Translation Approach for Dentine Regeneration Using GSK-3 Antagonists

Abstract

The canonical Wnt/β-catenin signaling pathway is crucial for reparative dentinogenesis following tooth damage, and the modulation of this pathway affects the rate and extent of reparative dentine formation in damaged mice molars by triggering the natural process of dentinogenesis. Pharmacological stimulation of Wnt/β-catenin signaling activity by small-molecule GSK-3 inhibitor drugs following pulp exposure in mouse molars results in reparative dentinogenesis. The creation of similar but larger lesions in rat molars shows that the adenosine triphosphate (ATP)–competitive GSK-3 inhibitor, CHIR99021 (CHIR), and the ATP noncompetitive inhibitor, Tideglusib (TG), can equally enhance reparative dentine formation to fully repair an area of dentine damage up to 10 times larger, mimicking the size of small lesions in humans. To assess the chemical composition of this newly formed dentine and to compare its structure with surrounding native dentine and alveolar bone, Raman microspectroscopy analysis is used. We show that the newly formed dentine comprises equal carbonate to phosphate ratios and mineral to matrix ratios to that of native dentine, both being significantly different from bone. For an effective dentine repair, the activity of the drugs needs to be restricted to the region of damage. To investigate the range of drug-induced Wnt-activity within the dental pulp, RNA of short-term induced (24-h) molars is extracted from separated roots and crowns, and quantitative Axin2 expression is assayed. We show that the activation of Wnt/β-catenin signaling is highly restricted to pulp cells in the immediate location of the damage in the coronal pulp tissue with no drug action detected in the root pulp. These results provide further evidence that this simple method of enhancement of natural reparative dentinogenesis has the potential to be translated into a clinical direct capping approach.

Macrophage modulation of dental pulp stem cell activity during tertiary dentinogenesis

“…Following a dental intervention, the host biological response to treatment is to secrete tertiary dentine. In deep cavities, reparative dentine is formed and Neves et al 20 and Zaugg et al 28 showed that Wnt activation via GSK-3 antagonists enhances biologic reparative dentine repair in dental cavities. Reparative dentine formation, however, is a complex process that requires a mild inflammatory response within the tooth 29,30 .…”

Odontoblast markers and dentine reactions in carious primary molars with and without hypomineralised enamel defects

“…Implantation of an exogenous liposome‐reconstituted form of Wnt3A protein into mice molar pulps activated Wnt/β‐catenin signalling, promoted differentiation of odontoblast‐like cells and reduced apoptosis, culminating in a superior repair response 14 . Similarly, direct pulp capping of mice molars with glycogen synthase kinase 3 (GSK‐3) inhibitors, Wnt/β‐catenin signalling agonists, resulted in greater reparative dentine formation at pulp exposure sites when compared with plain collagen sponge or mineral trioxide aggregate 27‐29 . The reparative dentine was found to be close to native dentine compositions at defect sizes translatable to small human lesions 29 .…”

Endodontic regeneration: hard shell, soft core

“…4 c) [ 44 ]. In a follow-up study, the authors took a closer look at the hard tissue formed in this model, now also in rats with even larger defects [ 46 ]. The formed tissue resembled dentin in its mineral composition, but no tubular structure was observed.…”

“…The formed tissue resembled dentin in its mineral composition, but no tubular structure was observed. Furthermore, it was shown that the pharmaceutical activity of the small-molecule inhibitor was spatially limited and without any systemic side effects [ 46 ].…”