gms | German Medical Science

Objectives: Osteoarthritis (OA) is a chronic degenerative disease of the whole joint characterized by cartilage degradation and calcification, synovitis, and subchondral bone (SB) sclerosis, resulting in the cardinal symptoms reduced joint function and chronic pain. Recent studies revealed that sympathetic neurotransmitters might play a role during OA pathogenesis. A typical cause for a long-term hyperactivity of the sympathetic nervous system (SNS) is chronic stress. To study the contribution of increased levels of sympathetic neurotransmitters, we analyzed the progression of OA in chronically stressed mice.

Methods: OA was induced in 12-week-old male C57BL/6J mice by surgical destabilization of the medial meniscus (DMM), while sham-operated mice served as controls. Half of the groups were subjected to chronic unpredictable mild stress (CUMS) daily. After 12 weeks, CUMS efficiency was evaluated by quantifying splenic norepinephrine (NE) and serum corticosterone (CORT) concentrations, monitoring body weight gain, and activity. OA progression was examined by histological scoring of cartilage degeneration and synovitis as well as microCT analysis of calcified cartilage (CC) and SB thickness. A Dynamic Weight Bearing system was used to monitor OA-related pain.

Results and conclusion: CUMS resulted in clear signs of chronic stress compared to the respective non-CUMS mice, with significantly increased splenic NE and serum CORT levels (NE: CUMS sham 2.3-fold p<0.01, CUMS DMM (5.2-fold p<0.01; CORT: CUMS sham 1.5-fold p<0.01, CUMS DMM 1.8-fold p<0.001). Interestingly, DMM surgery alone led to increased NE concentrations (1.9-fold p<0.01). In addition, a significant stress-related decrease in body weight gain (CUMS sham 1.4-fold p<0.01; CUMS DMM 1.3-fold p<0.01) and significantly decreased activity (both CUMS sham and DMM -60% p<0.01) was observed. Histological analysis and OARSI scoring revealed a significant increase in cartilage degeneration in WT DMM (p<0.05), while degeneration was even more pronounced in CUMS DMM mice (p<0.01). CUMS significantly increased synovitis in DMM (p<0.01) and surprisingly, also in sham mice (p<0.05). Furthermore, CUMS caused a significant increase in CC thickness in DMM mice (p<0.05) but had no effects on SB. OA-associated pain increased due to CUMS in DMM mice, as reflected by significantly decreased weight bearing on the operated right rear paw (p<0.01) and shorter rearing duration (p<0.01). Underlying cellular and molecular mechanisms using FACS and single cell RNAseq are currently analyzed.

Our study demonstrates that chronic stress exacerbates many aspects of OA and the genesis of pain. Interestingly, OA itself elevated SNS activity suggesting a bidirectional role of chronic stress as both a cause and a consequence of OA. Thus, targeting the autonomic nervous system might represent an innovative approach for preventive and/or causative treatment of OA.