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, 20 (23)

Assessment of Bones Deficient in Fibrillin-1 Microfibrils Reveals Pronounced Sex Differences

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Assessment of Bones Deficient in Fibrillin-1 Microfibrils Reveals Pronounced Sex Differences

Lukas Altinbas et al. Int J Mol Sci.

Abstract

Defects in the extracellular matrix protein fibrillin-1 that perturb transforming growth factor beta (TGFβ) 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 Fbn1mgR/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 TGFβ 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.

Keywords: Marfan syndrome; TGFβ signaling; biomechanics; bone architecture; fibrillin; sex.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Body mass of male (n = 5) and female (n = 6) Fbn1mgR/mgR mice at the age of 11 weeks. Data present mean ± SEM; *p < 0.05.
Figure 2
Figure 2
Cortical and trabecular microarchitecture of femora from male (n = 5) and female (n = 6) Fbn1mgR/mgR mice as determined by micro-computed tomography (μCT). (A) Representative μCT images of cortical bone cross sections (top) and 3D reconstructions showing cortical bone (bottom). (B) Representative μCT images of trabecular bone cross sections (top) and 3D reconstructions showing trabecular architecture (bottom). (C) Quantification of cortical parameters at the femoral diaphysis. (D) Quantification of trabecular parameters at the distal femoral metaphysis. BV/TV, % bone volume; Co.Th, cortical thickness; Tb.N, trabecular number; Tb.Sp, trabecular separation; Tb.Th, trabecular thickness. Data present mean ± SEM; **p < 0.01.
Figure 3
Figure 3
Trabecular microarchitecture of vertebrae from male (n = 5) and female (n = 6) Fbn1mgR/mgR mice as determined by μCT. (A) Representative μCT images of trabecular bone cross-sections (top), and 3D reconstructions showing trabecular architecture (bottom). (B) Quantification of trabecular parameters at the third lumbar vertebral body. BV/TV, % bone volume; N.S., not significant; Tb.N, trabecular number; Tb.Sp, trabecular separation; Tb.Th, trabecular thickness. Data present mean ± SEM; **p < 0.01.
Figure 4
Figure 4
Bone biomechanical integrity. The whole-bone mechanical parameters maximum load (A), stiffness (B), post-yield displacement (C), and work-to-fracture (D) of femora from male (n = 5) and female (n = 6) Fbn1mgR/mgR mice are shown. Data present mean ± SEM; *p < 0.05, **p < 0.01.
Figure 5
Figure 5
Assessment of transforming growth factor beta (TGFβ) pathway markers. The detection of phosphorylated and total Smad2 (A), and phosphorylated and total Erk1/2 (B), by immunoblotting with Gapdh as a loading control, as well as the corresponding quantification in tibiae from male (n = 5) and female (n = 5) Fbn1mgR/mgR mice, is shown. Data present mean ± SEM; *p < 0.05; AU, arbitrary unit.

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References

    1. Ramirez F., Sakai L.Y. Biogenesis and function of fibrillin assemblies. Cell Tissue Res. 2010;339:71–82. doi: 10.1007/s00441-009-0822-x. - DOI - PMC - PubMed
    1. Ramirez F., Caescu C., Wondimu E., Galatioto J. Marfan syndrome; A connective tissue disease at the crossroads of mechanotransduction, TGFbeta signaling and cell stemness. Matrix Biol. 2018;71:82–89. doi: 10.1016/j.matbio.2017.07.004. - DOI - PMC - PubMed
    1. Judge D.P., Dietz H.C. Marfan’s syndrome. Lancet. 2005;366:1965–1976. doi: 10.1016/S0140-6736(05)67789-6. - DOI - PMC - PubMed
    1. Ramirez F., Carta L., Lee-Arteaga S., Liu C., Nistala H., Smaldone S. Fibrillin-rich microfibrils-structural and instructive determinants of mammalian development and physiology. Connect. Tissue Res. 2008;49:1–6. doi: 10.1080/03008200701820708. - DOI - PubMed
    1. Smaldone S., Ramirez F. Fibrillin microfibrils in bone physiology. Matrix Biol. 2016;52:191–197. doi: 10.1016/j.matbio.2015.09.004. - DOI - PMC - PubMed
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