TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

Abstract

RUNX2 is a bone-specific transcription factor that plays a critical role in prenatal bone formation and postnatal bone development. It regulates the expression of genes that are important in committing cells into the osteoblast lineage. There is increasing evidence that RUNX2 is involved in osteoblast proliferation. RUNX2 expression increases during osteoblast differentiation, and recent data even suggest that it acts as a proapoptotic factor. The cytokine tumor necrosis factor a (TNF-a) is known to modulate osteoblast functions in a manner that depends on the differentiation stage. TNF-a affects the rate at which mesenchymal precursor cells differentiate into osteoblasts and induces apoptosis in mature osteoblasts. Thus we sought to establish whether or not the effects of TNF-a and fetal calf serum on proliferation and apoptosis in human mesenchymal stem cells (hMSCs) were dependent on RUNX2 level and activity. We transfected hMSCs with small interfering RNAs (siRNAs) directed against RUNX2 and found that they proliferated more quickly than control hMSCs transfected with a nonspecific siRNA. This increase in proliferation was accompanied by a rise in cyclin A1, B1, and E1 expression and a decrease in levels of the cyclin inhibitor p21. Moreover, we observed that RUNX2 silencing protected hMSCs from TNF-a's antiproliferative and apoptotic effects. This protection was accompanied by the inhibition of caspase-3 activity and Bax expression. Our results confirmed that RUNX2 is a critical link between cell fate, proliferation, and growth control. This study also suggested that, depending on the osteoblasts' differentiation stage, RUNX2 may control cell growth by regulating the expression of elements involved in hormone and cytokine sensitivity. ß

Role of IRAK1 on TNF-induced Proliferation and NF-?B Activation in Human Bone Marrow Mesenchymal Stem Cells

“…Opposing effects of TNF-a on MSC proliferation have also been reported. Boker et al reported that TNF-a caused an increase in the invasive and proliferative properties of human bone marrow-derived mesenchymal stem cells (hBMSCs) [12], but Ghali et al reported that TNF-a induced an inhibition of the proliferative and apoptotic properties of hBMSCs [13].…”

Inflammatory Periprosthetic Bone Loss

“…A study of the literature suggests that analysis of the involvement of osteoblasts in periprosthetic osteolysis has generally been limited to direct suppressive effect of particles on osteoblasts rather than through consideration of the possible effects of a pro-inflammatory environment on osteoblast biology. Considering that TNF-is also a potent inhibitor of osteoblast differentiation (Ghali et al, 2010;Yamazaki et al, 2009;Zhou et al, 2006;Karmakar et al 2010), additional investigations into possible involvement of particleactivated macrophages in the impaired osteogencity mediated by proinflammatory cytokines including TNF-would appear to be warranted. Although insufficient attention has been paid to the involvement of osteoblast, the cell type responsible for bone formation, more research should be conducted to delineate the potentially critical role of osteoblasts in periprosthetic osteolysis.…”

“…So far, most researches in terms of involvement of osteoblast in periprosthetic osteolyis have been limited to determine the direct suppressive effect of particle to osteoblast. However, the possibility that osteoblast can indirectly communicate with immune cells through many sectreted molecules such as TNF-, IL-1, ROS requires further exploration (Ghali et al, 2010;Yamazaki et al, 2009;Zhou et al, 2006). Following phagocytosis of particles and the resultant pro-inflammatory reaction, the released cytokines from macrophages can be regarded as a potent inhibitor of osteoblast differentiation.…”

Role of Transforming Growth Factor-Activated Kinase-1 on Tumor Necrosis Factor-α Actions in Human Adipose Tissue-Derived Stromal Cells

“…Opposing effects of TNF-α on MSC proliferation have also been reported. Boker et al [6] and Kim et al [14] reported that TNF-α increase the invasive and proliferative properties of human bone marrow-derived mesenchymal stem cells (hBMSCs), but Ghali et al reported conflicting results that TNF-α inhibit the proliferative and apoptotic properties of hBMSCs [15]. This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction.…”