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The aim of this study was to evaluate in vitro and ex vivo roles of bortezomib, a proteasome inhibitor that binds to the active site of the 26S proteasome, in tertiary dentin formation.We established pulpal access cavity preparation that was treated with or without bortezomib before direct pulp capping with a calcium hydroxide-based material. We also analyzed bone morphogenetic protein (Bmp)- and Wnt-related signaling molecules using quantitative real-time polymerase chain reaction.In the short-term observation period, the bortezomib-treated pulp specimens showed the period-altered immunolocalization patterns of nestin, CD31, and myeloperoxidase, whereas the control specimens did not. The bortezomib-treated group showed a complete dentin bridge with very few irregular tubules after 42 days. The micro-computed tomographic images showed more apparent dentin bridge structures in the treated specimens than were in the controls. Quantitative real-time polymerase chain reaction analysis showed up-regulated Bmp and Wnt.These findings revealed that treatment with 1 μmol/L bortezomib induced reparative dentin formation that facilitated the maintenance of the integrity of the remaining pulpal tissue via early vascularization and regulation of Bmp and Wnt signaling.Bortezomib facilitates reparative dentin formation through modulated vascularization and inflammatory response.Molecular mechanisms underlying bortezomib treatment would be related with Bmp and Wnt signaling.Pulpal access cavity preparation using a mice model system permits us to evaluate a range of drugs for their ability of reparative dentin formation.