MG132 facilitates dentin regeneration by modulating inflammation and odontoblast differentiation

Although regeneration of the dentin-pulp complex is a key goal in endodontic therapy, pulpal inflammation can impede effective tissue repair and sustained healing. Recent studies suggest that proteasome inhibitors can modulate key cellular processes involved in tissue regeneration. MG132 (carbobenzoxy-Leu-Leu-leucinal) is a reversible proteasome inhibitor used in experimental settings to study these mechanisms, although its efficacy in in vivo models of dental tissue regeneration remains unclear. In this study, we investigated the effects of MG132 in modulating inflammation and regenerating dentin using a murine pulp exposure model. Involved signaling pathways were examined using in vitro-cultivated human dental pulp stem cells (hDPSCs). MG132 was then locally administered into exposed pulp cavities. Inflammation, cellular differentiation, and hard tissue formation were assessed using histological staining, immunohistochemistry, and micro-computed tomography, respectively. Following MG132 treatment of hDPSCs, RT-qPCR revealed the elevated expression of Wnt signaling-related molecules involved in dentin formation. At day 5 of treatment, MG132 significantly reduced the expression of inflammatory markers, including myeloperoxidase, F4/80, nuclear factor kappa B, and tumor necrosis factor-alpha, indicating attenuation of early excessive inflammatory responses. In addition, treatment enhanced odontoblast differentiation and mineralization, as evidenced by the upregulated expression of Nestin, collagen type I alpha-1, transforming growth factor beta 1, runt-related transcription factor 2, osteopontin, and osteocalcin. Moreover, at 42 days, MG132-treated samples exhibited distinct dentin bridge formation.