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Skeletal Muscle Gender Dimorphism from Proteomics
Published on: December 14, 2011
Assessment of Bones Deficient in Fibrillin-1 Microfibrils Reveals Pronounced Sex Differences
Lukas Altinbas1, Nicole Bormann1,2, Daniel Lehmann1
1BIH Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany.
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 Fbn1 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.
Insights
Marfan syndrome (MFS) affects bone differently in males and females. This study found that female mice with MFS had poorer bone structure and mechanical properties, linked to increased TGFβ signaling.
Area of Science:
- Biomedical research
- Skeletal biology
- Genetics
Background:
- Marfan syndrome (MFS) results from fibrillin-1 defects affecting TGFβ bioavailability.
- MFS causes connective tissue and skeletal issues, but sex-specific bone effects are unknown.
Purpose of the Study:
- To investigate sex-based differences in bone microarchitecture and mechanical function in a mouse model of MFS.
- To explore the underlying molecular mechanisms, specifically TGFβ signaling pathways.
Main Methods:
- Examined femora and vertebrae from 11-week-old male and female Fbn1-deficient mice (MFS model).
- Utilized 3D micro-computed tomography for microarchitecture analysis.
- Performed three-point bending tests on femora for mechanical properties.
- Assessed TGFβ signaling activation via Smad2 and ERK1/2 phosphorylation.
Main Results:
- Female mice exhibited reduced trabecular bone volume, number, and thickness, with increased separation compared to males.
- Femora from female mice showed significantly lower post-yield displacement and work-to-fracture.
- Higher Smad2 and ERK1/2 phosphorylation indicated greater TGFβ signaling activation in females.
Conclusions:
- Significant sex differences exist in bone matrix and function in fibrillin-1 deficient mice.
- These findings suggest sex-specific analyses are crucial for MFS patient management.
- Sex-specific therapeutic strategies may improve clinical outcomes and quality of life for MFS patients.
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