gms | German Medical Science

Objectives: The sympathetic neurotransmitter norepinephrine aggravates catabolic processes in healthy but exerts anabolic effects in osteoarthritic (OA) chondrocytes. Most of these effects were mediated by the β2-adrenoceptor (AR). Moreover, first associations between anti-hypertensive drug treatment with cartilage degeneration and pain were described. The aim of the present study was to analyze the direct effect of anti-hypertensive (β-sympatholytic) or anti-asthmatic (β-sympathomimetic) drugs on human articular chondrocytes.

Methods: Cartilage samples were obtained from OA patients undergoing knee replacement surgery. Chondrocytes were isolated by enzymatic digestion, cultivated under physioxic conditions (2% O₂) and treated with adrenergic anti-hypertensive (Propranolol: β1/2-AR blocker, Carvedilol: β1/2- and α1-AR blocker, Metoprolol: β1-AR blocker) or anti-asthmatic drugs (Salbutamol, Formoterol: β2-AR agonists) in different concentrations (lowest and highest serum concentration during medication) with or without an OA-relevant IL-1 β (0.5 ng/ml) concentration. After 14 days, cytotoxicity of the drugs was assessed using lactate dehydrogenase assay and cell morphology was documented microscopically. Quantitative RT-PCR was performed to investigate changes in COL1A1, COL10A1, ACAN, MMP13, ADAMTS5, and IL6 gene expression. Activation of ERK1/2 and PKA was analyzed via immunoblotting.

Results and conclusion: On day 7, no cytotoxic effect was observed after any treatment. No significant changes in cell morphology were detected in the treatment groups without IL-1β compared to untreated control, while all IL-1β-treated groups displayed a more pronounced fibroblast-like phenotype indicating accelerated dedifferentiation. Without IL-1β, high Salbutamol significantly increased ACAN (p=0.029), IL6 (p=0.029) and slightly increased COL1A1 (p=0.057) expression compared to the untreated control. Low Salbutamol also increased IL6 expression (p=0.026). Low Formoterol as well as low and high Carvedilol treatment without IL-1β resulted in increased IL6 expression (low Formoterol p= 0.026, low Carvedilol p= 0.026, high Carvedilol p=0.021). As expected, IL-1β significantly decreased ACAN (p=0.026) but increased MMP13 (p<0.001) and IL6 expression (p<0.001). IL-1β-mediated ACAN decrease was significantly reversed by low Metoprolol (p=0.028) and by trend by low Salbutamol (0.057). All substances activated only the ERK1/2 pathway. COL2A1 and ADAMTS5 analyses are the focus of our present work.

This study demonstrates that anti-hypertensive and anti-asthmatic medication might act pro-inflammatory in a non-inflamed joint (increased IL6 expression). In contrast, these drugs seem to counteract low-grade inflammation and reverse IL-1β-induced catabolic effects (reversal of inhibited ACAN expression). Thus, our results suggest that anti-hypertensive and anti-asthmatic medication should be taken into consideration during the treatment of OA patients with different inflammatory states.