Prostaglandin E2 (
PGE2), a major
cyclooxygenase-2 (COX-2) product, is highly secreted by the osteoblast lineage in the subchondral bone tissue of
osteoarthritis (OA) patients. However,
NSAIDs, including
COX-2 inhibitors, have severe side effects during OA treatment. Therefore, the identification of novel drug targets of
PGE2 signaling in OA progression is urgently needed. Osteoclasts play a critical role in subchondral bone homeostasis and OA-related
pain. However, the mechanisms by which
PGE2 regulates osteoclast function and subsequently subchondral bone homeostasis are largely unknown. Here, we show that
PGE2 acts via EP4 receptors on osteoclasts during the progression of OA and OA-related
pain. Our data show that while
PGE2 mediates migration and osteoclastogenesis via its EP2 and EP4 receptors, tissue-specific knockout of only the EP4 receptor in osteoclasts (EP4LysM) reduced
disease progression and
osteophyte formation in a murine model of OA. Furthermore, OA-related
pain was alleviated in the EP4LysM mice, with reduced
Netrin-1 secretion and CGRP-positive sensory innervation of the subchondral bone. The expression of
platelet-derived growth factor-BB (
PDGF-BB) was also lower in the EP4LysM mice, which resulted in reduced type H blood vessel formation in subchondral bone. Importantly, we identified a novel potent EP4 antagonist, HL-43, which showed in vitro and in vivo effects consistent with those observed in the EP4LysM mice. Finally, we showed that the Gαs/PI3K/AKT/MAPK signaling pathway is downstream of EP4 activation via
PGE2 in osteoclasts. Together, our data demonstrate that
PGE2/EP4 signaling in osteoclasts mediates angiogenesis and sensory neuron innervation in subchondral bone, promoting OA progression and
pain, and that inhibition of EP4 with HL-43 has therapeutic potential in OA.