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Growth factors, oncogenes, and antioncogenes in the pathogenesis of osteopetrosis and osteosarcoma




Rebatchi, Abdelaziz, author
Norrdin, Robert W., advisor
Smith, Ralph, advisor
Pearson, Leonard D., committee member
Collins, James K., committee member
Gasper, Peter, committee member

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MAV-2(0) induced avian osteopetrosis is characterized by periosteal bone proliferation in long bones. Comprehensive cellular investigations to detect and understand factors involved in the proliferation of osteopetrosis cells have not been reported. In addition, osteopetrosis has never been shown to evolve to malignancy or neoplasia and this characteristic of the disease has not been studied. To investigate the evolution to neoplasia through the study of gene expression, canine osteosarcoma samples were also included in these investigations. cDNA probes specific for tumor suppressor genes, growth factors and oncogenes, were used to determine the expression of these genes in osteopetrotic, non-inoculated controls, 10 day-old inoculated chickens, and canine osteosarcoma samples. Prior to these investigations, a protocol for bone RNA extraction was developed. In these studies, mRNA specific for Wilms' tumor suppressor gene was detected in osteopetrotic samples. This gene was not expressed in non-infected chicken controls, 10 day-old-inoculated chickens or in canine osteosarcoma samples. The expression of a potent mitogenic factor c-erb B, confirmed the proliferative nature of osteopetrosis. Since osteopetrotic cells display some level of differentiation as opposed to canine osteosarcoma cells which are not differentiated, it is concluded that Wilms' tumor gene acts as a differentiating factor preventing osteoblastic cells from entering the cycle of neoplasia, since the action of Wilms' tumor gene is not antioncogenic. These results indicate that avian osteopetrosis appears to be the result of a concomitant expression of both an oncogene (c-erb B) feeding the proliferative phenotype, and a tumor suppressor gene (Wilms' tumor suppressor gene) that keeps these cells in check. Other supporting results were obtained; platelet-derived endothelial cell growth factor was significantly expressed in both osteopetrotic and osteosarcoma samples, suggesting a common pathogenic aspect of both clinical entities. Bone morphogenic protein-1 (BMP-1) was highly expressed in one sample only. Platelet-derived growth factor was weakly expressed in one osteopetrotic sample. These results suggest a sequel of a previous involvement in the pathogenesis of osteopetrosis and confirm that osteopetrotic cells are at higher stage of differentiation. BMP-2 and BMP-3 were not expressed in this system suggesting that they might be brought to the bone matrix by the circulation, or act at an earlier stage of differentiation. Finally, the observation that 10 day-old inoculated chickens did not show any expression of any mitogenic factor appears to confirm that these chickens do not develop osteopetrosis because their bone cells are differentiated and therefore have a different set of gene regulatory proteins which makes them non-permissive to the proliferative action of the virus.


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Oncogenic viruses


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