EP1 receptor: a negative regulator of the fracture healing process

Nearly 10% to 20% of all fractures have impaired healing, which has a marked impact on both the quality of life and the total cost of care. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been linked to decreased bone repair in several clinical studies. NSAIDs inhibit cyclooxygenase enzymes, and these enzymes have subsequently been shown to play a critical role in bone formation and repair. The cyclooxygenase enzymes, COX-1 and COX-2, are involved in the synthesis of prostaglandins (PGs) from arachidonic acid. While COX-1 is constitutively expressed and plays a largely homeostatic role in bone, COX-2 expression is induced by mitogens and inflammatory cytokines to upregulate PG synthesis during repair, inflammation, or tumorigenesis. COX-2−/− mice have reduced callus formation, delayed chondrogenesis, and impaired endochondral bone formation. The major downstream product of COX-2, prostaglandin E2, regulates bone formation. PGE2 has four different receptor subtypes (EP1 through EP4), each of which exerts different effects on bone. EP2 and EP4 induce bone formation through the protein kinase A (PKA) pathway, whereas EP3 inhibits bone formation. However, the effect of EP1 receptor signaling during bone formation remains unclear.

In a recent publication [1], Zhang and colleagues applied a femur fracture model to EP1-/- mice to explore the role of this receptor in bone repair. EP1-/- mouse fractures have increased formation of cartilage, increased fracture callus, and more rapid completion of endochondral ossification. Expression levels of osteoblast-specific transcripts such as Runx2, osterix and alkaline phosphatase were precociously increased in fracture calluses from the EP1-/- mice, suggesting an accelerated osteoblast differentiation. Accordingly, EP1-/- mesenchymal progenitor cells isolated from bone marrow have higher osteoblast differentiation capacity and accelerated bone nodule formation and mineralization in vitro. Fractures in EP1-/- mice also had an earlier appearance of osteoclasts, accelerated bone remodelling, and an earlier return to normal bone morphometry. In vitro differentiation of osteoclasts from splenocytes was not affected by EP1 invalidation. This suggests that the accelerated osteoclast formation in EP1-/- fractures is driven primarily by signals from osteoblasts. Finally, the authors showed that EP1 invalidation did not affect EP2 or EP4 expression or cyclic AMP production in response to PGE2.

This study establishes the EP1 receptor as a negative regulator of the fracture healing process. These results also suggest that inhibition of EP1 signaling is a potential mean to enhance fracture healing.

1. Zhang M et al. J Bone Miner Res. 2011;26:792-802.