Background/Purpose: Chronic pain is a major debilitating problem in many inflammatory diseases including rheumatoid arthritis and osteoarthritis. Pain is an important problem during active disease but often continues during minimal disease activity or even after sustained remission. Chronic pain is often difficult to treat and new insights into the mechanisms underpinning the development of chronic pain are needed. Recently we have identified involvement of the 5p15.2 region that includes the coding region for CCT5 and FAM173b in chronic widespread pain (CWP). The minor allele frequency of two highly correlated SNPs (rs13361160 and rs2386592) annotated to the 5p15.2 region were associated with a 30% increased risk for CWP. 130 associated SNPs were identified that were in linkage disequilibrium with these two top SNPs and included one non-synonymous SNP (rs2438652) located in the coding region in the FAM173B gene. Here we examined the role of FAM173b in regulating chronic inflammatory pain.

Methods: FAM173b antisense oligonucleotides (asODN) were injected intrathecally to establish in vivo knockdown of FAM173b in sensory neurons. Transient inflammatory hyperalgesia was induced by intraplantar injection of a low dose of carrageenan in mice. Chronic inflammatory hyperalgesia was induced by intraplantar injection of Complete Freund Adjuvant (CFA). Development of hyperalgesia was assessed by using the Hargreaves’ method to determine heat sensitivity, while Von Frey hairs were used to assess mechanical sensitivity.

Results: FAM173b is upregulated in the lumbar spinal cord and dorsal root ganglion after peripheral inflammation induced by intraplantar CFA. Knockdown of FAM173b by intrathecal injection of FAM173b antisense oligodeoxynucleotides reduced the intensity of transient carrageenan-induced inflammatory thermal and mechanical hyperalgesia. Importantly, FAM173b knockdown during established chronic CFA-induced hyperalgesia completely attenuated CFA-induced persistent thermal and mechanical hyperalgesia. Mechanistically, intrathecal FAM173b asODN treatment completely prevented CFA-induced increase in Iba1+ microglia/macrophages with an activated phenotype in the spinal cord and DRG.  Moreover, FAM173b asODN treatment reduced spinal cord and DRG Iba1 mRNA expression. Intrathecal FAM173b asODN prevented CFA-induced upregulation of the pro-inflammatory cytokine TNF-a in the lumbar spinal cord and dorsal root ganglia. In contrast, FAM173b asODN did not affect CFA-induced increase in BDNF mRNA expression in the DRG.

Conclusion: We have identified an as yet unrecognized role for FAM173b in chronic inflammatory pain. We propose that FAM173b promotes spinal cord and DRG microglia/macrophages activation and subsequent pro-inflammatory cytokine production leading to persistent inflammatory pain.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-role-of-fam173b-as-a-newly-identified-regulator-of-chronic-pain/