Pain is the most prominent symptom of osteoarthritis (OA) progression. However, the relationship between pain and OA progression remains largely unknown. Here we report osteoblast secret prostaglandin E2 (PGE2) during aberrant subchondral bone remodeling induces pain and OA progression in mice. Specific deletion of the major PGE2 producing enzyme cyclooxygenase 2 (COX2) in osteoblasts or PGE2 receptor EP4 in peripheral nerve markedly ameliorates OA symptoms. Mechanistically, PGE2 sensitizes dorsal root ganglia (DRG) neurons by modifying the voltage-gated sodium channel NaV1.8, evidenced by that genetically or pharmacologically inhibiting NaV1.8 in DRG neurons can substantially attenuate OA. Moreover, drugs targeting aberrant subchondral bone remodeling also attenuates OA through rebalancing PGE2 production and NaV1.8 modification. Thus, aberrant subchondral remodeling induced NaV1.8 neuronal modification is an important player in OA and is a potential therapeutic target in multiple skeletal degenerative diseases.
Source data files have been uploaded for Figures 1-6.
- Xu Cao
- Xu Cao
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All animal experiments were approved by the Institutional Animal Care andUse of Johns Hopkins University, School of Medicine. (Protocol number: Mo18M308).
Human subjects: human study was approved by the Johns Hopkins Medicine Institutional ReviewBoards. Written informed consent and consent to publish forms were obtained from all volunteers prior to providing samples. (Protocol number: Mo18M308).
- Mone Zaidi, Icahn School of Medicine at Mount Sinai, United States
© 2020, Zhu et al.
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