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 Gas/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.

Wenhao Jiang;Yunyun Jin;Shiwei Zhang;Yi Ding;Konglin Huo;Junjie Yang;Lei Zhao;Baoning Nian;Tao P.Zhong;Weiqiang Lu;Hankun Zhang;Xu Cao;Karan Mehul Shah;Ning Wang;Mingyao Liu;Jian Luo

Yangzhi Rehabilitation Hospital(Sunshine Rehabilitation Centre),Tongji University School of Medicine,Shanghai,PR China;Shanghai Key Laboratory of Regulatory Biology,Institute of Biomedical Sciences and School of Life Sciences,East China Normal University,Shanghai,PR China;Departments of Orthopaedic Surgery and Biomedical Engineering and Institute of Cell Engineering,The Johns Hopkins University School of Medicine,Baltimore,MD,USA;Department of Oncology and Metabolism,The University of Sheffield,Sheffield,UK

骨研究（英文版）

[1]Wenhao Jiang;Yunyun Jin;Shiwei Zhang;Yi Ding;Konglin Huo;Junjie Yang;Lei Zhao;Baoning Nian;Tao P.Zhong;Weiqiang Lu;Hankun Zhang;Xu Cao;Karan Mehul Shah;Ning Wang;Mingyao Liu;Jian Luo-.PGE2 activates EP4 in subchondral bone osteoclasts to regulate osteoarthritis)[J].骨研究（英文版）,2022(02):378-393

Osteoclasts,EP4LysM,osteophyte

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