Evaluation of musculoskeletal phenotype of the G608G progeria mouse model with lonafarnib, pravastatin, and zoledronic acid as treatment groups
Evaluation of musculoskeletal phenotype of the G608G progeria mouse model with lonafarnib, pravastatin, and zoledronic acid as treatment groups
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DOI：
10.1073/pnas.1906713117
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发表时间：
2020-06-02
影响因子：
11.1
通讯作者：
Nazarian, Ara
中科院分区：
文献类型：
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作者：
Cubria, Maria B.;Suarez, Sebastian;Nazarian, Ara
Hutchinson-Gilford早衰综合征（HGPS）是一种一致致命的疾病，在皮肤、心血管和肌肉骨骼系统中尤其普遍。在我们对这种疾病的了解和有希望的治疗或治愈方法之间存在着很大的差距。本研究的目的是首先表征纯合G608 G BAC转基因早衰小鼠模型的肌肉骨骼表型，并确定在用洛那法尼、普伐他汀和唑来膦酸进行不同治疗组合的五组临床前试验后HGPS小鼠的表型变化。进行微计算机断层扫描和基于CT的刚度分析，以评估皮质骨和松质骨结构、密度和刚度。通过三点弯曲将骨加载至失效，以评估强度。对小鼠股骨进行对比增强的mu CT成像，以测量股骨头关节软骨的糖胺聚糖含量、厚度和体积。晚期糖基化终产物用荧光测定法进行评估。HGPS G608 G小鼠模型的皮质骨结构、刚度、刚度和模量的变化可能增加弯曲和变形的风险，这可能导致HGPS特征性骨骼发育不良。在该HGPS模型中观察到的软骨异常类似于在年龄匹配的WT对照中观察到的变化，包括糖胺聚糖的早期损失以及软骨厚度和体积的减少。这种变化可能与老年人普遍存在的退行性关节疾病相似。洛那法尼单药治疗没有改善骨或软骨参数，但与普伐他汀和唑来膦酸的治疗组合显著改善了骨结构和机械性能以及软骨结构参数，这改善了疾病的肌肉骨骼表型。
Hutchinson-Gilford progeria syndrome (HGPS) is a uniformly fatal condition that is especially prevalent in skin, cardiovascular, and musculoskeletal systems. A wide gap exists between our knowledge of the disease and a promising treatment or cure. The aim of this study was to first characterize the musculoskeletal phenotype of the homozygous G608G BAC-transgenic progeria mouse model, and to determine the phenotype changes of HGPS mice after a five-arm preclinical trial of different treatment combinations with lonafarnib, pravastatin, and zoledronic acid. Microcomputed tomography and CT-based rigidity analyses were performed to assess cortical and trabecular bone structure, density, and rigidity. Bones were loaded to failure with three-point bending to assess strength. Contrast-enhanced mu CT imaging of mouse femurs was performed to measure glycosaminoglycan content, thickness, and volume of the femoral head articular cartilage. Advanced glycation end products were assessed with a fluorometric assay. The changes demonstrated in the cortical bone structure, rigidity, stiffness, and modulus of the HGPS G608G mouse model may increase the risk for bending and deformation, which could result in the skeletal dysplasia characteristic of HGPS. Cartilage abnormalities seen in this HGPS model resemble changes observed in the age-matched WT controls, including early loss of glycosaminoglycans, and decreased cartilage thickness and volume. Such changes might mimic prevalent degenerative joint diseases in the elderly. Lonafarnib monotherapy did not improve bone or cartilage parameters, but treatment combinations with pravastatin and zoledronic acid significantly improved bone structure and mechanical properties and cartilage structural parameters, which ameliorate the musculoskeletal phenotype of the disease.