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 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 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.

In the EU, the breeding of genetically modified laboratory animals is, by definition, an animal experiment if the offspring may experience pain, suffering, or harm. In order to determine the actual burden of genetically modified mice, established methods are available. However, the breeding of immunodeficient mice is considered an experiment requiring a permit, even if no pain, suffering or harm is observed under scientifically required defined hygienic housing conditions, as determined by established methods of severity assessment. This seems contradictory and leads to uncertainty among scientists. With this commentary, we would like to shed light on this topic from different perspectives and propose a solution in terms of individualized severity assessment and approval procedures.

Background: Farm animals (FAs) are frequently used in biomedical research. Recommendations for the purchase, housing and health monitoring of these animals (sheep, goats, cattle and pigs) are still missing, and many institutes have developed their own strategies and protocols to face the challenges associated with the use of farm animals. This may influence the comparability of research results and increase data variances, thus increasing animal use that contradicts the obligation to apply the 3Rs principle of reduction, refinement and replacement required in Directive 2010/63 EU and the German animal protection law. Methods: A survey was conducted to define the current state of the art in research institutes working with pigs, and large and small ruminants. Results: The results of the survey clearly show that there are no uniform procedures regarding the purchase, housing and hygiene management of farm animals contrary to small laboratory animals. The facilities make purpose-bound decisions according to their own needs and individual work instructions and implement their own useful protocols to improve and maintain the health of the animals. Conclusion: This survey was the first step to filling the gaps and identifying the status quo and practical applied measures regarding the purchase and hygiene monitoring of FAs in order to improve animal welfare and scientific validity.