Aberrant subchondral osteoblastic metabolism modifies Nav1.8 for osteoarthritis

Jianxi Zhu, Gehua Zhen, Senbo An, Xiao Wang, Mei Wan, Yusheng Li, Zhiyong Chen, Yun Guan, Xinzhong Dong, Yihe Hu, Xu Cao

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere57656
Pages (from-to)1-57
Number of pages57
JournaleLife
Volume9
DOIs
StatePublished - May 2020

Keywords

  • Na1.8
  • Osteoarthritis
  • Osteoblast
  • Pain
  • Prostaglandin E2

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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