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

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.

Sensitive asprosin detection in clinical samples reveals serum/saliva correlation and indicates cartilage as source for serum asprosin

“…Currently, there is only limited information available regarding sex-dependent expression rates of fibrillin-1 from which asprosin is derived after furin-mediated cleavage within the C-terminal region. However, analysis of fibrillin-1 mutant mice revealed sex-dependent differences in thoracic aorta contractility, as well as aortic media injury 36 , 37 . Interestingly, addition of 17β-estradiol was found to promote fibrillin-1 production by human aortic smooth muscle cells, but not by fibroblasts 38 , suggesting a sex- and tissue-dependent regulation of fibrillin-1 expression which may explain the observed increase of asprosin in serum samples from females.…”

Sex-Related Effects of Gut Microbiota in Metabolic Syndrome-Related Diabetic Retinopathy

“…In various diseases, including CVD, there are fundamental differences between the sexes in manifestation and outcome, as well as the response to treatment [ 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 ]. Overall, sex differences are generally attributed to genetic and epigenetic mechanisms, regulating major biological processes, including cell death, extracellular matrix deposition and inflammation, as well as sex hormones and their receptors [ 77 , 82 , 83 , 86 , 87 , 88 , 89 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 ,…”

Sex-Related Effects on Cardiac Development and Disease

“…Interestingly, it has been shown that the simultaneous presence of a single copy of TIMP1 and TIMP3 risk alleles raises the risk of aortopathy [ 61 ] ( Figure 1 ). TIMP imbalance is also responsible for ECM degradation that leads to excessive TGF-β signaling and the activation of SMAD signaling, both of which have been linked to an increase in fibrosis and inflammation in the aortas of patients with TS, similar to other rare disorders [ 63 , 64 ]. This over-activation leads to the induction of metalloproteases and eventually to aortic dilation and dissection [ 60 ].…”