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-β/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-β/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-β/Smad2 signaling in BMSSCs. This study demonstrates that caspase-3 is crucial for the differentiation of BMSSCs by influencing TGF-β/Smad2 pathway and cell cycle progression.
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, Songtao Shi
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Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans
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A non-apoptotic function of caspase-3 in pharmacologically-induced differentiation of K562 cells
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Hematopoietic Stem Cell Responsiveness to Exogenous Signals Is Limited by Caspase-3
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Cocaine exposure in vitro induces apoptosis in fetal locus coeruleus neurons by altering the Bax/Bcl-2 ratio and through caspase-3 apoptotic signaling
S Dey, CF Mactutus, RM Booze, DM Snow |
Neuroscience | 2007 |
Impaired posterior frontal sutural fusion in the biglycan/decorin double deficient mice
S Wadhwa, Y Bi, AT Ortiz, MC Embree, T Kilts, R Iozzo, LA Opperman, MF Young |
Bone | 2007 |
Caspase-8 and c-FLIPL Associate in Lipid Rafts with NF- B Adaptors during T Cell Activation
RS Misra, JQ Russell, A Koenig, JA Hinshaw-Makepeace, R Wen, D Wang, H Huo, DR Littman, U Ferch, J Ruland, M Thome, RC Budd |
The Journal of biological chemistry | 2007 |
Physiological functions of caspases beyond cell death
TQ Nhan, WC Liles, SM Schwartz |
The American Journal of Pathology | 2006 |
Cocaine exposure in vitro induces apoptosis in fetal locus coeruleus neurons by altering the Bax/Bcl-2 ratio and through caspase-3 apoptotic signaling.
Dey S, Mactutus CF, Booze RM, Snow DM |
Neuroscience | 2006 |
Defective osteogenesis of the stromal stem cells predisposes CD18-null mice to osteoporosis
Y Miura, M Miura, S Gronthos, MR Allen, C Cao, TE Uveges, Y Bi, D Ehirchiou, A Kortesidis, S Shi, L Zhang |
Proceedings of the National Academy of Sciences | 2005 |
Death receptors and caspases: role in lymphocyte proliferation, cell death, and autoimmunity.
Adam-Klages S, Adam D, Janssen O, Kabelitz D |
Immunologic research | 2005 |