Autophagy in orthodontic tooth movement: advances, challenges, and future perspectives

Abstract

Orthodontics aims to correct misaligned teeth by repositioning them into their proper three-dimensional positions through periodontal remodeling triggered by orthodontic forces. Orthodontic tooth movement (OTM) is an aseptic inflammation process characterized by osteoclast-mediated bone resorption on the compression side and osteoblast-induced bone deposition on the tension side. Orthodontic forces primarily include compressive force (CF), tensile force (TF), and flow shear stress (FSS), meanwhile, hypoxia is concomitantly induced during force application. Autophagy is a highly conserved catabolic mechanism mediating cellular degradation and recycling and is classified into three main types: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA), distinguished by their substrate delivery mechanisms to lysosomes. This review will first outline common autophagy classifications, describe the basic process of macroautophagy, and discuss autophagy regulators, as well as the theories of OTM mechanisms. Furthermore, it will systematically elucidate roles and mechanisms of autophagy in OTM across different cell types, with specific emphasis on hypoxia, CF, TF, and FSS. Additionally, mitophagy and CMA will be addressed. Hopefully, this comprehensive analysis aims to provide a theoretical foundation for accelerating OTM and mitigating orthodontically induced inflammatory root resorption through autophagy modulation.

Keywords: Autophagy; Hypoxia; Mechanical force; Mechanism; Orthodontic tooth movement; Orthodontically induced inflammatory root resorption.

Fig. 1

Three main types of autophagy and the basic processes. Macroautophagy starts with a phagophore, and forms autophagosome containing substrates, then fuses with a lysosome, thereby degrading substrates. Microautophagy wraps cargoes through a dimpled lysosomal membrane. Chaperone-mediated autophagy is mediated by chaperones to transfer substrates into lysosomes

Fig. 2

Target points of autophagy regulators applied in OTM. Rapa inhibits MTORC1 to initiate autophagy. UA activates AMPK to induce mitophagy. LiCl induces autophagy by inhibiting IMPase. 3-MA, Wortmannin, and LY294002 suppress autophagy via inhibition of class III PI3K and blocking phagophore formation. Mdivi-1 and CsA inhibit mitochondrial permeability transition and prevent mitochondrial function. Knockdown of ATG5 and ATG7 prevents autophagosome formation, therefore blocking autophagy. BafA1 prevents the maturation of autolysosomes and inhibits lysosomal hydrolases. CQ and HCQ prevent the final maturation of autolysosomes, thus interrupting the autophagic flux and obstructing the content degradation. Rapa, Rapamycin; MTORC1, mechanistic target of rapamycin complex 1; UA, Urolithin A; AMPK, adenosine monophosphate-activated protein kinase; LiCl, lithium chloride; IMPase, inositol monophosphatase; 3-MA, 3-Methyladenine; PI3K, phosphatidylinositol 3-kinase; CsA, Cyclosporin A; ATG5/7, autophagy-related 5/7; BafA1, Bafilomycin A1; CQ, chloroquine; HCQ, hydroxychloroquine

Fig. 3

Several prominent mechanism hypotheses of OTM. In 1911, Oppenheim laid out two hypotheses. Schwarz fully completed the ‘Compression-Tension Hypothesis’ in 1932. Stuteville and Bien proposed the ‘Hydraulic Theory’ and ‘Hydrodynamic Damping Hypothesis’ in 1938 and 1966, respectively. In 1969, Baumrind advocated a ‘Comprehensive Theory’. Alikhani et al. introduced the ‘Biphasic Theory’ of OTM in 2018. Li et al. proposed a ‘New Hypothetical Theory’ in 2021

Fig. 4

Roles of autophagy in OTM. Under CF, autophagy is activated in most OTM-related cells except for cementoblasts, with inconsistent results of osteoclast autophagy. TF, FSS, and hypoxia activate autophagy in studied cells

Fig. 5

Effects and mechanisms of autophagy in OTM. CF inhibits autophagy to suppress cementogenesis but activates autophagy to promote osteogenesis, apoptosis, and M1 polarization and to impede cell migration. CF differently regulates autophagy and affects osteoclastogenesis. TF induces autophagy to enhance osteogenesis, cementogenesis, spherical change, and anaerobic oxidation, but to decrease cell death and osteoclastogenesis. Hypoxia enhances autophagy to inhibit osteogenesis but increases osteoclastogenesis and apoptosis CF, compressive force; TF, tensile force; CMS, Cyclic mechanical stretch; CTS, cyclic tensile strain/cyclic tensile stress; STS, static tensile strain; SMS, static mechanical stretch; FoxO3, Forkhead box O3; IL-6, Interleukin 6; MTORC2, mechanistic target of rapamycin complex 2; TFE3, transcription factor E3; NLRP3, nucleotide-binding domain (NBD), leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3; BECN1, Beclin-1; p-AKT, phosphorylation of protein kinase B; MMP9/13, matrix metalloproteinase 9/13; YAP, Yes-associated protein; ULK1, unc-51 like autophagy activating kinase 1; AMPK, adenosine monophosphate-activated protein kinase; p-ERK1/2, phosphorylation of extracellular signal-regulated kinase 1/2