Abstract
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.
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Funding
National Institutes of Health (AR071432)
- Xu Cao
National Institutes of Health (AR063943)
- Xu Cao
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
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).
Copyright
© 2020, Zhu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Aberrant subchondral osteoblastic metabolism modifies NaV1.8 for osteoarthritis
eLife 9:e57656.
https://doi.org/10.7554/eLife.57656
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