RESUMO
Deletion of the tumor suppressor gene p53 has been shown to improve the outcome in experimental models of focal cerebral ischemia and kainate-induced seizures. To evaluate the potential role of p53 in traumatic brain injury, genetically modified mice lacking a functional p53 gene (p53(-/-), n = 9) and their wild-type littermates (p53(+/+), n = 9) were anesthetized and subjected to controlled cortical impact (CCI) experimental brain trauma. After brain injury, neuromotor function was assessed by using composite neuroscore and rotarod tests. By 7 days posttrauma, p53(-/-) mice exhibited significantly improved neuromotor function, in the composite neuroscore (P = 0.002) as well as in two of three individual tests, when compared with brain-injured p53(+/+) animals. CCI resulted in the formation of a cortical cavity (mean volume = 6.1 mm(3)) 7 days postinjury in p53(+/+) as well as p53(-/-) mice. No difference in lesion volume was detected between the two genotypes (P = 0.95). Although significant cell loss was detected in the ipsilateral hippocampus and thalamus of brain-injured animals, no differences between p53(+/+) and p53(-/-) mice were detected. Although our results suggest that lack of the p53 gene results in augmented recovery of neuromotor function following experimental brain trauma, they do not support a role for p53 acting as a mediator of neuronal death in this context, underscoring the complexity of its role in the injured brain.
Assuntos
Lesões Encefálicas/genética , Lesões Encefálicas/patologia , Atividade Motora/fisiologia , Neurônios/patologia , Proteína Supressora de Tumor p53/genética , Animais , Camundongos , Camundongos Knockout , Recuperação de Função FisiológicaRESUMO
CONTEXT: Bone morphogenetic proteins (BMPs) are thought to be responsible for bone formation; they cause bone to form in soft tissues and are clinically used in helping fracture union or tumor reconstructions. Skeletal metastases from epithelial tumors may be either bone-forming (blastic) or non-bone-forming (lytic). OBJECTIVE: We studied the expression of BMPs in a variety of primary and secondary lesions of bone (both bone-forming and non-bone-forming) to determine if there was a consistent relationship between bone formation and BMP expression. DESIGN: We compared a bone-forming lesion (fibrous dysplasia) with a non-bone-forming lesion (desmoid tumor), using reverse transcription-polymerase chain reaction, Northern blot analysis, and immunohistochemistry to detect BMPs. We also studied a number of non-bone-forming secondary lesions (carcinomas that formed lytic metastases to the skeleton) and found BMP production in most of these tumors. RESULTS: We found that BMPs were expressed in both bone-forming and non-bone-forming benign musculoskeletal lesions. In the first part of the study, BMPs were found in both fibrous dysplasia and desmoid tumors. Bone morphogenetic proteins were also expressed by several tumors. In the next part of the study (paraffin-embedded tissue), BMPs were expressed by a variety of tumors, irrespective of the radiological nature (blastic or lytic) of their metastases. CONCLUSIONS: We conclude that BMP production alone cannot explain bone formation, and other factors either alone or in combination may be responsible for blastic metastases to the skeleton and for bone formation by primary bone lesions, such as fibrous dysplasia.
Assuntos
Proteínas Morfogenéticas Ósseas/biossíntese , Fibromatose Agressiva/genética , Displasia Fibrosa Monostótica/genética , Displasia Fibrosa Poliostótica/genética , Proteína Morfogenética Óssea 2 , Proteína Morfogenética Óssea 4 , Receptores de Proteínas Morfogenéticas Ósseas Tipo I , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/imunologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Carcinoma/genética , Carcinoma/secundário , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Fibroblastos/citologia , Regulação da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imuno-Histoquímica/métodos , Osteossarcoma/genética , Osteossarcoma/patologia , Proteínas Serina-Treonina Quinases/imunologia , RNA/genética , RNA Neoplásico/genética , Receptores de Fatores de Crescimento/imunologia , Fator de Crescimento Transformador beta/biossíntese , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologiaRESUMO
Context.-Bone morphogenetic proteins (BMPs) are thought to be responsible for bone formation; they cause bone to form in soft tissues and are clinically used in helping fracture union or tumor reconstructions. Skeletal metastases from epithelial tumors may be either bone-forming (blastic) or non-bone-forming (lytic).Objective.-We studied the expression of BMPs in a variety of primary and secondary lesions of bone (both bone-forming and non-bone-forming) to determine if there was a consistent relationship between bone formation and BMP expression.Design.-We compared a bone-forming lesion (fibrous dysplasia) with a non-bone-forming lesion (desmoid tumor), using reverse transcription-polymerase chain reaction, Northern blot analysis, and immunohistochemistry to detect BMPs. We also studied a number of non-bone-forming secondary lesions (carcinomas that formed lytic metastases to the skeleton) and found BMP production in most of these tumors.Results.-We found that BMPs were expressed in both bone-forming and non-bone-forming benign musculoskeletal lesions. In the first part of the study, BMPs were found in both fibrous dysplasia and desmoid tumors. Bone morphogenetic proteins were also expressed by several tumors. In the next part of the study (paraffin-embedded tissue), BMPs were expressed by a variety of tumors, irrespective of the radiological nature (blastic or lytic) of their metastases.Conclusions.-We conclude that BMP production alone cannot explain bone formation, and other factors either alone or in combination may be responsible for blastic metastases to the skeleton and for bone formation by primary bone lesions, such as fibrous dysplasia.