RESUMO
Long bone formation starts early during embryonic development through a process known as endochondral ossification. This is a highly regulated mechanism that involves several mechanical and biochemical factors. Because long bone development is an extremely complex process, it is unclear how biochemical regulation is affected when dynamic loads are applied, and also how the combination of mechanical and biochemical factors affect the shape acquired by the bone during early development. In this study, we develop a mechanobiological model combining: (1) a reaction-diffusion system to describe the biochemical process and (2) a poroelastic model to determine the stresses and fluid flow due to loading. We simulate endochondral ossification and the change in long bone shapes during embryonic stages. The mathematical model is based on a multiscale framework, which consisted in computing the evolution of the negative feedback loop between Ihh/PTHrP and the diffusion of VEGF molecule (on the order of days) and dynamic loading (on the order of seconds). We compare our morphological predictions with the femurs of embryonic mice. The results obtained from the model demonstrate that pattern formation of Ihh, PTHrP and VEGF predict the development of the main structures within long bones such as the primary ossification center, the bone collar, the growth fronts and the cartilaginous epiphysis. Additionally, our results suggest high load pressures and frequencies alter biochemical diffusion and cartilage formation. Our model incorporates the biochemical and mechanical stimuli and their interaction that influence endochondral ossification during embryonic growth. The mechanobiochemical framework allows us to probe the effects of molecular events and mechanical loading on development of bone.
Assuntos
Biofísica , Simulação por Computador , Modelos Biológicos , Osteogênese , Animais , Cartilagem/fisiologia , Fêmur/anatomia & histologia , Análise de Elementos Finitos , Lâmina de Crescimento/crescimento & desenvolvimento , Proteínas Hedgehog/metabolismo , Camundongos Endogâmicos BALB C , Morfogênese , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Reologia , Estresse MecânicoRESUMO
Birds have a distally reduced, splinter-like fibula that is shorter than the tibia. In embryonic development, both skeletal elements start out with similar lengths. We examined molecular markers of cartilage differentiation in chicken embryos. We found that the distal end of the fibula expresses Indian hedgehog (IHH), undergoing terminal cartilage differentiation, and almost no Parathyroid-related protein (PTHrP), which is required to develop a proliferative growth plate (epiphysis). Reduction of the distal fibula may be influenced earlier by its close contact with the nearby fibulare, which strongly expresses PTHrP. The epiphysis-like fibulare however then separates from the fibula, which fails to maintain a distal growth plate, and fibular reduction ensues. Experimental downregulation of IHH signaling at a postmorphogenetic stage led to a tibia and fibula of equal length: The fibula is longer than in controls and fused to the fibulare, whereas the tibia is shorter and bent. We propose that the presence of a distal fibular epiphysis may constrain greater growth in the tibia. Accordingly, many Mesozoic birds show a fibula that has lost its distal epiphysis, but remains almost as long as the tibia, suggesting that loss of the fibulare preceded and allowed subsequent evolution of great fibulo-tibial disparity.
Assuntos
Evolução Biológica , Aves/anatomia & histologia , Aves/genética , Fíbula/anatomia & histologia , Animais , Proteínas Aviárias/genética , Proteínas Aviárias/metabolismo , Aves/classificação , Aves/embriologia , Cartilagem/metabolismo , Dinossauros/anatomia & histologia , Fíbula/embriologia , Fíbula/fisiologia , Fósseis/anatomia & histologia , Lâmina de Crescimento/metabolismo , Proteínas Hedgehog/metabolismo , OsteogêneseRESUMO
PURPOSE: This study evaluated the immunohistochemical presence of Indian Hedgehog (IHH), transforming growth factor-ß (TGF-ß), and parathyroid-1 receptor (PTH1R) in calvaria bone repair, and compared these results with the histological bone matrix features in defects treated with autograft in the presence or absence of L-PRP. MATERIAL AND METHODS: An artificial bone defect measuring 5 × 1 mm was produced in the calvaria of 28 Wistar rats. Randomly the defects were treated with autograft and autograft mixed with L-PRP. The animals were euthanized at 15 and 40 days post-surgery. Data were analyzed by Student-Newman-Keuls test (p ≤ .05) for immunohistochemical interpretation. RESULTS: The results revealed that the histological characteristic of bone matrix deposited in the defect was different in the defects treated with L-PRP. The group that received only the autograft demonstrated larger haversian bone matrix deposited, whereas the group that received autograft mixed with L-PRP revealed trabecular bone deposition. These results coincided with significantly higher immunopositivity for IHH, TGF-ß1, and PTH1R in the L-PRP group. CONCLUSION: These results suggest that L-PRP altered the biological characteristic of the autograft, increasing the bone cells IHH+ but inducing a trabecular bone associated with intense quantities of TGF-ß and PTH1R.
Assuntos
Autoenxertos/transplante , Matriz Óssea/fisiologia , Proteínas Hedgehog/análise , Leucócitos/fisiologia , Osteogênese/fisiologia , Plasma Rico em Plaquetas/fisiologia , Receptor Tipo 1 de Hormônio Paratireóideo/análise , Crânio/cirurgia , Fator de Crescimento Transformador beta1/análise , Animais , Doenças Ósseas/cirurgia , Matriz Óssea/patologia , Osso Esponjoso/patologia , Osso Esponjoso/fisiologia , Ósteon/patologia , Ósteon/fisiologia , Processamento de Imagem Assistida por Computador/métodos , Imuno-Histoquímica , Masculino , Fotografação/métodos , Distribuição Aleatória , Ratos , Ratos Wistar , Crânio/patologia , Crânio/fisiologiaRESUMO
La displasia septo-óptica (DSO) es una condición rara y altamente heterogénea, definida por la combinación de hipoplasia del nervio óptico (HNO), malformaciones cerebrales de la línea media, tales como aplasia/hipoplasia de septum pellucidum y cuerpo calloso, e insuficiencia hipotálamo-hipofisaria de grado variable. Se realizó un trabajo que tuvo como objetivo caracterizar la población de pacientes con diagnóstico de DSO seguidos en nuestro Hospital durante 7 años. Se incluyeron 46 pacientes (18 mujeres) que fueron divididos en 2 grupos, según tuviesen o no insuficiencia hipotálamo-hipofisaria (IHH). El 58.7% (n=27) presentó IHH de algún tipo, mientras que el 41.3% (n=19) no la presentó. En aquellos 19 pacientes con IHH se diagnosticaron deficiencia de GH y TSH (85.1%) y de ACTH (48.1%). La longitud corporal (mediana) del grupo con IHH fue más baja (p = 0,01) que la del grupo sin IHH, a pesar de que la edad fue menor a 2 años en todos los casos. Los pacientes fueron seguidos 1,3-8,3 años. Se observaron incidencias similares de agenesia del cuerpo calloso, del septum pellucidum, y ventriculomegalia, pero las alteraciones del desarrollo cortical se observaron con mayor frecuencia en los pacientes sin IHH. La ictericia neonatal, convulsiones y/o hipoglucemia, y micropene en neonatos y lactantes con DSO se presentaron en el subgrupo con IHH. El 58,7% de los pacientes con DSO presentaron algún grado de insuficiencia hipotálamo-hipofisaria. En la mayoría de los casos el diagnóstico de IHH no se realizó en el momento de aparición de los síntomas, sino más tardíamente en su seguimiento. En el 45% de los pacientes se evaluaron alteraciones radiológicas del SNC, específicamente en la región hipofisaria. Una fracción importante de las deficiencias de TSH/T4 (36,4%), GH (50%) y ACTH (23%) aparecieron mas tardíamente en el curso de la evolución. En 10 niños con déficit de hormona de crecimiento (2 tests farmacológicos sin respuesta) se realizó el tratamiento sustitutivo con rhGH (durante un periodo de 4±3 años), observándose una mejoría promedio de + 1,5 SDS en la talla de estos pacientes. En conclusión, la hipoplasia neonatal de nervios ópticos, asociada o no a ictericia e hipoglucemia, debe ser un signo de alarma para el diagnóstico de DSO, con riesgo de insuficiencia suprarrenal, shock y muerte, y puede requerir, por lo tanto, urgente tratamiento. Las deficiencias pueden aparecer en el curso de la evolución, a pesar del carácter congénito de la anomalía. Finalmente, se deben sustituir las deficiencias hormonales y tener presente que el tratamiento con rhGH puede mejorar la talla final en estos pacientes (AU)
Septo-optic dysplasia (SOD) is a rare and highly heterogeneous condition consisting of a combination of optic nerve hypoplasia (ONH), midline brain abnormalities, such as aplasia/hypoplasia of the septum pellucidum (ASP) and corpus callosum; and variable degree of hypoyalamo-pituitary insufficiency. The aim of this study was to characterize a population of SOD patients diagnosed and followed at the Garrahan Pediatric Hospital, from 1989 to 2006. We included 46 patients (18 females), that were divided into two groups according to the presence or absence of hypothalamic-pituitary insufficiency (IHH). Fifty nine% of SOD patients presented with IHH. GH and TSH deficiencies were diagnosed in 85.1% of IHH patients, while ACTH deficiency was found in 48.1%. Height (median) for the IHH group was shorter (p = 0,01) than for the group without IHH. Patients were followed for 1.3-8.3 years. Similar incidence of corpus callosum and/or septum pellucidum agenesis and ventriculomegaly were found in the two groups, but we observed more association with cortical developmental disorders in patients without IHH. In newborns, the association of ophthalmologic disorders and jaundice, seizures and/or hypoglycemia and micropene should frequently lead to the diagnosis of SOD and IHH. While 58,7% of DSO patients presented with hypothalamic-pituitary deficiency, only 45% of them showed sellar radiological abnormalities. Although SOD is a congenital disease, hormonal deficiencies may appear during follow-up. In 10 children with SOD and GH deficiency, rhGh treatment (for 4±3 years) improved height in 1.5 SDSs. In conclusion: in newborns with nerve optic hypoplasia, associated or not with jaundice, seizures and hypoglycaemia, the diagnosis of SOD and IHH should be considered. Treatment could be an emergency need because of risk of adrenal insufficiency and hypoglycemia (AU)