Yu Zefeng, Fan Lihong, Li Jia, Ge Zhaogang, Dang Xiaoqian, Wang Kunzheng
Department of Orthopedics, The Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xi'an, 710004, Shaanxi Province, People's Republic of China.
Endocrine. 2016 May;52(2):380-90. doi: 10.1007/s12020-015-0747-y. Epub 2015 Oct 12.
This study explored the use of lithium to prevent rat steroid-related osteonecrosis of the femoral head (ONFH) through the modulation of the β-catenin pathway. ONFH was induced by methylprednisolone combined with lipopolysaccharide, and serum lipids were analyzed. ONFH was detected by hematoxylin-eosin staining. Micro-CT-based angiography and bone scanning were performed to analyze vessels and bone structure, respectively. Immunohistochemical staining for peroxisome proliferator-activated receptor gamma (PPARγ), bone morphogenetic protein-2 (BMP-2), and vascular endothelial growth factor (VEGF) was analyzed. Protein levels of phospho-glycogen synthase kinase-3β at Tyr-216 (p-Tyr(216) GSK-3β), total glycogen synthase kinase-3β (GSK-3β) and β-catenin, as well as mRNA levels of GSK-3β and β-catenin in femoral heads, were assessed. The rate of empty bone lacunae in the femoral heads was lower in the lithium and control groups than in the model group. The lithium group showed preventive effects against steroid-related vessel loss by micro-CT-based angiography and VEGF staining. Lithium treatment improved hyperlipidemia and reduced PPARγ expression. Moreover, lithium improved steroid-related bone loss in micro-CT bone scans and BMP-2 staining analyses. Furthermore, local β-catenin was reduced in steroid-related ONFH, and lithium treatment increased β-catenin expression while reducing p-Tyr(216) GSK-3β levels. The local β-catenin pathway was inhibited during steroid-related ONFH. Lithium may enhance angiogenesis and stabilize osteogenic/adipogenic homeostasis during steroid-related ONFH in rats by activating the β-catenin pathway.
本研究通过调节β-连环蛋白通路，探索锂预防大鼠类固醇相关股骨头坏死（ONFH）的作用。采用甲基强的松龙联合脂多糖诱导ONFH，并分析血脂。通过苏木精-伊红染色检测ONFH。分别进行基于微计算机断层扫描（Micro-CT）的血管造影和骨扫描，以分析血管和骨结构。分析过氧化物酶体增殖物激活受体γ（PPARγ）、骨形态发生蛋白-2（BMP-2）和血管内皮生长因子（VEGF）的免疫组化染色。评估股骨头中酪氨酸216位点磷酸化糖原合酶激酶-3β（p-Tyr(216) GSK-3β）、总糖原合酶激酶-3β（GSK-3β）和β-连环蛋白的蛋白水平，以及GSK-3β和β-连环蛋白在股骨头中的mRNA水平。锂组和对照组股骨头中空骨陷窝的发生率低于模型组。通过基于Micro-CT的血管造影和VEGF染色，锂组显示出对类固醇相关血管丢失的预防作用。锂治疗改善了高脂血症并降低了PPARγ表达。此外，在Micro-CT骨扫描和BMP-2染色分析中，锂改善了类固醇相关的骨质流失。此外，在类固醇相关的ONFH中局部β-连环蛋白减少，锂治疗增加了β-连环蛋白表达，同时降低了p-Tyr(216) GSK-3β水平。在类固醇相关ONFH期间，局部β-连环蛋白通路受到抑制。锂可能通过激活β-连环蛋白通路，在大鼠类固醇相关ONFH期间增强血管生成并稳定成骨/成脂稳态。
