<b>Caspase-mediated Apoptosis by Compressive Force Induces RANKL in Cementoblasts </b>

Abstract

Orthodontic root resorption (ORR) is one of the serious adverse events related to orthodontic treatment. Caspases are important effector molecules that mediate the process of apoptosis. However, the relationship between the mechanism underlying ORR and apoptosis in the cementum has not been clarified. In this study, human cementoblast-like cells (HCEMs) were cultured and subjected to pressure conditions assumed during orthodontic tooth movement in vitro. We then examined the effect of compressive force on caspase 3, caspase 8, receptor activator of nuclear factor -B ligand (RANKL) and osteoprotegerin(OPG)release. Furthermore, the association between root resorption and caspase was examined using z-VAD-fmk, a caspase inhibitor. In addition, we used HCEMs to examine the expression of caspase 3, caspase 8, RANKL and OPG under heavy force (HF)or optimum force(OF)in vitro. We then assessed the effects of HF with caspase inhibition using z-VAD-fmk [heavy force+inhibition(HI)group] on RANKL release from HCEMs. The application of HF induced higher levels of caspase 3 and 8 than OF. RANKL expression in cementoblasts was observed after the release of caspase 3 and 8 in the HF group. RANKL expression was significantly decreased protein production was suppressed in the HI group compared with the HF group (p < 0.05). The RANKL/OPG ratio was significantly decreased to about 57% at 9 h and 40% at 12 h in the HI group compared with the HF group(p < 0.05). These findings suggest that cementoblasts produce caspase 3 and 8 under HF conditions to activate the apoptotic pathway and then induce osteoclasts via RANKL. We considered that it as part of the mechanism involved in ORR.

Reactive oxygen species‐mediated endoplasmic reticulum stress contributes to osteocyte death induced by orthodontic compressive force

“…These findings are consistent with previous in vivo and in vitro studies, which have demonstrated that osteocyte apoptosis occurs under the orthodontic compressive force (Hoshi et al, 2014; Sakai et al, 2009). Moreover, compression can trigger apoptosis in other periodontal tissue cells like cementoblasts, osteoblasts and periodontal ligament cells (PDLCs) (Funakoshi et al, 2013; Goga et al, 2006; Yamaguchi et al, 2018). Intriguingly, the minimum force that caused osteocyte apoptosis (0.125 kPa, equivalent to 1.275 g/cm 2 ) is relatively close to that of cementoblasts (2.0 g/cm 2 ) and PDLCs (1.0 g/cm 2 ), but much higher than that of osteoblasts (2.04 × 10 −4 N/cm 2 , nearly 0.01 g/cm 2 ).…”

“…The non‐physiological mechanical stimuli are known to promote apoptosis through the mitochondrial‐ or death‐receptor‐mediated signaling pathways in several periodontal cells (Funakoshi et al, 2013; Song et al, 2016; Yamaguchi et al, 2018). However, there have been few mechanistic studies on compressive force‐induced osteocyte apoptosis.…”

RANKL+ senescent cells under mechanical stress: a therapeutic target for orthodontic root resorption using senolytics

“…8,9 For instance, a human immortalized cementoblast cell line and PDL cells significantly express RANKL under stress; [10][11][12][13][14] Orthodontic tooth movement (OTM) activates cementoblasts to induce RANKL expression. 15,16 Thus, considering the similarities between osteoclastogenesis and odontoclastogenesis, 17 osteoporosis drugs (e.g., bisphosphate, which causes direct cell death, and denosumab, an anti-RANKL antibody that prevents osteoclast formation) have been exclusively investigated to treat root resorption. 18,19 However, thus far, these drugs have not yet reached clinical application.…”