A crucial role of caspase-3 in osteogenic differentiation of bone marrow stromal stem cells.
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.
Miura
Masako
M
Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research (NIDCR), NIH, Bethesda, MD 20892, USA.
Chen
Xiao-Dong
XD
Allen
Matthew R
MR
Bi
Yanming
Y
Gronthos
Stan
S
Seo
Byoung-Moo
BM
Lakhani
Saquib
S
Flavell
Richard A
RA
Feng
Xin-Hua
XH
Robey
Pamela Gehron
PG
Young
Marian
M
Shi
Songtao
S
D000328:Adult; D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology*; D053148:Caspase 3; D020169:Caspases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D017690:Cell Transplantation; D002478:Cells, Cultured; D016922:Cellular Senescence; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005260:Female; D005269:Femur / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein; D013234:Stem Cells / Q000166:cytology; D017154:Stromal Cells / Q000378:metabolism*; D013997:Time Factors; D014025:Titanium / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014965:X-Rays; D001616:beta-Galactosidase / Q000378:metabolism
D004268:DNA-Binding Proteins; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D014025:Titanium; D001616:beta-Galactosidase; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)