RESUMEN
The segmental premature aging disease Hutchinson-Gilford Progeria (HGPS) is caused by a truncated and farnesylated form of Lamin A. In a mouse model for HGPS, a similar Lamin A variant causes the proliferative arrest and death of postnatal, but not embryonic, fibroblasts. Arrest is due to an inability to produce a functional extracellular matrix (ECM), because growth on normal ECM rescues proliferation. The defects are associated with inhibition of canonical Wnt signaling, due to reduced nuclear localization and transcriptional activity of Lef1, but not Tcf4, in both mouse and human progeric cells. Defective Wnt signaling, affecting ECM synthesis, may be critical to the etiology of HGPS because mice exhibit skeletal defects and apoptosis in major blood vessels proximal to the heart. These results establish a functional link between the nuclear envelope/lamina and the cell surface/ECM and may provide insights into the role of Wnt signaling and the ECM in aging.
Asunto(s)
Matriz Extracelular/metabolismo , Lámina Nuclear/metabolismo , Progeria/metabolismo , Transducción de Señal/fisiología , Proteínas Wnt/metabolismo , Xenopus laevis/embriología , Animales , Apoptosis , Biomarcadores/metabolismo , Western Blotting , Proliferación Celular , Células Cultivadas , Inmunoprecipitación de Cromatina , Embrión de Mamíferos/citología , Embrión de Mamíferos/metabolismo , Ensayo de Inmunoadsorción Enzimática , Fibroblastos/citología , Fibroblastos/metabolismo , Perfilación de la Expresión Génica , Humanos , Lamina Tipo A/fisiología , Luciferasas/metabolismo , Ratones , Ratones Noqueados , Análisis de Secuencia por Matrices de Oligonucleótidos , Progeria/patología , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , SíndromeRESUMEN
In this article, we summarize the results of six different tomographic/biomechanical rat studies involving hypophysectomy (Hx), ovariectomy, treatment with rhGH, olpadronate, alendronate, and toxic doses of aluminum and the development of a genetic diabetes in the eSS strain. All these conditions induced some interesting and rarely reported effects on postyield bone strength. These effects were generally related neither to the degree of mineralization or the elastic modulus of the bone tissue nor to the preyield behavior of the bones. In two particular cases (Hx, eSS), the elastic modulus of bone tissue varied independently of its degree of mineralization. These results suggest the involvement of some microstructural factor(s) of bone tissue resistance to crack progression (a postyield feature of bone behavior), rather than to crack initiation (the yield-determining factor) in the corresponding mechanism. Changes in collagen or crystal structure may play that role. These changes are relevant to the mechanism of fracture production during plastic deformation, a feature of bone strength that might be independent from mineralization. Therefore, these changes might help to explain some effects of novel treatments on bone strength unrelated to bone mineralization. This questions the belief that the remaining bone mass in metabolic osteopenias is biologically and mechanically normal.
Asunto(s)
Densidad Ósea/fisiología , Calcificación Fisiológica/fisiología , Animales , Enfermedades Óseas Metabólicas/fisiopatología , Femenino , Fracturas Óseas/fisiopatología , Humanos , Ratas , Ratas Sprague-Dawley , Estrés Mecánico , Resistencia a la Tracción/fisiologíaRESUMEN
This report summarizes some preliminary absorptiometric (DXA, QCT/pQCT) studies from our laboratory, supporting the following assumptions. 1. In Homo sapiens at all ages, natural proportionality between DXA-assessed bone mineral mass (bone mineral content, BMC) and muscle mass (lean mass, LM) of the whole body or limbs is specific for ethnicity, gender, and reproductive status, but not for body weight, height, or body mass index. 2. This proportionality is sensitive to many kinds of endocrine-metabolic perturbations. 3. Percentilized or Z-scored charts of the BMC/LM correlations as determined in large samples of healthy individuals can provide a diagnostic reference for evaluating proportionality in different conditions. 4. Employing exclusively DXA, this methodology can be applied to discriminate between "disuse-related" and "metabolic" osteopenias based on the finding of normal or low BMC/LM percentiles or Z-scores respectively, with important therapeutic and monitoring implications.
Asunto(s)
Densidad Ósea , Huesos/diagnóstico por imagen , Músculo Esquelético/diagnóstico por imagen , Osteoporosis/diagnóstico por imagen , Absorciometría de Fotón , Huesos/patología , Femenino , Humanos , Masculino , Músculo Esquelético/patología , Tamaño de los Órganos , Osteoporosis/patologíaRESUMEN
OBJECTIVE: In our study, we evaluated the potential of micro-CT for the assessment of the rat knee joint using ex vivo micro-CT arthrography. The aims of the study were to introduce the technique of micro-CT arthrography and to visualize the normal anatomy of the rat knee. The secondary aims were the quantification of retropatellar cartilage thickness and the analysis of microstructural cancellous bone parameters within the tibial epiphysis. CONCLUSION: Micro-CT arthrography is a novel technique for the indirect visualization of the distinct features and structural analysis of the rat knee joint. This technique represents an additional imaging and analysis tool in small-animal research.
Asunto(s)
Artrografía/métodos , Articulación de la Rodilla/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Animales , Femenino , Procesamiento de Imagen Asistido por Computador , Proyectos Piloto , Ratas , Ratas Sprague-DawleyRESUMEN
Morphological and biomechanical features of the mandible are negatively affected by protein-energy malnutrition, whose effects are apparently dependent on the time of life of application. The aim here was to investigate, in neonatal rats nursed by dams put on a protein-free diet to depress milk production and thus create a state of protein-energy malnutrition in the offspring, subsequent growth and long-term effects by analyzing mandibular dimensions and bone quality in adulthood. Pregnant Wistar rats were fed a 20% protein diet (control) or a protein-free diet (malnourished) to obtain normal or subnormal milk production, respectively. After weaning, the offspring (males) were fed a 20% protein diet for 70 days. The dimensions of their excised mandibles were measured directly between anatomical points; the geometry and material quality of mandibular bone were assessed by peripheral quantitative computed tomography. Pups suckling from malnourished dams weighed 49.4% of those suckling from control dams at weaning; the actual difference between control and malnourished pups was 25.1g, which persisted until day 91 of age, indicating the absence of catch-up growth. As with body size, the mandibular base length, height and area (an index of mandibular size) were significantly smaller in malnourished than control rats at the end of the study. The mandibular cortical area, volumetric cortical bone mineral content and volumetric cortical bone mineral density assessed by peripheral quantitative computed tomography were similar in both groups of rats at the end of the observation period, but there was a significant reduction in the cortical axial moment of inertia in malnourished rats at this time of postnatal life. These findings suggest that catch-up growth was incomplete in rats malnourished during the suckling period and that the adaptation of mandibular bone architecture to body growth was apparently insufficient to attain normal values, thus not allowing complete compensation in mechanical competence at the end of the study because of an inadequate spatial distribution of resistive material through its cross-section rather than qualitative or quantitative impairment of cortical bone.