SEX-DEPENDENT CORTICAL NEUROIMMUNE REMODELING ASSOCIATED WITH CHRONIC OSTEOARTHRITIS PAIN IN A MIA MOUSE MODEL

Osteoarthritis (OA) is a leading cause of disability worldwide, with chronic pain representing its most debilitating symptom. Notably, pain can persist in a subset of patients even after total joint arthroplasty, indicating the involvement of central mechanisms beyond peripheral joint pathology. Increasing evidence implicates maladaptive supraspinal plasticity within cortical regions involved in pain processing, including the anterior cingulate cortex (ACC) and anterior insular cortex (AIC). However, the contribution of cortical neuroimmune mechanisms to these alterations, and their potential sex dependence, remains poorly understood.
Using a monosodium iodoacetate (MIA) mouse model of knee OA, we investigated the temporal progression of pain sensitivity in adult male and female mice across different stages of disease development. Then, histological and immunohistochemical analyses of cortical alterations in the ACC and AIC.
At advanced stages of OA, we observed changes consistent with potential microglial activation in both cortical regions, characterized by increased microglial density and pronounced morphological remodeling. These neuroimmune alterations were associated with disrupted cortical circuit organization, including a shift in excitatory/inhibitory balance and enhanced neuronal activity. Importantly, several of these cortical changes exhibited sex-dependent differences, with females showing greater vulnerability at late stages of disease.
Together, these findings suggest that chronic OA pain is associated with sex-dependent cortical remodeling involving neuroimmune and neuronal alterations in brain regions critical for pain modulation. Such maladaptive microglia–neuron interactions may contribute to central sensitization and the persistence of pain in OA, even after resolution of peripheral joint pathology, highlighting relevant targets for future therapeutic strategies.