Assessment of Bones Deficient in Fibrillin-1 Microfibrils Reveals Pronounced Sex Differences
Assessment of Bones Deficient in Fibrillin-1 Microfibrils Reveals Pronounced Sex Differences
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DOI：
10.3390/ijms20236059
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发表时间：
2019-12-01
影响因子：
5.6
通讯作者：
Kararigas, Georgios
中科院分区：
文献类型：
--
作者：
Altinbas, Lukas;Bormann, Nicole;Kararigas, Georgios
细胞外基质蛋白纤维蛋白-1的缺陷会干扰转化生长因子β (TGF β)的生物利用度，从而导致马凡氏综合征（MFS）。MFS是一种常染色体显性疾病，与结缔组织和骨骼缺陷等有关。迄今为止，尚不清楚生物性别如何影响MFS中骨的结构和功能特性。本研究的目的是研究性别对人类MFS模型-纤原蛋白-1缺失小鼠骨微结构和力学性能的影响。研究了11周龄雄性和雌性Fbn1（mgR/mgR）小鼠的骨骼。股骨和椎骨的三维显微计算机断层扫描显示，女性与男性相比，小梁体积与组织体积之比更低，小梁数量和厚度减少，小梁分离程度更高。股骨三点弯曲显示，与男性相比，女性屈服后移位和工作到骨折明显更低。在机制上，我们发现女性比男性更高的Smad2和ERK1/2磷酸化，表明女性更容易激活TGF β信号。总之，目前的研究结果表明，在缺乏纤维蛋白1微原纤维的骨骼中，基质和功能存在明显的性别差异。因此，通过发展性别特异性治疗方法，对MFS患者的骨骼特征进行性别特异性分析可能有助于改善这些患者的临床管理和生活质量。
Defects in the extracellular matrix protein fibrillin-1 that perturb transforming growth factor beta (TGF beta) bioavailability lead to Marfan syndrome (MFS). MFS is an autosomal-dominant disorder, which is associated with connective tissue and skeletal defects, among others. To date, it is unclear how biological sex impacts the structural and functional properties of bone in MFS. The aim of this study was to investigate the effects of sex on bone microarchitecture and mechanical properties in mice with deficient fibrillin-1, a model of human MFS. Bones of 11-week-old male and female Fbn1(mgR/mgR) mice were investigated. Three-dimensional micro-computed tomography of femora and vertebrae revealed a lower ratio of trabecular bone volume to tissue volume, reduced trabecular number and thickness, and greater trabecular separation in females vs. males. Three-point bending of femora revealed significantly lower post-yield displacement and work-to-fracture in females vs. males. Mechanistically, we found higher Smad2 and ERK1/2 phosphorylation in females vs. males, demonstrating a greater activation of TGF beta signaling in females. In summary, the present findings show pronounced sex differences in the matrix and function of bones deficient in fibrillin-1 microfibrils. Consequently, sex-specific analysis of bone characteristics in patients with MFS may prove useful in improving the clinical management and life quality of these patients, through the development of sex-specific therapeutic approaches.