Osteoblasts Display Different Responsiveness to TRAIL-Induced Apoptosis During Their Differentiation Process

Abstract

Apoptosis can occur throughout the life span of osteoblasts (OBs), beginning from the early stages of differentiation and continuing throughout all stages of their working life. Here, we investigated the effects of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on normal human OBs showing for the first time that the expression of TRAIL receptors is modulated during OB differentiation. In particular, the TRAIL receptor ratio was in favor of the deaths because of the low expression of DcR2 in undifferentiated OBs, differently it was shifted toward the decoys in differentiated ones. Undifferentiated OBs treated with TRAIL showed reduced cell viability, whereas differentiated OBs displayed TRAIL resistance. The OB sensitiveness to TRAIL was due to the up-regulation of DR5 and the down-regulation of DcR2. The main death receptor involved in TRAIL-reduced OB viability was DR5 as demonstrated by the rescue of cell viability observed in the presence of anti-DR5 neutralizing antibody. Besides the ratio of TRAIL receptors, the sensitivity of undifferentiated OBs to TRAIL-cytotoxic effect was also associated with low mRNA levels of intracellular anti-apoptotic proteins, such as cFLIP, the activation of caspase-8 and -3, as well as the DNA fragmentation. This study suggests that apoptotic effect exerted by TRAIL/ TRAIL-receptor system on normal human OB is strictly dependent upon cell differentiation status.

STAT-6 mediates TRAIL induced RANK ligand expression in stromal/preosteoblast cells

“…Human osteoblasts have been shown to express TRAIL-R and are resistant to TRAIL mediated apoptosis [30]. It has been reported that the osteoblast sensitivity to TRAIL was due to the upregulation of DR5 and down-regulation of DcR2 [41]. However, this study demonstrated that TRAIL induced the expression of DR5 and DcR1 receptors with no change in proliferation of human bone marrow stromal/preosteoblast cells.…”

“…Recent evidence suggests that TRAIL directly promotes osteoclast differentiation/bone resorption activity [21] and modulates osteoblast differentiation [41]. However, TRAIL regulation of RANKL expression in human bone marrow stromal/preosteoblast cells is unknown.…”

Titanium With Nanotopography Induces Osteoblast Differentiation by Regulating Endogenous Bone Morphogenetic Protein Expression and Signaling Pathway

“…The downregulation of TGFBR2, a TGF‐β receptor, may have contributed to reduce the expression of osteoblastic markers, as a significant decrease in RUNX2 and osterix was previously observed in TGFBR2 knockdown calvaria‐derived cells [Seo and Serra, ]. In addition, the overexpression of TRAIL, an apoptosis‐induced protein, could reduce osteoblastogenesis in BMPR1A‐silenced cells by promoting apoptosis of osteoblast precursors [Brunetti et al, ]. STAT1 mediates interferon signaling and also may inhibit RUNX2 nuclear translocation that is essential for osteoblast differentiation [Kim et al, ; Lian et al, ].…”

Periodontal Disease: Linking the Primary Inflammation to Bone Loss

“…Alveolar bone loss in PD could also be determined by a decreased bone formation by osteoblasts. Osteoblasts obtained from alveolar bone fragments of PD patients exhibit a weaker characteristic phenotype compared to control cells and are more sensitive to the apoptotic effect induced by TRAIL [66, 70, 71]. The sensitiveness to TRAIL-induced apoptosis is determined by the ratio between death and decoy receptors.…”