RESUMO
Marfan syndrome (MFS) is a connective tissue disorder caused by pathogenic mutations in FBN1. In bone, the protein fibrillin-1 is found in the extracellular matrix where it provides structural support of elastic fiber formation, stability for basement membrane, and regulates the bioavailability of growth factors. Individuals with MFS exhibit a range of skeletal complications including low bone mineral density and long bone overgrowth. However, it remains unknown if the bone phenotype is caused by alteration of fibrillin-1's structural function or distortion of its interactions with bone cells. To assess the structural effects of the fibrillin-1 mutation, we characterized bone curvature, microarchitecture, composition, porosity, and mechanical behavior in the Fbn1 C1041G/+ mouse model of MFS. Tibiae of 10, 26, and 52-week-old female Fbn1 C1041G/+ and littermate control (LC) mice were analyzed. Mechanical behavior was assessed via in vivo strain gauging, finite element analysis, ex vivo three-point bending, and nanoindentation. Tibial bone morphology and curvature were assessed with micro computed tomography (µCT). Bone composition was measured with Fourier transform infrared (FTIR) imaging. Vascular and osteocyte lacunar porosity were assessed by synchrotron computed tomography. Fbn1 C1041G/+ mice exhibited long bone overgrowth and osteopenia consistent with the MFS phenotype. Trabecular thickness was lower in Fbn1 C1041G/+ mice but cortical bone microarchitecture was similar in Fbn1 C1041G/+ and LC mice. Whole bone curvature was straighter below the tibio-fibular junction in the medial-lateral direction and more curved above in LC compared to Fbn1 C1041G/+ mice. The bone matrix crystallinity was 4 % lower in Fbn1 C1041G/+ mice compared to LC, implying that mineral platelets in LCs have greater crystal size and perfection than Fbn1 C1041G/+ mice. Structural and mechanical properties were similar between genotypes. Cortical diaphyseal lacunar porosity was lower in Fbn1 C1041G/+ mice compared to LC; this was a result of the average volume of an individual osteocyte lacunae being smaller. These data provide valuable insights into the bone phenotype and its contribution to fracture risk in this commonly used mouse model of MFS.
RESUMO
It is hypothesized that bone cells can sense mechanical force in the extracellular network via an electrical signal. This has led to the use of electrical stimulation (ES) to improve fracture repair and mitigate bone loss. Although overlap exists in bone maintenance and fracture healing mechanics, the processes involved in both are very different, resulting in dissimilar behaviors from the cells. Osteocytes are the most abundant cell type in bone tissue, and their basic structure and lineage are fairly well understood, but much debate is present regarding their behavior, with even less known about their behavior in electrical environments. A wide range of research exists on cell behavior under different types of ES, but it is difficult to draw conclusions due to the large variance in stimulation parameters, cell types, and origins (locations and species). By exploring behavior of multiple bone-cell types under different forms of ES, as well as mechanical stimulation through fluid flow, we can determine more about cell reactions to stimuli. In turn, a better understanding of cell response has the potential to improve and broaden therapeutic applications of ES for bone healing and bone loss mitigation, and enhance outcomes for osseointegration into implantable medical devices. These require greater understanding of the bone cellular environment from an electrical perspective as well as cellular responses to ES.
