Wang Gang, Ma Chao, Mo Liang, Chen Jiazhi, Yuan Jinbo, Xu Jiake, He Wei
Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518000, China.
Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
J Orthop Translat. 2024 Mar 23;45:178-187. doi: 10.1016/j.jot.2024.01.009. eCollection 2024 Mar.
Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a common bone and joint disease. There is currently a lack of effective treatment for GIONFH, and the disease progression may lead to total hip arthroplasty (THA). The exact mechanism of GIONFH pathogenesis remains unsettled, and emerging evidence indicates that the overactivation of osteoclasts plays a pivotal role in the occurrence and progression of this condition. Our previous study has shown that cycloastragenol (CAG), a triterpenoid saponin with multiple bioactivities, is a natural osteoclast inhibitor and has a protective effect on bone loss. However, its effect on GIONFH remains unclear.
In this study, methylprednisolone (MPS) (20 mg/kg) was administered via gluteal muscle injection to female Sprague-Dawley (SD) rats to induce GIONFH, and different doses of CAG (5 and 15 mg/kg) were dispensed intraperitoneally for intervention. Micro-CT screening and angiography were applied to determine the shaping of necrotic lesions, the loss of trabecular bone, and the change in the local blood supply. The molecular mechanism was established by Real-time qPCR and Western blotting. Hematoxylin and eosin (H&E) staining was performed to identify empty lacunae in the femoral head.
CAG treatment shanked the necrotic lesion area, inhibited the trabecular bone loss, and improved the local blood supply in the femoral head. In addition, CAG medication lowered the ratio of Tnfsf11 (encoding RANKL) to Tnfrsf11b (encoding OPG) and the expression of osteoclast-specific genes, including Acp5 and Ctsk. Consistently, CAG treatment exhibited a dose-dependent weakening effect on the expression of osteoclastogenesis and bone resorption-related proteins, including TRAP, CTSK, and MMP9. CAG addition also alleviated the occurrence of empty lacunae in the subchondral region.
Our discoveries demonstrate that CAG is a potential option for hip preservation therapy in GIONFH patients.
The protective effect of CAG on rats with GIONFH can be translated into clinical use.
糖皮质激素性股骨头坏死（GIONFH）是一种常见的骨与关节疾病。目前GIONFH缺乏有效的治疗方法，疾病进展可能导致全髋关节置换术（THA）。GIONFH发病的确切机制仍未明确，新出现的证据表明破骨细胞的过度活化在该病的发生和发展中起关键作用。我们之前的研究表明，环黄芪醇（CAG），一种具有多种生物活性的三萜皂苷，是一种天然的破骨细胞抑制剂，对骨质流失具有保护作用。然而，其对GIONFH的影响仍不清楚。
在本研究中，通过臀肌注射给予雌性Sprague-Dawley（SD）大鼠甲基强的松龙（MPS）（20mg/kg）以诱导GIONFH，并腹腔注射不同剂量的CAG（5和15mg/kg）进行干预。应用显微CT扫描和血管造影来确定坏死灶的形成、小梁骨的丢失以及局部血供的变化。通过实时定量PCR和蛋白质印迹法确定分子机制。进行苏木精-伊红（H&E）染色以识别股骨头中的空骨陷窝。
CAG治疗缩小了坏死灶面积，抑制了小梁骨丢失，并改善了股骨头的局部血供。此外，CAG用药降低了Tnfsf11（编码RANKL）与Tnfrsf11b（编码OPG）的比值以及破骨细胞特异性基因（包括Acp5和Ctsk）的表达。一致地，CAG治疗对破骨细胞生成和骨吸收相关蛋白（包括TRAP、CTSK和MMP9）的表达呈现剂量依赖性的减弱作用。添加CAG还减轻了软骨下区域空骨陷窝的发生。
我们的发现表明，CAG是GIONFH患者保髋治疗的一种潜在选择。
CAG对GIONFH大鼠的保护作用可转化为临床应用。
