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Change in weight of TSK and WT mice during growth Age/weeks TSK mice (mean ± s.d., g) WT mice (mean ± s.d., g) P-value
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Tight-skin (TSK) mice are commonly used as an animal model to study the pathogenesis of Marfan syndrome (MFS), but little is known of their skeletal phenotype and in particular of the development of the spinal deformities, common in MFS. Here we examined growth of the axial skeletons of TSK and wild-type(B6) mice during their period of rapid growth...
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... weight of TSK and B6 mice at different times is showed in Table 1. An unpaired T-test showed no statistical difference between TSK mice and B6 mice at the Bone Research (2017) 16053 Spinal deformation in TSK mice B Li et albeginning of growth (4-6 weeks). ...Context 2
... there were also significant differences in the sizes of the mice themselves and in heights of lumbar vertebrae themselves between the mouse strains. At 4 weeks of age, the TSK mice were lighter than the B6 mice (Table 1) and their the vertebral bodies ( Figure 3) and ribs ( Figure 6) were shorter those of the B6 mice. From 6 weeks onwards, the TSK mice were significantly heavier than the B6 mice. ...Context 3
... weight of TSK and B6 mice at different times is showed in Table 1. An unpaired T-test showed no statistical difference between TSK mice and B6 mice at the Bone Research (2017) 16053 Spinal deformation in TSK mice B Li et albeginning of growth (4-6 weeks). ...Context 4
... there were also significant differences in the sizes of the mice themselves and in heights of lumbar vertebrae themselves between the mouse strains. At 4 weeks of age, the TSK mice were lighter than the B6 mice (Table 1) and their the vertebral bodies ( Figure 3) and ribs ( Figure 6) were shorter those of the B6 mice. From 6 weeks onwards, the TSK mice were significantly heavier than the B6 mice. ...Citations
... However, it should be noted that the FOV of the intervertebral window at different parts of the spinal cord is different due to variation of the vertebral structure from cervical to lumbar region. In general, intervertebral window at the lower thoracic region provides the largest FOV in comparison with the cervical and lumbar regions [104][105][106][107][108] . To further extend the FOV, multiple adjacent intervertebral windows can be created on the same mouse and vertebrae can be thinned as demonstrated in a previous study 24 . ...
The spinal cord accounts for the main communication pathway between the brain and the peripheral nervous system. Spinal cord injury is a devastating and largely irreversible neurological trauma, and can result in lifelong disability and paralysis with no available cure. In vivo spinal cord imaging in mouse models without introducing immunological artifacts is critical to understand spinal cord pathology and discover effective treatments. We developed a minimally invasive intervertebral window by retaining the ligamentum flavum to protect the underlying spinal cord. By introducing an optical clearing method, we achieve repeated two-photon fluorescence and stimulated Raman scattering imaging at subcellular resolution with up to 15 imaging sessions over 6–167 days and observe no inflammatory response. Using this optically cleared intervertebral window, we study neuron-glia dynamics following laser axotomy and observe strengthened contact of microglia with the nodes of Ranvier during axonal degeneration. By enabling long-term, repetitive, stable, high-resolution and inflammation-free imaging of mouse spinal cord, our method provides a reliable platform in the research aiming at interpretation of spinal cord physiology and pathology. Wu et al. developed a technique for longitudinal imaging with subcellular resolution of the spinal cord without causing inflammation or microglia activation in live mouse through an optically cleared intervertebral window.
... The z-stack of images was imported into Mimics (Materialize, NV) and segmented using a combination of thresholding and a regiongrowing algorithm to create a 3D model of the skeleton. The degree of spinal deformity was quantified using dorsal-ventral asymmetries in the length of the spine between thoracic vertebra T4 and lumbar vertebra L6 (Li et al. 2017). Lengths of the dorsal and ventral vertebral aspects were measured in the midsagittal plane using Mimics. ...
... Lengths of the dorsal and ventral vertebral aspects were measured in the midsagittal plane using Mimics. Increased differences between dorsal and ventral lengths of the spine arise in kyphosis due to ventral wedging of the vertebral bodies (Li et al. 2017). Unlike graphical methods that estimate the severity of spinal deformity by measuring the angle between the endplates of the most tilted vertebrae (Cobb's angle), the chosen approach is independent of the position assumed by the mice during image acquisition and is thus insensitive to postural adjustments occurring postmortem due to any change in muscle tone (Stephens et al. 2015). ...
... Note that the mgR mutation, even in the absence of LTBP-3, predisposes to excessive thoracic kyphosis, which might be related to the abnormal residual shape of the DTA in Fbn1 mgR/mgR and Fbn1 mgR/mgR :Ltbp3 −/− mice (Fig. 3C-D). The severity of thoracic kyphosis is measured in a position-independent manner (Li et al. 2017) through ventral wedging of the vertebrae (G), calculated as the difference between the dorsal (E) and the ventral (F) length of the vertebral bodies in the thoracic (vertebrae T4-T13) and lumbar (vertebrae L1-L3) spine. The aortic curvature index (H), calculated as the ratio of the contour length to the end-to-end distance between the left subclavian and the sixth pair of intercostal arteries (Fig. 3D), quantifies the extent to which the profile of control and mutant DTAs deviates from a straight line. ...
Fibrillin-1 is an elastin-associated glycoprotein that contributes to the long-term fatigue resistance of elastic fibers as well as to the bioavailability of transforming growth factor-beta (TGFβ) in arteries. Altered TGFβ bioavailability and/or signaling have been implicated in aneurysm development in Marfan syndrome (MFS), a multi-system condition resulting from mutations to the gene that encodes fibrillin-1. We recently showed that the absence of the latent transforming growth factor-beta binding protein-3 (LTBP-3) in fibrillin-1-deficient mice attenuates the fragmentation of elastic fibers and focal dilatations that are characteristic of aortic root aneurysms in MFS mice, at least to 12 weeks of age. Here, we show further that the absence of LTBP-3 in this MFS mouse model improves the circumferential mechanical properties of the thoracic aorta, which appears to be fundamental in preventing or significantly delaying aneurysm development. Yet, a spinal deformity either remains or is exacerbated in the absence of LTBP-3 and seems to adversely affect the axial mechanical properties of the thoracic aorta, thus decreasing overall vascular function despite the absence of aneurysmal dilatation. Importantly, because of the smaller size of mice lacking LTBP-3, allometric scaling facilitates proper interpretation of aortic dimensions and thus the clinical phenotype. While this study demonstrates that LTBP-3/TGFβ directly affects the biomechanical function of the thoracic aorta, it highlights that spinal deformities in MFS might indirectly and adversely affect the overall aortic phenotype. There is a need, therefore, to consider together the vascular and skeletal effects in this syndromic disease.
The shorter life spans of mice provide an exceptional experimental gerontology scenario. We previously described increased bizarre (disruptive) behaviors in the 6-month-old 3xTg-AD mice model for Alzheimer's disease (AD), compared to C57BL/6J wildtype (NTg), when confronting new environments. In the present work, we evaluated spontaneous gait and exploratory activity at old age, using 16-month-old mice. Male sex was chosen since sex-dependent psychomotor effects of aging are stronger in NTg males than females and, at this age, male 3xTg-AD mice are close to an end-of-life status due to increased mortality rates. Mice's behavior was evaluated in a transparent test box during the neophobia response. Stretching, jumping, backward movements and bizarre circling were identified during the gait and exploratory activity. The results corroborate that in the face of novelty and recognition of places, old 3xTg-AD mice exhibit increased bizarre behaviors than mice with normal aging. Furthermore, bizarre circling and backward movements delayed the elicitation of locomotion and exploration, in an already frail scenario, as shown by highly prevalent kyphosis in both groups. Thus, the translational study of co-occurrence of psychomotor impairments and anxiety-like behaviors can be helpful for understanding and managing the progressive functional deterioration shown in aging, especially in AD.
Marfan syndrome (MFS) is an autosomal dominant disease affecting cardiovascular, ocular and skeletal systems. It is caused by mutations in the fibrillin-1 (FBN1) gene, leading to structural defects of connective tissue and increased activation of TGF-β. Angiotensin II (ang-II) is involved in TGF-β activity and in bone mass regulation. Inhibition of TGF-β signaling by blockage of the ang-II receptor 1 (AT1R) via losartan administration leads to improvement of cardiovascular and pulmonary phenotypes, but has no effect on skeletal phenotype in the haploinsufficient mouse model of MFS mgR, suggesting a distinct mechanism of pathogenesis in the skeletal system. Here we characterized the skeletal phenotypes of the dominant-negative model for MFS mgΔlpn and tested the effect of inhibition of ang-II signaling in improving those phenotypes. As previously shown, heterozygous mice present hyperkyphosis, however we now show that only males also present osteopenia. Inhibition of ang-II production by ramipril minimized the kyphotic deformity, but had no effect on bone microstructure in male mutant animals. Histological analysis revealed increased thickness of the anterior longitudinal ligament (ALL) of the spine in mutant animals (25.8 ± 6.3 vs. 29.7 ± 7.7 μm), coupled with a reduction in type I (164.1 ± 8.7 vs. 139.0 ± 4.4) and increase in type III (86.5 ± 10.2 vs. 140.4 ± 5.6) collagen in the extracellular matrix of this ligament. In addition, we identified in the MFS mice alterations in the erector spinae muscles which presented thinner muscle fibers (1035.0 ± 420.6 vs. 655.6 ± 239.5 μm2) surrounded by increased area of connective tissue (58.17 ± 6.52 vs. 105.0 ± 44.54 μm2). Interestingly, these phenotypes were ameliorated by ramipril treatment. Our results reveal a sex-dependency of bone phenotype in MFS, where females do not present alterations in bone microstructure. More importantly, they indicate that hyperkyphosis is not a result of osteopenia in the MFS mouse model, and suggest that incompetent spine ligaments and muscles are responsible for the development of that phenotype.
