A crucial role of caspase-3 in osteogenic differentiation of bone marrow stromal stem cells

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

Research output: Contribution to journalArticle

182 Citations (Scopus)

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-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.

Original languageEnglish (US)
Pages (from-to)1704-1713
Number of pages10
JournalJournal of Clinical Investigation
Volume114
Issue number12
DOIs
StatePublished - Jan 1 2004
Externally publishedYes

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Mesenchymal Stromal Cells
Caspase 3
Stem Cells
Caspase Inhibitors
Cell Aging
Osteogenesis
Bone Density
Cell Survival
Cell Cycle
Down-Regulation
Apoptosis
Bone and Bones
Enzymes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

A crucial role of caspase-3 in osteogenic differentiation of bone marrow stromal stem cells. / Miura, Masako; Chen, Xiao-dong; Allen, Matthew R.; Bi, Yanming; Gronthos, Stan; Seo, Byoung Moo; Lakhani, Saquib; Flavell, Richard A.; Feng, Xin Hua; Robey, Pamela Gehron; Young, Marian; Shi, Songtao.

In: Journal of Clinical Investigation, Vol. 114, No. 12, 01.01.2004, p. 1704-1713.

Research output: Contribution to journalArticle

Miura, M, Chen, X, Allen, MR, Bi, Y, Gronthos, S, Seo, BM, Lakhani, S, Flavell, RA, Feng, XH, Robey, PG, Young, M & Shi, S 2004, 'A crucial role of caspase-3 in osteogenic differentiation of bone marrow stromal stem cells', Journal of Clinical Investigation, vol. 114, no. 12, pp. 1704-1713. https://doi.org/10.1172/JCI20427
Miura, Masako ; Chen, Xiao-dong ; Allen, Matthew R. ; Bi, Yanming ; Gronthos, Stan ; Seo, Byoung Moo ; Lakhani, Saquib ; Flavell, Richard A. ; Feng, Xin Hua ; Robey, Pamela Gehron ; Young, Marian ; Shi, Songtao. / A crucial role of caspase-3 in osteogenic differentiation of bone marrow stromal stem cells. In: Journal of Clinical Investigation. 2004 ; Vol. 114, No. 12. pp. 1704-1713.
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