PGE2 activates EP4 in subchondral bone osteoclasts to regulate osteoarthritis

Abstract

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.

Inhibition of PGE2 in Subchondral Bone Attenuates Osteoarthritis

“…The causal role of subchondral bone PGE2 in osteoarthritis progression has recently been investigated [ 29 , 30 , 31 ]. Elevated PGE2 in subchondral bone results in both spontaneous osteoarthritis and rheumatoid arthritis, which is mediated by a deterioration of the subchondral bone structure [ 29 ].…”

“…Recently, the role of subchondral bone PGE2 in osteoarthritis progression has been investigated [ 29 , 30 , 31 ]. Elevated PGE2 levels have been found to cause aberrant subchondral bone in spontaneous osteoarthritis and rheumatoid arthritis [ 29 ].…”

“…Elevated PGE2 levels have been found to cause aberrant subchondral bone in spontaneous osteoarthritis and rheumatoid arthritis [ 29 ]. Increased PGE2/EP4 signaling promotes osteoarthritis progression, which is mediated by osteoclast-induced angiogenesis [ 30 ]. Subchondral bone remodeling is also controlled by sensory innervation [ 25 ], but whether the regulation of sensory nerves is affected by PGE2 in subchondral bone formation remains unclear.…”

Osteomyelitis, Oxidative Stress and Related Biomarkers

“…It has also been shown [ 36 ] that osteoclasts infected with S. aureus give way to massive production of PGE 2 , a molecule capable of up-regulating the production of RANKL after binding to its specific EP 4 receptor. The successful PGE 2 -EP 4 bond leads to a further and massive increase in RANKL, greatly accelerating the osteoclastogenesis rate [ 37 ].…”

Natural Compounds Affecting Inflammatory Pathways of Osteoarthritis

“…It mainly focuses on the inhibition of catabolic factors such as nitrite, iNOS, ROS, PGE2, COX-2, MMP1, MMP2, MMP3, MMP9, MMP13, ADAMTS4, IL-1, IL-6, and IL-8 while cynaroside [ 55 ] is able to inhibit both catabolic and anabolic factors including collage type II and aggrecan when being exposed to OA-induced chondrocytes. Inhibition of iNOS and nitrite prevents damage to cartilages by hindering the activity of MMP [ 35 ] while suppression of PGE2 restores homeostasis in the bone [ 125 ]. Similarly, the inhibition of COX-2 modulates controlled apoptosis and proliferation and reduces the release of PGE2 in the articular cartilage thus leading to healthy chondrocytes [ 126 ].…”