Compressive force‐induced autophagy in periodontal ligament cells downregulates osteoclastogenesis during tooth movement

Abstract

Background Autophagy has recently emerged as a protective mechanism in response to compressive force and an important process in maintenance of bone homeostasis. It appears to be involved in the degradation of osteoclasts, osteoblasts, and osteocytes. The aim of this study was to investigate the role of compressive force‐induced autophagy in periodontal ligament (PDL) cells in regulating osteoclastogenesis of orthodontic tooth movement (OTM). Methods An OTM model and compressive force on PDL cells were employed to investigate the expression of autophagy markers in vivo and in vitro, respectively. Autophagosomes and autolysosomes were observed in PDL cells by transmission electron microscope (TEM) and autophagy LC3 double labelling. 3‐Methyladenine (3‐MA) and rapamycin were respectively used to inhibit and promote autophagy, and the effect of autophagy on osteoclastogenesis was explored via microcomputed tomography, hematoxylin and eosin (H&E) staining, histochemistry of titrate‐resistant acid phosphatase, and real‐time polymerase chain reaction (RT‐PCR) in vivo. Receptor activator of nuclear factor‐kappa B ligand/osteoprotegerin (RANKL/OPG) was investigated by RT‐PCR and ELISA in vitro. Results Orthodontic force‐induced autophagy was prominent on the pressured side of PDL tissues. Administration of 3‐MA downregulated bone density and upregulated osteoclasts, while rapamycin had reverse results in OTM. The autophagy activity increased initially then decreased in PDL cells during compressive force application and responded to light force. In PDL cells, administration of 3‐MA upregulated while rapamycin downregulated the RANKL/OPG ratio. Conclusion Autophagy is activated by compressive force in PDL cells. Besides, it could modulate OTM by negatively regulating osteoclastogenesis and keep bone homeostasis via RANKL/OPG signaling.

Establishment of in�vitro three‑dimensional cementocyte differentiation scaffolds to study orthodontic root resorption

“…The results of the present study suggested that cementocytes may participate in the modulation of the force-related osteoclast differentiation via the Wnt/β-catenin signaling pathway. These results are consistent with those of previous studies, where animal models have been demonstrated to exhibit root resorption and bone remodeling under compression (53,54). Other in vitro studies have also indicated that mechanoreceptor cells, including PDLs and osteocytes, detected forces and activated an intercellular signaling cascade that ultimately results in bone and tooth resorption (11,55,56).…”

Long Non-coding RNA FER1L4 Mediates the Autophagy of Periodontal Ligament Stem Cells Under Orthodontic Compressive Force via AKT/FOXO3 Pathway

“…Previous studies have showed that autophagy is regulated in specialized mechanosensitive cells, such as nucleus pulposus cells (Ma et al, 2013), podocytes (Li et al, 2016), and skeletal muscle cells (Teng et al, 2011). In current study, autophagy was activated in PDLSCs in response to compressive stress, consistent with the recent preliminary study (Chen et al, 2019). Autophagy is a form of endogenous defense mechanism to maintain cellular homeostasis and prevent mechanical damage of environmental change (Mizushima and Levine, 2010).…”

“…However, it remains largely unknown about the role of autophagy in periodontal ligament under orthodontic compressive force. Recent study preliminarily found that autophagy is increased in periodontal ligament fibroblasts under biomechanical loading (Chen et al, 2019;Memmert et al, 2019). However, the precise mechanism by which the autophagy is regulated at the compressed area during tooth movement remains unclear.…”

Current Trends in In Vitro Modeling to Mimic Cellular Crosstalk in Periodontal Tissue

“…For example, in this tissue we find variable aspects of periodontal remodeling that can be studied in the context of osteoimmunology, activation of specific internal molecular mechanisms (e.g., cell signaling, mechanotransduction, autophagy), or alteration of the ECM features. [25,26] Each of these processes is controlled by a dynamic interaction between principal cellular elements of the PDL that includes osteoblasts, fibroblasts, cementoblasts, and fiber-like ECM. All together, these components are crucial for adjacent alveolar bone formation and regeneration into functional moieties.…”