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https://hdl.handle.net/2440/9592
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Type: | Journal article |
Title: | A crucial role of caspase-3 in osteogenic differentiation of bone marrow stromal stem cells |
Author: | Miura, M. Chen, X. Allen, M. Bi, Y. Gronthos, S. Seo, B. Lakhani, S. Flavell, R. Feng, X. Robey, P. Young, M. Shi, S. |
Citation: | Journal of Clinical Investigation, 2004; 114(12):1704-1713 |
Publisher: | Amer Soc Clinical Investigation Inc |
Issue Date: | 2004 |
ISSN: | 0021-9738 1558-8238 |
Statement of Responsibility: | Masako Miura, Xiao-Dong Chen, Matthew R. Allen, Yanming Bi, Stan Gronthos, Byoung-Moo Seo, Saquib Lakhani, Richard A. Flavell, Xin-Hua Feng, Pamela Gehron Robey, Marian Young, and Songtao Shi |
Abstract: | Caspase-3 is a critical enzyme for apoptosis and cell survival. Here we report delayed ossification and decreased bone mineral density in caspase-3-deficient (Casp3(-/-) and Casp3(+/-)) mice due to an attenuated osteogenic differentiation of bone marrow stromal stem cells (BMSSCs). The mechanism involved in the impaired differentiation of BMSSCs is due, at least partially, to the overactivated TGF-beta/Smad2 signaling pathway and the upregulated expressions of p53 and p21 along with the downregulated expressions of Cdk2 and Cdc2, and ultimately increased replicative senescence. In addition, the overactivated TGF-beta/Smad2 signaling may result in the compromised Runx2/Cbfa1 expression in preosteoblasts. Furthermore, we demonstrate that caspase-3 inhibitor, a potential agent for clinical treatment of human diseases, caused accelerated bone loss in ovariectomized mice, which is also associated with the overactivated TGF-beta/Smad2 signaling in BMSSCs. This study demonstrates that caspase-3 is crucial for the differentiation of BMSSCs by influencing TGF-beta/Smad2 pathway and cell cycle progression. |
Keywords: | Femur Bone Marrow Cells Cells, Cultured Osteoclasts Osteoblasts Stromal Cells Stem Cells Animals Mice, Inbred C3H Mice, Transgenic Humans Mice Disease Progression Titanium beta-Galactosidase Caspases Transforming Growth Factor beta DNA-Binding Proteins Trans-Activators Tomography, X-Ray Computed Cell Transplantation Signal Transduction Cell Cycle Apoptosis Cell Differentiation Cell Proliferation Cell Survival Down-Regulation Dose-Response Relationship, Drug Heterozygote Phenotype Transgenes X-Rays Time Factors Adult Female Tumor Suppressor Protein p53 Proto-Oncogene Proteins p21(ras) Smad2 Protein Caspase 3 Cellular Senescence |
DOI: | 10.1172/JCI200420427 |
Published version: | http://dx.doi.org/10.1172/jci20427 |
Appears in Collections: | Aurora harvest Medicine publications |
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