目的:家族性自主神经障碍(FD)与骨折的高患病率相关,但该疾病对骨量和质量的影响尚不清楚。本研究的目的是通过全骨尺度评估FD小鼠模型中的组织骨质量。
方法:对来自成年Tuba1a-Cre的股骨;Elp1LoxP/LoxP条件性敲除(CKO)(F=7,M=4)和对照组(F=5,M=6)的全骨弯曲材料性能进行了评估,小梁微结构和皮质几何结构,和面骨矿物质密度(BMD)。跨越股骨中段皮质骨厚度的相邻图评估了组织尺度模量(纳米压痕),骨矿化,矿物成熟度,和胶原二级结构(拉曼光谱)。
结果:与先前对该小鼠模型的研究一致,Elp1CKO小鼠模型概括了人类FD的几个关键标志,一个区别是雄性小鼠的表型往往比雌性小鼠更严重。神经元中Elp1的缺失(使用神经元特异性Tuba1a-cre)导致全骨韧性显着降低,但强度或模量却没有降低。Elp1CKO雌性小鼠的小梁微结构减少(BV/TV,TB。Th,康涅狄格州),但不是皮质几何形状。突变小鼠的皮质骨纳米压痕模量也有少量但显著的降低。虽然骨组织矿化和矿物质成熟度没有受损,FD小鼠可能具有改变的胶原二级结构。胶原二级结构的变化与骨韧性呈负相关。双能X射线吸收法(DXA)的BMD与FD没有变化。
结论:神经元中Elp1的缺失足以产生表明全骨韧性丧失的小鼠系,与临床上怀疑的不良骨骼质量一致。Elp1CKO模型,和人类FD一样,影响神经系统,gut,gut肾功能,移动性,步态,和姿势。Elp1CKO小鼠的骨质量表型,其中包括改变的微观结构和组织尺度材料特性,是复杂的,可能受到这些多系统变化的影响。这种小鼠模型可能提供了一个有用的平台,不仅可以研究FD中骨脆性的机制,也是一个强大的模型系统,用于评估FD患者骨脆性的潜在治疗干预措施。
OBJECTIVE: Familial dysautonomia (FD) is associated with a high prevalence of bone fractures, but the impacts of the disease on bone mass and quality are unclear. The purpose of this study was to evaluate tissue through whole-bone scale bone quality in a mouse model of FD.
METHODS: Femurs from mature adult Tuba1a-Cre; Elp1LoxP/LoxP conditional knockouts (CKO) (F = 7, M = 4) and controls (F = 5, M = 6) were evaluated for whole-bone flexural material properties, trabecular microarchitecture and cortical geometry, and areal bone mineral density (BMD). Adjacent maps spanning the thickness of femur midshaft cortical bone assessed tissue-scale modulus (nanoindentation), bone mineralization, mineral maturity, and collagen secondary structure (Raman spectroscopy).
RESULTS: Consistent with prior studies on this mouse model, the Elp1 CKO mouse model recapitulated several key hallmarks of human FD, with one difference being the male mice tended to have a more severe phenotype than females. Deletion of Elp1 in neurons (using the neuronal-specific Tuba1a-cre) led to a significantly reduced whole-bone toughness but not strength or modulus. Elp1 CKO female mice had reduced trabecular microarchitecture (BV/TV, Tb.Th, Conn.D.) but not cortical geometry. The mutant mice also had a small but significant reduction in cortical bone nanoindentation modulus. While bone tissue mineralization and mineral maturity were not impaired, FD mice may have altered collagen secondary structure. Changes in collagen secondary structure were inversely correlated with bone toughness. BMD from dual-energy x-ray absorptiometry (DXA) was unchanged with FD.
CONCLUSIONS: The deletion of Elp1 in neurons is sufficient to generate a mouse line which demonstrates loss of whole-bone toughness, consistent with the poor bone quality suspected in the clinical setting. The Elp1 CKO model, as with human FD, impacts the nervous system, gut, kidney function, mobility, gait, and posture. The bone quality phenotype of Elp1 CKO mice, which includes altered microarchitecture and tissue-scale material properties, is complex and likely influenced by these multisystemic changes. This mouse model may provide a useful platform to not only investigate the mechanisms responsible for bone fragility in FD, but also a powerful model system with which to evaluate potential therapeutic interventions for bone fragility in FD patients.