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1.
J Orthop Res ; 23(6): 1345-53, 2005 Nov.
Article in English | MEDLINE | ID: mdl-15994055

ABSTRACT

We have previously shown p53 to have a specific role in osteoblast differentiation by its ability to regulate expression of certain bone specific proteins. In this study, we show mineralized matrix formation in vivo to be directly related to the presence of wild type p53 in osteoblastic osteosarcoma cells. In order to further understand the importance of p53 in differentiation, we investigated the relationship between p53 and Bone Morphogenetic Proteins (BMPs) (BMP 1, 2, 3A, 3B (GDF-10), 4, 5, 6, 7, 8A and 8B) during osteoblast differentiation. The expression of several BMPs were tested using RNase Protection Assay in differentiating ROS17/2.8 osteoblastic osteosarcoma cells. The expression of BMPs 1, 2, 3a, 3b and 7 showed time dependent modulation during in vitro differentiation. In order to determine if p53 has a role in this process, we used a murine osteosarcoma cell line stably expressing a temperature sensitive p53. Cells were exposed to ascorbic acid and glycerophosphates to hasten in vitro osteoblast differentiation and maintained either at 32 or 37 degrees C for expression of the wild type or mutant p53 phenotype. The expression of BMP-2, BMP-4 and BMP-7 were modulated in a p53 dependent fashion. We were able to confirm the p53 dependency of BMP-2 independently by RT-PCR. While BMP-2 expression was evident in the presence of both wild type and mutant p53, regulated expression was seen only in cells expressing wild type p53. Transient over expression of wild type p53 did not result in the same BMP-2 response as stable expression showing that the presence of p53 may be important for an orderly development of osteoblast differentiation rather than a direct effect on gene expression. The functional relationship between p53 and these bone specific markers is discussed.


Subject(s)
Bone Morphogenetic Proteins/physiology , Cell Differentiation , Osteoblasts/cytology , Tumor Suppressor Protein p53/physiology , Animals , Bone Morphogenetic Protein 2 , Bone Morphogenetic Proteins/genetics , Cell Line, Tumor , Osteocalcin/genetics , Osteosarcoma/chemistry , Osteosarcoma/pathology , Promoter Regions, Genetic , RNA, Messenger/analysis , Rats , Transfection , Transforming Growth Factor beta/genetics , Tumor Suppressor Protein p53/analysis
2.
Life Sci ; 75(17): 2045-55, 2004 Sep 10.
Article in English | MEDLINE | ID: mdl-15312749

ABSTRACT

Estrogen is known to be anabolic for bone and we have used estrogen treatment as a paradigm to understand how p53 may affect osteoblast differentiation. In previous studies we have shown estrogen treatment to increase p53 functional activity in osteoblasts. Estrogen has been suggested to inhibit apoptosis in osteoblasts. Since the significance of a p53 increase during estrogen treatment is not apparent, we investigated the environment within osteoblasts after treatment with estrogen. We observed two peaks of p53 activity during continuous treatment of 17-[beta]-estradiol (E2) for 72h. The gene expression profile of different cell cycle regulators and apoptosis related genes at different times during treatment with 17-[beta]-estradiol were tested using gene arrays. There was an early increase in expression of several genes involved in apoptosis. This was followed by changes in expression of several genes involved in cell survival and stress response. The second peak of activity was associated with increase in expression of cell cycle regulators. Our results suggest that p53 activity may be a result of activation of several signaling pathways involving apoptosis, cell survival and cell cycle arrest. P53 may have a role in integrating these responses, which eventually results in cell cycle arrest and expression of differentiation markers.


Subject(s)
Apoptosis/drug effects , Cell Differentiation/drug effects , Estradiol/pharmacology , Gene Expression Regulation/drug effects , Osteoblasts/metabolism , Signal Transduction/physiology , Tumor Suppressor Protein p53/metabolism , Apoptosis/genetics , Blotting, Western , Cell Cycle Proteins/metabolism , Cell Survival/physiology , Chromatography, Thin Layer , Estradiol/metabolism , Humans , Oligonucleotide Array Sequence Analysis , Osteoblasts/drug effects
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