The effects of PPARγ inhibitor on bones and bone marrow fat in aged glucocorticoid-treated female rats
The effects of PPARγ inhibitor on bones and bone marrow fat in aged glucocorticoid-treated female rats
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DOI：
10.1016/j.exger.2023.112281
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发表时间：
2023-09-01
影响因子：
3.9
通讯作者：
Qian, Zhiyong
中科院分区：
文献类型：
--
作者：
Fan, Jingzheng;Zhang, Dalong;Qian, Zhiyong
进行性骨髓（BM）脂肪蓄积是老年人群和糖皮质激素（GC）诱导的骨骼破坏中常见的骨丢失特征，与骨合成呈负相关，与过氧化物酶体增殖物激活受体γ（PPAR γ）表达增加直接相关。PPAR-gamma抑制是老年和GC相关骨骼疾病的有效治疗策略。本研究旨在评价过氧化物酶体增殖物激活受体γ抑制剂对老年GC处理雌性大鼠的影响。据推测，双酚A二缩水甘油醚（BADGE）可以抑制骨髓肥胖，并通过抑制过氧化物酶体增殖物激活受体γ，从而防止GC诱导的骨质疏松症（GIO），改善骨生成。将雌性Sprague-Dawley大鼠（n = 32，年龄= 18个月）随机分配至以下组之一：（1）对照组，（2）BADGE（30 mg/kg/天，腹膜内）组，（3）甲泼尼龙（MP; 30 mg/kg/天，皮下）组和（4）MP + BADGE组。治疗8周后，通过显微计算机断层扫描（CT）定量骨密度（BD）和骨小梁微结构，并通过组织病理学定量BM脂肪细胞。此外，通过逆转录-定量聚合酶链反应定量成脂和成骨标志物的mRNA和蛋白表达。此外，通过酶联免疫吸附试验定量血清骨转换生物标志物水平。MP治疗导致骨髓脂肪生成和骨退化。然而，用MP + BADGE处理的大鼠显示出较低的骨髓脂肪形成，如通过较小的骨髓脂肪细胞直径、降低的密度和面积百分比、降低的骨髓脂肪形成基因和蛋白的表达、改善的BD和小梁微结构、增加的成骨基因和蛋白的表达以及较高水平的血清骨形成标志物所指示的。这些结果与对照组和BADGE单药治疗组大鼠之间观察到的差异一致。总之，BADGE治疗通过抑制PPAR γ减轻BM肥胖并改善老年GC治疗雌性大鼠的骨形成。因此，PPAR γ可能是治疗老年人群GIO的潜在靶点。
Progressive bone marrow (BM) fat accumulation is a common bone loss characteristic in older populations and glucocorticoid (GC)-induced skeletal destruction that is inversely associated with bone synthesis and directly associated with increased peroxisomal proliferator-activated receptor gamma (PPAR gamma) expression. PPAR gamma inhibition is an efficient therapeutic strategy for aged- and GC-related skeletal disorders. This study aimed to evaluate the effect of PPAR gamma inhibition on aged GC-treated female rats. It was hypothesised that bisphenol A diglycidyl ether (BADGE) could inhibit marrow adiposity and improve osteogenesis by inhibiting PPAR gamma, thereby preventing GC-induced osteoporosis (GIO). Female Sprague-Dawley rats (n = 32, age = 18 months) were randomly allocated to one of the following groups: (1) control, (2) BADGE (30 mg/kg/day, intraperitoneal), (3) methylprednisolone (MP; 30 mg/kg/day, subcutaneous), and (4) MP + BADGE. After eight weeks of treatment, bone density (BD) and trabecular bone microarchitectures were quantified by micro-computed tomography (CT), and BM adipocytes were quantified by histopathology. Additionally, mRNA and protein expression of adipogenic and osteogenic markers were quantified by reverse transcription-quantitative polymerase chain reaction. Furthermore, serum bone turnover biomarker levels were quantified by enzyme-linked immunosorbent assay. MP treatment led to marrow adipogenesis and bone deterioration. However, rats treated with MP + BADGE showed lower marrow adipogenesis, as indicated by smaller marrow adipocyte diameter, decreased density and area percentages, reduced expression of marrow adipogenic genes and proteins, improved BD and trabecular microarchitectures, increased expression of osteogenic genes and proteins, and higher levels of serum bone formation markers. These results were consistent with the differences observed between control and BADGE mono-treated rats. In conclusion, BADGE treatment attenuates BM adiposity and improves bone formation in aged GC-treated female rats by inhibiting PPAR gamma. Therefore, PPAR gamma might be a potential target for treating GIO in older populations.