A BIDIRECTIONAL RELATIONSHIP BETWEEN CHRONIC STRESS AND OSTEOARTHRITIS

Osteoarthritis (OA) is a chronic degenerative disease, characterized by cartilage degradation, synovial inflammation, and subchondral bone changes, leading to joint pain and stiffness. Recent research implicates the sympathetic nervous system (SNS), particularly the neurotransmitter noradrenaline (NE), in OA pathogenesis. Chronic stress, a prevalent health issue, sustains SNS activation and stimulates the hypothalamic-pituitary-adrenal (HPA) axis, elevating stress hormones such as NE and cortisol, both of which exert catabolic effects on joint cells in vitro . This study investigates in vivo the impact of chronic stress on OA progression. OA was induced in 12-week old male C57BL/6J mice using the destabilization of the medial meniscus (DMM), with sham-operated mice as controls. Half of the mice underwent 12 weeks of chronic unpredictable mild stress (CUMS). Stress was validated by monitoring behavioral changes, body weight gain, and stress hormone levels including splenic NE and serum corticosterone (CORT). OA progression was assessed by histological evaluation of cartilage and synovial tissue, micro-computed tomography (μCT), pain behavior using the Dynamic weight-bearing system, and immune cell profiling via flow cytometry in the synovium and dorsal root ganglia (DRGs). CUMS significantly elevated stress parameters, with increased splenic NE ( p <0.01) and serum corticosterone (p<0.01). Interestingly, OA alone increases NE levels in DMM mice. Stress led to reduced activity and impaired body weight gain (p<0.01). Chronic stress exacerbated OA progression, with increased cartilage damage (p<0.01), synovial inflammation (p<0.01), and calcified cartilage thickness (p<0.05). Pain behavior worsened in stressed DMM mice, as shown by reduced weight-bearing on the affected paw (p<0.01) and diminished rearing time (p<0.01). In the synovium, CUMS elevated proinflammatory CD3 + T-cells (p<0.01) and CD11b + F4/80 + Ly6C high proinflammatory monocytes (p<0.01), while reducing anti-inflammatory CD301 + CD150 - M2a macrophages (p<0.05). These immune changes appeared early after 4 weeks but partially regressed by week 12. In the DRGs, CUMS increased proinflammatory CD11b + Ly6G + neutrophils (p<0.05) and CD3 + T-cells (p<0.01). Our results demonstrate that chronic stress exacerbates OA progression, indicated by increased cartilage degeneration, calcification, synovial inflammation, and pain. The observed elevation in synovial inflammation and pain can be attributed to the stress-induced mobilization and migration of pro-inflammatory immune cells to the synovium and DRGs. Interestingly, OA itself induced an increased release of NE and CORT. Our findings highlight the bidirectional relationship between OA and chronic stress, suggesting that stress can both contribute to OA development and be a consequence of the disease. Targeting stress pathways may represent a promising therapeutic strategy for managing OA symptoms.