Zhu Kai, Liu Wanxin, Peng Yuanyuan, Wang Xiaoqiang, Wang Zhenhao, Zheng Jun, Deng Guoying, Wang Qiugen
Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, P.R. China.
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, P.R. China.
J Orthop Surg Res. 2025 Feb 26;20(1):202. doi: 10.1186/s13018-025-05619-0.
Steroid-induced osteonecrosis of the femoral head (SONFH) is a challenging and debilitating orthopedic condition with a rising incidence in recent years. Shuanghe Decoction (SHD), a traditional Chinese medicine formula, has shown significant efficacy in treating SONFH, though its underlying mechanisms remain unclear.
This study aims to elucidate the therapeutic effects and potential mechanisms of SHD on SONFH through in vivo experiments, combined with network pharmacology, metabolomics, and gut microbiota analysis.
Forty male Sprague-Dawley rats (300 ± 20 g) were randomly assigned to four groups: Control, Model, SHD-L, and SHD-H, with 10 rats each. SONFH was induced in all groups except the Control group using lipopolysaccharide and methylprednisolone. The SHD-L and SHD-H groups were treated with Shuanghe decoction at doses of 4.86 g/kg/day and 9.72 g/kg/day, respectively, for eight weeks. Bone morphology, pathological changes, and osteogenic factors were evaluated using Micro-CT, histological staining, and immunohistochemistry. Network pharmacology, metabolomics, and gut microbiota analyses were conducted to explore SHD's mechanisms.
SHD improved bone morphology and increased osteogenic factor expression (RUNX2, OCN, COL-I). Network pharmacology indicated that metabolic pathways play a key role in SHD's therapeutic effects. Metabolomic analysis identified 14 differential metabolites, including 21-hydroxypregnenolone and tyramine, which were restored to normal levels by SHD. Gut microbiota analysis revealed that SHD modulated bacterial abundance, particularly Verrucomicrobia, Allobaculum, and Burkholderiales. A comprehensive network identified two key metabolites (tyramine, 21-hydroxypregnenolone), seven targets (CYP19A1, CYP1A2, CYP1B1, CYP2C9, CYP3A4, MIF, and HSD11B1), two metabolic pathways (tyrosine metabolism, steroid hormone biosynthesis), and four bacterial taxa (Jeotgalicoccus, Clostridium, Corynebacterium, rc4-4) as central to SHD against SONFH.
SHD alleviates SONFH by reshaping gut microbiota, reversing metabolic imbalances, and enhancing osteogenesis. Our findings provide novel insights into the pharmacological mechanisms of SHD, laying a foundation for its clinical application in treating SONFH.
类固醇诱导的股骨头坏死（SONFH）是一种具有挑战性且使人衰弱的骨科疾病，近年来发病率呈上升趋势。双和汤（SHD）作为一种中药方剂，在治疗SONFH方面已显示出显著疗效，但其潜在机制仍不清楚。
本研究旨在通过体内实验，结合网络药理学、代谢组学和肠道微生物群分析，阐明双和汤对SONFH的治疗作用及潜在机制。
将40只雄性Sprague-Dawley大鼠（300±20 g）随机分为四组：对照组、模型组、双和汤低剂量组（SHD-L）和双和汤高剂量组（SHD-H），每组10只。除对照组外，其余各组均采用脂多糖和甲基强的松龙诱导SONFH。SHD-L组和SHD-H组分别以4.86 g/kg/天和9.72 g/kg/天的剂量给予双和汤治疗，持续8周。采用Micro-CT、组织学染色和免疫组织化学评估骨形态、病理变化和成骨因子。进行网络药理学、代谢组学和肠道微生物群分析以探索双和汤的作用机制。
双和汤改善了骨形态，增加了成骨因子表达（RUNX2、OCN、COL-I）。网络药理学表明，代谢途径在双和汤的治疗作用中起关键作用。代谢组学分析鉴定出14种差异代谢物，包括21-羟基孕烯醇酮和酪胺，双和汤将其恢复到正常水平。肠道微生物群分析显示，双和汤调节细菌丰度，尤其是疣微菌门、别氏菌属和伯克霍尔德氏菌目。一个综合网络确定了两种关键代谢物（酪胺、21-羟基孕烯醇酮）、七个靶点（CYP19A1、CYP1A2、CYP1B1、CYP2C9、CYP3A4、MIF和HSD11B1）、两条代谢途径（酪氨酸代谢、类固醇激素生物合成）和四个细菌分类群（嗜盐放线菌属、梭菌属、棒状杆菌属、rc4-4）是双和汤治疗SONFH的核心。
双和汤通过重塑肠道微生物群、逆转代谢失衡和增强成骨作用来减轻SONFH。我们的研究结果为双和汤的药理机制提供了新的见解，为其在治疗SONFH中的临床应用奠定了基础。
