Autophagy Plays Multiple Roles in the Soft-Tissue Healing and Osseointegration in Dental Implant Surgery-A Narrative Review

Abstract

Dental endo-osseous implants have become a widely used treatment for replacing missing teeth. Dental implants are placed into a surgically created osteotomy in alveolar bone, the healing of the soft tissue lesion and the osseointegration of the implant being key elements to long-term success. Autophagy is considered the major intracellular degradation system, playing important roles in various cellular processes involved in dental implant integration. The aim of this review is an exploration of autophagy roles in the main cell types involved in the healing and remodeling of soft tissue lesions and implant osseointegration, post-implant surgery. We have focused on the autophagy pathway in macrophages, endothelial cells; osteoclasts, osteoblasts; fibroblasts, myofibroblasts and keratinocytes. In macrophages, autophagy modulates innate and adaptive immune responses playing a key role in osteo-immunity. Autophagy induction in endothelial cells promotes apoptosis resistance, cell survival, and protection against oxidative stress damage. The autophagic machinery is also involved in transporting stromal vesicles containing mineralization-related factors to the extracellular matrix and regulating osteoblasts' functions. Alveolar bone remodeling is achieved by immune cells differentiation into osteoclasts; autophagy plays an important and active role in this process. Autophagy downregulation in fibroblasts induces apoptosis, leading to better wound healing by improving excessive deposition of extracellular matrix and inhibiting fibrosis progression. Autophagy seems to be a dual actor on the scene of dental implant surgery, imposing further research in order to completely reveal its positive features which may be essential for clinical efficacy.

Keywords: autophagy; dental implant; osseointegration; osteoimmunity; wound healing.

Figure 1

The oral soft-tissue wound healing, a highly ordered biological process, comprises the following overlapping phases: (1) hemostasis and inflammation, (2) proliferative phase, and (3) remodeling phase.

Figure 2

Molecular events sequence in autophagy: (1) activation of the ULK complex by signals such as starvation; (2) phagophore assembly at the phagophore assembly site; (3) phagophore elongation to the autophagosome; (4) the autophagosome fuses with a lysosome, resulting the formation of autolysosome.

Figure 3

(a): Autophagy roles in the main cellular types involved in oral soft tissue healing post-implant surgery: (1) promotes neutrophil proliferation and migration; (2) ensures the survival, migration, and proliferation of macrophages (MFs); mediates M1-M2 phenotype conversion of MFs; (3) sustains the survival of endothelial cells (ECs) and controls their migratory and tube-forming functions; (4) ensures the survival, migration, and proliferation of fibroblasts (FBs); mediates myofibroblasts (MFBs) differentiation from FBs; (5) plays important roles in activating migration, proliferation and differentiation of keratinocytes (KCs). (b): Autophagy roles in the main cellular types involved in the osseointegration of the dental implant: (1) by mediating M1-M2 MFs phenotypes interconversion, autophagy controls osteoclasts (OCs) differentiation; (2) plays a key role in the osteoblast (OBs) driven-mineralization during bone formation; (3) is important for the differentiation and the bone resorption function of (OCs).

Figure 4

An overview of autophagy multiple roles in the oral soft-tissue healing phases and osseointegration in dental implant surgery.