P＜0.05）；BMD、Tb.Th、Tb.N，股骨组织中VEGF、BMP2mRNA的表达水平以及胱天蛋白酶8（caspase-8）的表达水平均显著降低（P＜0.05）；股骨组织中骨细胞分布不均，骨小梁排列稀疏。与Model组比较，PACs各剂量组上述定量指标（P＜0.05）和病理变化均显著改善。与PACs-H组比较，PACs-H+rRIPK1组上述定量指标（P＜0.05）和病理变化均显著逆转。结论PACs可改善兔SONFH，其作用机制可能与抑制RIPK1/RIPK3/MLKL信号通路激活、抑制股骨组织细胞凋亡、促进血管新生有关。 |
| ABSTRACT： | OBJECTIVE To study the improvement effects and mechanism of proanthocyanidins （PACs） on steroid-induced osteonecrosis of the femoral head （SONFH） in rabbits based on the receptor-interacting protein kinase 1 （RIPK1）/RIPK3/mixed lineage kinase domain-like protein （MLKL） signaling pathway. METHODS SONFH model in rabbits was induced by injecting Escherichia coli endotoxin+methylprednisolone. The successfully modeled rabbits were randomly divided into Model group （normal saline）， low-dose PACs group （PACs-L group， 11 mg/kg）， high-dose PACs group （PACs-H group， 22 mg/kg）， high-dose PACs+ RIPK1 activator （rRIPK1） group （PACs-H+rRIPK1 group， 22 mg/kg PACs+4 μg/kg rRIPK1）， along with a control group （normal saline）， with 6 rabbits in each group. Each administration group was given relevant medicine once a day intragastrically/via injection， for 4 consecutive weeks. After the last administration， the levels of tumor necrosis factor-α （TNF-α） and interleukin-6 （IL-6） in rabbit serum were measured. The changes in the microstructure of rabbit femurs， including bone mineral density （BMD）， trabecular thickness （Tb.Th）， trabecular number （Tb.N）， and trabecular separation （Tb. Sp） were examined. The histopathological features of rabbit femoral tissues were observed， and the apoptotic status of cells within the rabbit femoral tissues was detected. The mRNA expressions of vascular endothelial growth factor （VEGF） and bone morphogenetic protein 2 （BMP2） in rabbit femoral tissues were determined. The expressions of RIPK1/RIPK3/MLKL signaling pathway-related proteins in femoral tissues were detected. RESULTS Compared with the Control group， serum contents of TNF-α and IL-6， Tb.Sp， empty bone cavity rate， cell apoptosis rate， phosphorylation levels of RIPK1， RIPK3 and MLKL in femoral tissue were significantly increased in the Model group （P＜0.05）. BMD， Tb.Th， Tb.N， as well as the mRNA expression of VEGF and BMP2， along with protein expression of caspase-8， in the femoral tissues were all decreased （P＜0.05）. The bone cells in the femoral tissue were unevenly distributed， and the trabeculae were arranged sparsely. Compared with the Model group， the aforementioned quantitative indicators （P＜0.05） and pathological changes in all dosage groups of PACs showed significant improvements. Compared with the PACs-H group， the aforementioned quantitative indicators （P＜0.05） and pathological changes in the PACs-H+rRIPK1 group showed significant reversal. CONCLUSIONS PACs can ameliorate SONFH in rabbits， and its mechanism of action may be related to the inhibition of the activation of the RIPK1/RIPK3/MLKL signaling pathway， suppression of apoptosis in femoral tissue cells， and promotion of angiogenesis. |
| 期刊： | 2025年第36卷第20期 |
| 作者： | 吴春立；刘利婷；赵旭婷；孙瑞芬；王文选 |
| AUTHORS： | WU Chunli，LIU Liting，ZHAO Xuting，SUN Ruifen，WANG Wenxuan |
| 关键字： | 原花青素；激素性股骨头坏死；RIPK1/RIPK3/MLKL信号通路；血管新生 |
| KEYWORDS： | proanthocyanidins； steroid-induced osteonecrosis of the femoral head； RIPK1/RIPK3/MLKL signaling pathway； |
| 阅读数： | 1 次 |
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