Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Exp Biol Med (Maywood). 2014 Mar;239(3):347-55. doi: 10.1177/1535370213519215. Epub 2014 Feb 7.
Steroid-induced osteonecrosis of the femoral head (steroid-induced ONFH) is characterized by increase of intraosseous pressure because of lipid metabolism disturbance such as elevation of adipogenesis and fat cell hypertrophy in the bone marrow, subsequently leading to disturbances of coagulation-fibrinolysis system in the femoral head and finally resulting in bone ischemia. Pravastatin has been demonstrated to be useful in preventing steroid-induced ONFH in animal models. However, its exact mechanisms acting on this disease have not been fully elucidated. To address this problem, steroid-induced ONFH rat model was constructed to evaluate the effects of pravastatin treatment on the osteonecrotic changes and repair processes. Then, Micro-CT-based micro-angiography was performed to assess the effects of pravastatin treatment on vascularization. In addition, serum lipid levels were detected by haematological examination. After that, the expression of peroxisome proliferator-activated receptor gamma (PPARγ), Wnt3a, low density lipoprotein receptor-related protein 5 (LRP5), β-catenin and runt-related transcription factor 2 (RUNX2) at both mRNA and protein levels were further detected by immunohistochemistry, real-time quantitative PCR, and Western blot analyses. The results, the ratio of empty lacuna, adipose tissue area, and adipocyte perimeter in the bone marrow were dramatically lower in the pravastatin treatment groups than in the model group (all P < 0.05). Moreover, by micro-CT quantification, pravastatin treatment dose-dependently increased vessel volume, vessel surface, percentage of vessel volume, and vessel thickness of the femoral heads of steroid-induced ONFH rats. Importantly, pravastatin treatment could prevent steroid-induced ONFH by suppressing the expression of PPARγ, and increasing the expression of Wnt3a, LRP5, β-catenin, and RUNX2, at both mRNA and protein levels, in the femoral heads of steroid-induced ONFH rats. In conclusion, Pravastatin may prevent steroid-induced ONFH by suppressing PPARγ expression and activating Wnt signaling pathway.
激素诱导性股骨头坏死（steroid-induced osteonecrosis of the femoral head，steroid-induced ONFH）的特征是由于骨髓中脂质代谢紊乱，如脂肪生成和脂肪细胞肥大增加，导致骨内压升高，随后导致股骨头凝血-纤溶系统紊乱，最终导致骨缺血。普伐他汀已被证明可有效预防动物模型中的激素诱导性 ONFH。然而，其在该疾病中的确切作用机制尚未完全阐明。为了解决这个问题，构建了激素诱导性 ONFH 大鼠模型，以评估普伐他汀治疗对骨坏死变化和修复过程的影响。然后，通过基于 Micro-CT 的微血管造影评估普伐他汀治疗对血管生成的影响。此外，通过血液学检查检测血清脂质水平。之后，通过免疫组织化学、实时定量 PCR 和 Western blot 分析进一步检测过氧化物酶体增殖物激活受体 γ（peroxisome proliferator-activated receptor gamma，PPARγ）、Wnt3a、低密度脂蛋白受体相关蛋白 5（low density lipoprotein receptor-related protein 5，LRP5）、β-连环蛋白和 runt 相关转录因子 2（runt-related transcription factor 2，RUNX2）的 mRNA 和蛋白水平的表达。结果，普伐他汀治疗组的骨髓空骨陷窝比、脂肪组织面积和脂肪细胞周长比模型组明显降低（均 P<0.05）。此外，通过 Micro-CT 定量分析，普伐他汀治疗剂量依赖性地增加了激素诱导性 ONFH 大鼠股骨头的血管体积、血管表面积、血管体积百分比和血管厚度。重要的是，普伐他汀治疗可通过抑制 PPARγ 的表达，增加 Wnt3a、LRP5、β-连环蛋白和 RUNX2 的表达，从而预防激素诱导性 ONFH，在激素诱导性 ONFH 大鼠的股骨头中，mRNA 和蛋白水平均有表达。总之，普伐他汀可能通过抑制 PPARγ 的表达和激活 Wnt 信号通路来预防激素诱导性 ONFH。
