Mechanobiology of Bone Development and Computational Simulations

Bone is important because it provides the skeleton structural integrity and enables movement and locomotion. Its development and morphology follow its function. It adapts to changes of mechanical loading and has the ability to repair itself after damage or fracture. The processes of bone development, bone adaptation, and bone regeneration in fracture healing are regulated, in part, by mechanical stimuli that result when the bone is loaded.

Effect of a high fat maternal diet on body composition and bone development in male offspring

Direct high fat (HF) feeding has adverse effects on body composition and bone development in rodents. However, it is unclear whether maternal HF feeding has similar effects in male rat offspring. The objectives of this thesis were to determine if maternal HF feeding altered body composition, plasma hormones, bone development, and bone fatty acid composition in male offspring at weaning and 3 months of age. Maternal HF feeding increased bone mass and altered femur fatty acid composition at weaning, without differences in fat mass, lean mass, plasma hormones, or bone mass (femur or lumbar vertebrae). However, early differences did not persist at 3 months of age or contribute to lower bone strength – following consumption of a control diet post-weaning. These findings suggest that maternal HF feeding can alter body composition and bone development in weanling male offspring, without long-lasting effects if a healthy control diet is consumed post-weaning.

Citalopram and sertraline exposure compromises embryonic bone development

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed treatments for depression and, as a class of drugs, are among the most used medications in the world. Concern regarding possible effects of SSRI treatment on fetal development has arisen recently as studies have suggested a link between maternal SSRI use and an increase in birth defects such as persistent pulmonary hypertension, seizures and craniosynostosis. Furthermore, SSRI exposure in adults is associated with decreased bone mineral density and increased fracture risk, and serotonin receptors are expressed in human osteoblasts and osteoclasts. To determine possible effects of SSRI exposure on developing bone, we treated both zebrafish, during embryonic development, and human mesenchymal stem cells (MSCs), during differentiation into osteoblasts, with the two most prescribed SSRIs, citalopram and sertraline. SSRI treatment in zebrafish decreased bone mineralization, visualized by alizarin red staining and decreased the expression of mature osteoblast-specific markers during embryogenesis. Furthermore, we showed that this inhibition was not associated with increased apoptosis. In differentiating human MSCs, we observed a decrease in osteoblast activity that was associated with a decrease in expression of the osteoblast-specific genes Runx2, Sparc and Spp1, measured with quantitative real-time PCR (qRT-PCR). Similar to the developing zebrafish, no increase in expression of the apoptotic marker Caspase 3 was observed. Therefore, we propose that SSRIs inhibit bone development by affecting osteoblast maturation during embryonic development and MSC differentiation. These results highlight the need to further investigate the risks of SSRI use during pregnancy in exposing unborn babies to potential skeletal abnormalities.Molecular Psychiatry advance online publication, 8 September 2015; doi:10.1038/mp.2015.135.

Chemical modulators of lipid abundance and bone development

 My research focussed on the analysing the lipid profile during development. I further studied potential chemicals to modulate lipid abundaces. Furthermore, I explored the effects of SSRIs on bone development.

Effect of Environmental Temperature During the First Week of Brooding Period on Broiler Chick Body Weight, Viscera and Bone Development

O presente trabalho teve como objetivo estudar o efeito de diferentes temperaturas-ambiente durante a primeira semana de vida de pintos de corte sob parâmetros zootécnicos, desenvolvimento visceral e crescimento ósseo. Foram utilizados 240 pintos de um dia, alojados em 3 câmaras climáticas, com temperaturas constantes de 20, 25 e 35°C do 1° ao 7° dia de vida. Diariamente, o consumo de água e ração, bem como o peso vivo, o peso relativo do fígado, moela, coração, saco vitelino e bursa de Fabricius foram avaliados. A tíbia e o fêmur também foram pesados e o comprimento e espessura (diâmetro médio) mensurados. As aves criadas a 20°C ganharam menos peso e consumiram menos ração do que aves mantidas a 25°C e menos água do que aves mantidas a 35°C. O peso relativo do fígado, coração e moela foram afetados pela temperatura ambiente, entretanto, não foi observado efeito da temperatura de criação sobre o peso do saco vitelino e bursa de Fabricius. Os dados mostraram que todos os parâmetros ósseos pesquisados aumentaram com a idade das aves. A temperatura ambiente não afetou a espessura da tíbia e do fêmur, mas foi observado um aumento significativo no peso e comprimento dos ossos com o aumento da temperatura ambiente. Os resultados desse experimento mostraram que o estresse por frio (20°C) reduziu o crescimento ósseo bem como o peso vivo das aves, durante os primeiros sete dias após a eclosão.

Breeder age and bone development in broiler chicken embryos

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Influence of early qualitative feed restriction and environmental temperature on long bone development of broiler chickens

This investigation was carried out to study the influence of early qualitative feed restriction and environmental rearing temperature on long bone development in broiler. Energy and protein restriction reduced femur width and humerus weight, but did not affect tibia parameters. Broilers kept at cold environmental temperature showed reduced femur, tibia and humerus length and tibia weight, but the calculated density was not affected by rearing temperature. These findings suggest that qualitative feed restriction and environmental temperature influenced the normal long bone growth; however, bone weight/bone length index (calculated density) was not affected by rearing temperature. (c) 2007 Elsevier Ltd. All rights reserved.

Role of annexin 1 gene expression in mouse craniofacial bone development

BACKGROUND: Annexin 1 is a 37-kDa protein that has complex intra- and extracellular effects. To discover whether the absence of this protein alters bone development, we monitored this event in the annexin-A1 null mice in comparison with littermate wild-type controls. METHODS: Radiographic and densitometry methods were used for the assessment of bone in annexin-A1 null mice at a gross level. We used whole-skeleton staining, histological analysis, and Western blotting techniques to monitor changes at the tissue and cellular levels. RESULTS: There were no gross differences in the appendicular skeleton between the genotypes, but an anomalous development of the skull was observed in the annexin-A1 null mice. This was characterized in the newborn annexin-A1 null animals by a delayed intramembranous ossification of the skull, incomplete fusion of the interfrontal suture and palatine bone, and the presence of an abnormal suture structure. The annexin-A1 gene was shown to be active in osteocytes during this phase and COX-2 was abundantly expressed in cartilage and bone taken from annexin-A1 null mice. CONCLUSIONS: Expression of the annexin-A1 gene is important for the normal development of the skull in mice, possibly through the regulation of osteoblast differentiation and a secondary effect on the expression of components of the cPLA2-COX-2 system. © 2007 Wiley-Liss, Inc.

Identification of the bovine Arachnomelia mutation by massively parallel sequencing implicates sulfite oxidase (SUOX) in bone development

Arachnomelia is a monogenic recessive defect of skeletal development in cattle. The causative mutation was previously mapped to a approximately 7 Mb interval on chromosome 5. Here we show that array-based sequence capture and massively parallel sequencing technology, combined with the typical family structure in livestock populations, facilitates the identification of the causative mutation. We re-sequenced the entire critical interval in a healthy partially inbred cow carrying one copy of the critical chromosome segment in its ancestral state and one copy of the same segment with the arachnomelia mutation, and we detected a single heterozygous position. The genetic makeup of several partially inbred cattle provides extremely strong support for the causality of this mutation. The mutation represents a single base insertion leading to a premature stop codon in the coding sequence of the SUOX gene and is perfectly associated with the arachnomelia phenotype. Our findings suggest an important role for sulfite oxidase in bone development.

The parathyroid hormone/parathyroid hormone-related peptide receptor coordinates endochondral bone development by directly controlling chondrocyte differentiation

During vertebrate limb development, growth plate chondrocytes undergo temporally and spatially coordinated differentiation that is necessary for proper morphogenesis. Parathyroid hormone-related peptide (PTHrP), its receptor, the PTH/PTHrP receptor, and Indian hedgehog are implicated in the regulation of chondrocyte differentiation, but the specific cellular targets of these molecules and specific cellular interactions involved have not been defined. Here we generated chimeric mice containing both wild-type and PTH/PTHrP receptor (−/−) cells, and analyzed cell–cell interactions in the growth plate in vivo. Abnormal differentiation of mutant cells shows that PTHrP directly signals to the PTH/PTHrP receptor on proliferating chondrocytes to slow their differentiation. The presence of ectopically differentiated mutant chondrocytes activates the Indian hedgehog/PTHrP axis and slows differentiation of wild-type chondrocytes. Moreover, abnormal chondrocyte differentiation affects mineralization of cartilaginous matrix in a non-cell autonomous fashion; matrix mineralization requires a critical mass of adjacent ectopic hypertrophic chondrocytes. Further, ectopic hypertrophic chondrocytes are associated with ectopic bone collars in adjacent perichondrium. Thus, the PTH/PTHrP receptor directly controls the pace and synchrony of chondrocyte differentiation and thereby coordinates development of the growth plate and adjacent bone.

Swimming training repercussion on metabolic and structural bone development: benefits of the incorporation of whole body vibration or pilometric training; the RENACIMIENTO project

Introduction: Enviromental factors such as exercise participation and nutrition have often been linked to bone improvements. However, not all sports have the same effects, being non-osteogenic sports such as swimming defined as negative or neutral sports to practice regarding bone mass by some authors, similarly exercise-diet interaction in especific groups is still not clear. Objective: To present the methodology of the RENACIMENTO project that aims to evaluate body composition and more specifically bone mass by several techniques in adolescent swimmers and to observe the effects and perdurability of whole body vibration (WBV) and jumping intervention (JIN) on body composition and fitness on this population and explore posible diet interactions. Design: Randomized controlled trial. Methods: 78 swimmers (12-17 y) and 26 sex- and age-matched controls will participate in this study. Dual energy X-ray, peripheral Quantitative Computed Tomography, Quantitative Ultrasound, Bioelectrical Impedance Analysis, and anthropometry measurements will be performed in order to evaluate body composition. Physical activity, nutrition, pubertal development and socio-economical status may act as confounders of body composition and therefore will also be registered. Several fitness factors regarding strength, endurance, performance and others will also be registered to evaluate differences with controls and act as confounders. A 7-month WBV therapy will be performed by 26 swimmers consisting of a training of 15 minutes 3 times per week. An 8 month JIM will also be performed by 26 swimmers 3 times per week. The remaining 26 swimmers will continue their normal swimming training. Four evaluations will be performed, the first one in order to describe differences between swimmers and controls. The second one to describe the effects of the interventions and the third and fourth evaluations to describe the perdurability of the effects of the WBV and JIN. Conclusion: The RENACIMIENTO project will allow to answer several questions regarding body composition, fitness, bone mass and interaction with diet of adolescent swimmers, describe swimming as a positive, negative or neutral sport to practice regarding these parameters and elucidate the effects and perdurability of WBV and JIM on body composition.

Development and scientific validation of a neonatal ultrasound axial bone scanner

Preterm infants have an increased risk of low bone mass and subsequent fracture due to limited bone mass accretion in utero and a greater need for bone nutrients. The diagnosis of ostepeonia of prematurity remains difficult as there is no sctreening test which is both sensitive and specific.