Vagotomy accelerates the onset of symptoms during early disease progression and worsens joint-level pathogenesis in a male rat model of chronic knee osteoarthritis

Objective: Low vagal tone is common in osteoarthritis (OA) comorbidities and results in greater peripheral inflammation. Characterizing vagal tone's role in OA pathogenesis may offer insights into OA's influences beyond the articular joint. We hypothesized that low vagal tone would accelerate onset of OA-related gait changes and worsen joint damage in a rat knee OA model. Methods: Knee OA was induced in male Sprague Dawley rats by transecting the medial collateral ligament and medial meniscus. Then, left cervical vagus nerve transection (VGX, n = 9) or sham VGX (non-VGX, n = 6) was performed. Gait and tactile sensitivity were assessed at baseline and across 12 weeks, with histology and systemic inflammation evaluated at endpoint. Results: At week 4, VGX animals showed limping gait characteristics through shifted stance times from their OA to non-OA limb (p = 0.055; stance time imbalance = 1.6 +/- 1.6%) and shifted foot strike locations (p < 0.001; spatial symmetry = 48.4 +/- 0.835%), while non-VGX animals walked with a balanced and symmetric gait. Also at week 4, while VGX animals had a mechanical sensitivity (50% withdrawal threshold) of 13.97 +/- 7.70 compared to the non-VGX animal sensitivity of 29.74 +/- 9.43, this difference was not statistically significant. Histologically, VGX animals showed thinner tibial cartilage and greater subchondral bone area than non-VGX animals (p = 0.076; VGX: 0.80 +/- 0.036 mm(2) ; non-VGX: 0.736 +/- 0.066 mm(2) ). No group differences in systemic inflammation were observed at endpoint. Conclusions: VGX resulted in quicker onset of OA-related symptoms but remained unchanged at later timepoints. VGX also had thinner cartilage and abnormal bone remodeling than non-VGX. Overall, low vagal tone had mild effects on OA symptoms and joint remodeling, and not at the level seen in common OA comorbidities.