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 journalArticlepeer-review

237 Scopus citations

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 - Dec 2004
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine

Fingerprint

Dive into the research topics of 'A crucial role of caspase-3 in osteogenic differentiation of bone marrow stromal stem cells'. Together they form a unique fingerprint.

Cite this