Prostaglandin E2 Modulates Bone Morphogenetic Protein-2 Induced Osteogenic Differentiation on a Biomimetic 3D Nanofibrous Scaffold

It is a significant challenge to improve the efficacy of biomaterials-delivered bone morphogenetic proteins (i.e., BMP2 and 7) for bone repair. Emerging evidences suggest the traditionally inflammatory factor, prostaglandin E2 (PGE2), may serve as an intriguing target to promote bone regeneration through modulating both inflammation and osteogenesis. Therefore, we developed a three-dimensional (3D) bone matrix-mimicking nanofibrous gelatin scaffold to study the role of PGE2 and a novel and highly selective EP4 receptor agonist (EP4A), CAY10598, in osteogenic differentiation in vitro and bone formation in a mouse model. Our data indicated that EP4A, similar to PGE2, significantly improved osteoblasts differentiation on the 3D scaffolds. Importantly, EP4A significantly inhibited the tumor necrosis factor-alpha protein (TNFα), a key inflammatory cytokine, expression in macrophage cells, and largely rescued TNFα-suppressed alkaline phosphatase (ALP) activity in vitro. Surprisingly, BMP2-induced bone formation on the 3D scaffolds was significantly inhibited by EP4A after 4-week transplantation. These results indicated the complicity of the role of PGE2/EP4A-modulated TNFα expression and subsequent bone regeneration. Therefore, our study strongly suggests that substantial studies are essential before PGE2/EP4A can be developed as a new therapeutic because the closely related inflammation and osteogenesis are required to be coordinately regulated for bone regeneration.