EP4 agonist KMN-159 induces osteogenesis in rodent and porcine dental models.

Abstract

The selective EP4 receptor (PTGER4) agonist KMN-159 stimulates osteoblast function and may support applications in dental bone tissue regeneration and tissue engineering. The goal of this study was to further validate stimulation of osteogenic differentiation ex vivo and in vivo by KMN-159. We tested KMN-159 in cultured human bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) and rat BM-MSCs grown in a three-dimensional deproteinized bone explant culture model. The effects of KMN-159 treatment in vivo were also investigated in two different alveolar bone repair models (i.e., male rat tooth socket model with and without a dental implant), as well as in a pilot study with a dental repair model in which human implants were insert into the mandibles of male minipigs. Our results show that KMN-159 promotes osteogenic differentiation of human BM-MSCs, (e.g., ALPL enzyme and mineralization) and the temporal expression of osteoblast markers (e.g., RUNX2, SP7, BMP2, TNFRSF11B) and extracellular matrix (ECM) proteins (e.g., BGLAP). KMN-159 also stimulates osteogenesis in rat BM-MSCs in bone-derived 3D scaffolds by accelerating proliferation and modulating expression of osteoblast phenotype markers. In the in vivo studies of bone repair KMN-159 increases bone volume in the tooth socket or around the coronal aspect of the implant in the rat maxillary extraction models. Similar results were obtained in the porcine dental implant repair model. We conclude that KMN-159 is a viable pharmacotherapeutic candidate to promote bone mass accrual or to support bone tissue engineering in dental, craniofacial and skeletal applications.