gms | German Medical Science

Objectives: Recently, increasing evidence emerged that the autonomic nervous system contributes to osteoarthritis (OA) pathogenesis. The two major autonomic branches, the sympathetic (SNS) and the parasympathetic nervous system (PNS), exhibit opposing effects via the respective neurotransmitters norepinephrine (NE) and acetylcholine (Ach). Under healthy conditions, both systems are well-balanced. However, in chronic pathological situations, this balance may be disturbed and affect different cell types in the joint. Therefore, we investigated the response of human articular chondrocytes to different SNS/PNS neurotransmitter ratios in vitro.

Methods: Articular cartilage samples were obtained from OA patients undergoing total knee-replacement surgery. Chondrocytes were isolated enzymatically, cultivated under physioxic conditions (2% O₂) with or without IL-1β (0.5 ng/ml) and additionally treated for 7 days with different combinations and concentrations of NE and Ach (high 10^-6 M, low 10^-8 M) mimicking low and high SNS and/or PNS tones. Expression changes in genes encoding matrix proteins (ACAN, COL1A1, COL2A1), the inflammatory cytokine IL6 and the matrix degrading protease MMP13 were determined by qRT-PCR. Activation of the most relevant intracellular signaling pathways (ERK1/2 and PKA) was analyzed via Western blotting.

Results and conclusion: After 7 days, chondrocytes cultivated with or without IL-1β exhibited a significant higher IL6 (p<0.05) and MMP13 (p<0.05) expression compared to freshly isolated cells. In addition, cells treated with IL-1βdemonstrated a significantly higher increase compared to cells cultured without the cytokine (p<0.05). The IL-1β-induced increase in IL6 expression was diminished by the application of low and high Ach concentrations, regardless of whether NE was also present. Similarly, the IL-1β-induced increase in MMP13 expression was reversed by applying a high concentration of Ach, or a balanced quantity of low or high Ach and NE. Overall, high and low Ach and/or NE treatment decreased IL-1β-induced ERK1/2 phosphorylation. This effect was more pronounced when Ach and NE were administered alone than in combined treatment conditions. PKA phosphorylation was not altered by any treatment.

This study confirmed that IL-1β promotes inflammation- and matrix degradation-related gene expression in human OA chondrocytes. While Ach counteracted these IL-1β-induced effects, NE had no impact. This finding indicates that PNS activity might beneficially influence chondrocyte function during OA pathogenesis likely via the ERK1/2 pathway. Our results provide a first insight into the complex interplay of SNS and PNS during OA progression and might open exciting avenues for novel future strategies for OA prevention and therapy.