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

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.

Old, new and emerging functions of caspases

“…88 Osteogenic differentiation of mesenchymal stem cells involves caspase-3 activity, and caspase-3-deficient mice exhibit attenuated differentiation of the bone marrow stromal stem cells and consequently decreased bone mineral density. 89 It is noteworthy that the process of normal osteoblast differentiation requires the transient and potent activation of other caspases, including caspase-8 and -2, without any increase in osteoblast apoptotic cell death. 90 Caspase-7 has an additional role in proper functioning of odontoblasts as caspase-7 knockout mice show reduced dental mineralization.…”

Osteosarcoma

“…(1,3,4) Cells of this type exist in multiple compartments and include the adherent cell populations obtained in a bone marrow aspiration, hence the intramedullary space within bones, with cells of this type generally referred to as mesenchymal stem cells. (12) They also include osteoblasts, which are concentrated along both the endosteal and periosteal surfaces of the bone and involved in fracture repair and remodeling. Longitudinal growth of long bones is accomplished by proliferation of chondrocytes at the growth plates with subsequent bone mineralization as part of endochondral ossification, although the site of initial tumor formation (intramedullary or surface lesions) is a matter of speculation based on the radiographic appearance of the primary tumor.…”

Vanin-1 Pantetheinase Drives Increased Chondrogenic Potential of Mesenchymal Precursors in ank/ank Mice

“…We speculate that regulation of GSH stores by Vanin-1 and regional accumulation of cysteamine could have effects on chondrogenic differentiation and on chondrocyte growth and mineralization in ank/ank mice that change over time. Physiological cysteamine and cystamine interconversion 26 also could indirectly regulate osteoblast differentiation and chondrocyte maturation in ank/ank mice, since cystamine inhibits caspase-3 [41][42][43] and transglutaminase activities, 41,44,45 respectively.…”