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Parathyroid hormone-related protein plays an important role in bone remodeling. Its N-terminal domain parathyroid hormone-related protein (107–111) is called osteostatin (OST). OST has demonstrated osteogenic potential when combined with biomaterials such as hydroxyapatite or bioceramics. However, the odontogenic potential of OST has not yet been reported. Therefore, the aim of this study was to determine whether OST has an odontogenic effect or a synergistic effect with mineral trioxide aggregate (MTA) in human dental pulp cells (hDPCs) and to examine the underlying signaling mechanisms involved in OST-mediated odontogenic differentiation.Viability of hDPCs on stimulation with OST or MTA was measured. Real-time polymerase chain reaction and Western blot analyses were performed to evaluate the expression levels of odontogenic markers and the activation of extracellular signal-regulated kinase (ERK). To evaluate mineralized nodule formation, alkaline phosphatase (ALP) staining and alizarin red S staining were performed. Combined effects of OST and MTA were evaluated.OST promoted odontogenic differentiation, as evidenced by the formation of mineralized nodules, induction of ALP activity, and upregulation of odontogenic markers (dentin sialophosphoprotein, dentin matrix protein-1, and ALP). Phosphorylation of ERK was increased by OST. However, ERK inhibitor (U0126) inhibited the increase in dentin sialophosphoprotein and dentin matrix protein-1 expression and mineralization induced by OST. A combination of MTA and OST upregulated odontogenic differentiation-associated gene expression and calcium nodule mineralization in hDPCs compared with MTA alone.The present study revealed that OST can promote odontogenic differentiation and mineralization through activating the ERK signaling pathway. A combination of MTA and OST showed a synergistic effect compared with MTA alone in hDPCs.OST promotes odontogenic differentiation through ERK signaling pathway in hDPCs.Combination of MTA and OST has synergistic effect compared with MTA alone in hDPCs.OST can be used as an therapeutic agent for pulp capping by itself or in combination with MTA.