<scp>Age‐Associated</scp> Changes in Knee Osteoarthritis, <scp>Pain‐Related</scp> 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. We undertook this study to characterize age‐associated changes in knee OA, pain‐related behaviors, and dorsal root ganglion (DRG) molecular phenotypes in mice of both sexes. Methods Male or female C57BL/6 mice 6 or 20 months of age were evaluated for histopathologic knee OA, pain‐related behaviors, and L3–L5 DRG immune characterization via flow cytometry. DRG gene expression in older mice and humans was also examined. Results Male mice at 20 months of age had worse cartilage degeneration than 6‐month‐old mice. Older female mouse knees showed increased cartilage degeneration but to a lesser degree than those of male mice. 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 mouse DRGs showed increased expression of Ccl2 and Ccl5 , and older female mouse DRGs showed increased Cxcr4 and Ccl 3 expression compared to 6‐month‐old mouse DRGs, among other differentially expressed genes. Human DRG analysis from 6 individuals >80 years of age revealed elevated CCL2 in men compared to women, whereas CCL3 was higher in DRGs from women. Conclusion We found 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 OA therapies. image