¹Dr Rolf M. Schwiete Research Unit for Osteoarthritis, Department of Trauma Surgery and Orthopedics, Goethe University Frankfurt, University Hospital, Frankfurt, Deutschland
²Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe University Frankfurt, University Hospital, Frankfurt, Deutschland
³Department of Trauma Surgery, Orthopedic Surgery and Plastic Surgery, University Medical Center Göttingen, Göttingen, Deutschland
⁴Department of Orthopedics and Trauma Surgery, University Hospital Kiel, Kiel, Deutschland

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Objectives and questions: Osteoarthritis (OA) is characterized by cartilage degradation and calcification, synovial inflammation, and subchondral bone sclerosis, leading to chronic pain and disabilities. The stress hormones norepinephrine (NE) and cortisol (CORT) play a role in OA pathophysiology by promoting catabolic and inflammatory processes. Under chronic stress, continuous activation of sympathetic and hypothalamic-pituitary-adrenal axes results in release of NE and CORT in high concentrations. Since the impact of chronic stress on OA pathogenesis in vivo has not been investigated, we examined how it influences disease progression in a murine OA model.

Material and methods: Twelve-week-old male C57BL/6J mice underwent destabilization of the medial meniscus (DMM) to induce OA, while sham surgeries served as controls. A subset of mice was subjected to chronic unpredictable mild stress (CUMS). After 12 weeks, CUMS efficacy was evaluated by determining activity levels and measuring splenic NE and serum CORT. OA severity was assessed by OARSI and synovitis scoring as well as micro-computed tomography (μCT) analysis of calcified cartilage (CC) thickness and subchondral bone (SB) remodeling. Pain behavior was analyzed using the Dynamic Weight Bearing system (^®Bioseb). Immune cell populations in the synovium and dorsal root ganglia (DRGs) were assessed by flow cytometry.

Results: CUMS reduced activity in DMM and sham mice (-60%,p<0.01) compared to non-stressed groups. Splenic NE levels increased due to CUMS (CUMS sham: +2.3-fold, CUMS DMM: +5.2-fold, p<0.01), as did serum CORT (CUMS sham: +1.5-fold, CUMS DMM: +1.8-fold, p<0.001). Interestingly, OA induction alone elevated splenic NE levels (+1.9-fold, p<0.01). Compared to non-stressed DMM animals, OA severity was exacerbated in CUMS DMM mice, with increased OARSI (p<0.01) and synovitis (p<0.01) scores and CC thickness (p<0.05). Synovial immune cell profiling revealed an early increase in pro-inflammatory CD3+ T cells (p<0.01) and CD11b+F4/80+Ly6Chigh monocytes (p<0.01) and reduced anti-inflammatory CD301+CD150- M2a macrophages (p<0.05). While no nociceptive changes were observed in CUMS sham or non-stressed DMM mice, pain was significantly higher in CUMS DMM mice (p<0.01). The corresponding lumbar DRGs exhibited increased pro-inflammatory neutrophil (CD11b+Ly6G+, p<0.05) and T cell (CD3+, p<0.01) infiltration.

Discussion and conclusions: Our study demonstrates that CUMS exacerbated OA progression by accelerating cartilage degeneration, calcification, synovitis, and pain, contributing to immune cell recruitment into synovium and DRGs. Additionally, DMM itself induced NE, indicating a bidirectional relationship between OA and chronic stress. Thus, stress can be both the cause and consequence of OA. Current analyses, including spatial proteomics of the joint and serum cytokine profiling, will help dissect underlying mechanisms.