Gene expression analyses in mouse sensory ganglia determine a crucial role of NGF/TrkA in knee osteoarthritis chronification

Abstract

[EN] Objective Osteoarthritis (OA) can be experimentally induced by injecting monoiodoacetate (MIA) in the knee capsule of mice. Our aim was to assess the role of nerve growth factor (NGF)/TrkA axis in OA, identifying differentially expressed genes (DEGs) and functional pathways in knee-innervating dorsal root ganglia (DRG) from wild type (WT) and hypersensitive TrkAP782S knock-in (KI) mice after MIA injection. Method We performed saline or MIA-injection in knee joints of WT and KI mice and harvested L3-L5 DRGs at 5 and 21 days after injection, pooling males and females (n = 4/group). RNA was extracted, and microarray analysis was performed. Upon comparisons between different groups, identification of DEGs was defined as adjusted P < 0.01. Gene ontology, pathway analysis and protein interactions were conducted using Gene Set Enrichment Analysis over Gene Ontology and REACTOME databases, and STRING database. Results For each comparison regarding genotype (WT vs KI), numerous DEGs were identified but with limited overlap, being Lingo1, Socs2, and Slc4a4 already related to pain, OA and/or NGF/TrkA axis. Regarding comparisons of early vs late OA (D5 vs D21), many more DEGs were revealed including genes previously implicated in OA such as Gal, Gja1, and Lep. Moreover, we found enriched pathways in the KI_MIA group, such as gene expression, neuronal system and signal transduction, in which NTRK1 and MAPK pathways indicate specificity in the NGF/TrkA axis and in the transition from early to late OA pain. Conclusions Our results identify new mouse DEGs and pathways that demonstrate the relevance of the NGF/TrkA system in the chronification of OA pain.