Age-associated changes in knee osteoarthritis, pain-related behaviors, and dorsal root ganglia immunophenotyping of male and female mice

Objective Osteoarthritis (OA) is a leading cause of chronic pain, yet OA pain management remains poor. Age is the strongest predictor of OA development, and mechanisms driving OA pain are unclear. While injury-induced OA models are useful, only a subset of OA is linked to traumatic injury. Here, we aimed to characterize age-associated joint damage, mechanical sensitization, and dorsal root ganglia (DRG) immune phenotypes in mice of both sexes. Methods Male or female mice aged 6- or 20-months old were evaluated for histopathologic knee OA, pain-related behaviors, and L3-L5 dorsal root ganglia (DRG) immune characterization via flow cytometry. DRG gene expression in aged mice and humans was also examined. Results Twenty-month old male mice had worse cartilage degeneration than 6-month old mice. Older female knees showed increased cartilage degeneration, but to a lesser degree than males. Older mice of both sexes had worse mechanical allodynia, knee hyperalgesia, and grip strength compared to younger mice. For both sexes, DRGs from older mice showed decreased CD45+ cells, and a significant increase in F4/80+ macrophages and CD11c+ dendritic cells. Older male DRGs showed increased expression of Ccl2 and Ccl5 and older female DRGs showed increased Cxcr4 and Ccl 3 compared to 6-month DRGs, among other differentially expresssed genes. Human DRG analysis from six individuals >80 years old revealed elevated CCL2 in male DRGs compared to females, whereas CCL3 was higher in female DRGs. Conclusions Here we show that aging in male and female mice is accompanied by mild knee OA, mechanical sensitization, and changes to immune cell populations in the DRG, suggesting novel avenues for development of analgesic therapies. ### Competing Interest Statement The following authors declare no conflicts of interest: TG, AMO, SI, MJW, JL, EBP, CRS, TMG and REM. AMM received consulting fees from Asahi Kasei Pharma Corporation, Eli Lilly, Pfizer, and Collegium Pharma.