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Objectives and questions: Chronic stress activates both the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS) and is increasingly recognized as a risk factor for osteoarthritis (OA). However, the role of local glucocorticoid and adrenergic signaling remains unclear. Therefore, we investigated the changes in adrenergic receptor (AR) and corticosterone (CORT)-converting enzyme expression linked to degeneration and inflammation in a murine model of OA.

Material and methods: OA was induced in twelve-week-old male C57BL/6J mice by destabilization of the medial meniscus (DMM), with sham controls. A subset was exposed to chronic mild stress (CMS) for 4 or 12 weeks. Stress response was evaluated by measuring serum CORT and splenic noradrenaline (NE). Cartilage degeneration and synovitis were quantified using histological scoring. ARs (α2A and β2) and CORT-converting enzyme (11β-hydroxysteroid dehydrogenase-1/-2 (11β-HSD1/2)) expression in cartilage and synovium was analyzed using immunohistochemistry (IHC) and quantified as the ratio of positive cells to total cells. Ongoing analyses include glucocorticoid receptor (GR) and tyrosine hydroxylase (TH) expression. Data were analyzed using Kruskal-Wallis/Dunn's test and Spearman’s rank correlation. A p-value <0.05 was considered statistically significant.

Results: Serum CORT and splenic NE increased in all CMS groups at both time points (CORT: both CMS-Sham and CMS-DMM p<0.05 at 4 and 12 weeks, NE: both CMS-Sham and CMS-DMM p<0.01 at 4 weeks, p<0.001 at 12 weeks). CMS exacerbated DMM-associated cartilage degeneration and synovitis at both 4 (cart.: p<0.05, syn.: p<0.05) and 12 weeks (cart.: p<0.01, syn.: p<0.01). No change in 11β-HSD1 expression was observed, while 11β-HSD2 decreased in CMS-Sham and DMM cartilage (both: p<0.05) and increased in DMM synovium (p<0.05) at 4 weeks, with both returning to baseline by 12 weeks. α2A-AR expression increased in CMS-Sham and CMS DMM cartilage at both 4 (both: p<0.001) and 12 weeks (both: p<0.01) and increased only in CMS DMM synovium after 12 weeks (p<0.05). β2-AR was elevated in CMS-Sham and DMM cartilage (both: p<0.05 at 4 weeks, both: p<0.01 at 12 weeks) at all time points and in the synovium of CMS-DMM mice at 12 weeks (p<0.001). Moreover, synovial β2-AR expression positively correlated with splenic NE (r=0.650, p<0.01), cartilage degeneration (r=0.518, p<0.01), and synovitis (r=0.506, p<0.01).

Discussion and conclusions: CMS seems to accelerate local OA-associated processes primarily via SNS/AR-mediated mechanisms rather than HPA/glucocorticoid signaling indicated by an early loss of 11β-HSD2 (converts CORT in its inactive form) in the cartilage as well as general β2-AR dominance. Our findings underscore the potential of the β2-AR as therapeutic target in OA.