Bradykinin and B2 receptor antagonism in rat and human articular chondrocytes

BACKGROUND AND PURPOSE In osteoarthritis (OA), bradykinin (BK) is known to contribute to pain and synovitis, but not to cartilage degradation. Here, we investigated effects of BK and its antagonists on chondrocytes, cells involved in cartilage homeostasis. EXPERIMENTAL APPROACH BK receptor density and affinities of BK, its analogues and antagonists were measured in cultured human and rat chondrocytes by radioligand binding. Effects of BK were assessed by accumulation of inositol phosphates (IP) and release of interleukin (IL)-6 and IL-8. KEY RESULTS Density of [3H]-BK binding sites was higher (13-30-fold) and BK evoked a greater (48-fold) IP production, in human than in rat chondrocytes. The BK B-2 receptor antagonists MEN16132 and icatibant displayed similar binding affinity. MEN16132 was 40-fold more potent than icatibant in the IP assay. In human chondrocytes, BK increased release (over 24 h) of IL-6 and IL-8, effects blocked by MEN16132 but not by the B-1 receptor antagonist Lys-[Leu8][desArg9]BK. BK-induced release of IL-6, but not of IL-8, was partially inhibited by indomethacin (10 mu M) and nordihydroguaiaretic acid (10 mu M). Antagonists for the prostanoid EP receptors (AH6809 10 mu M; L-798 196, 200 nM; L-161 982, 1 mu M) were ineffective. Dexamethasone (100 nM) partially inhibited release of both IL-6 and IL-8. Inhibitors of intracellular downstream signalling pathways (SB203580 10 mu M; PD98059, 30 mu M; SP600125, 30 mu M; BAY-117085, 5 mu M) indicated the involvement of p38 MAPK and the activation of NF-kappa B. CONCLUSION AND IMPLICATIONS BK mediated inflammatory changes and cartilage degradation and B-2 receptor blockade would, therefore, be a potential treatment for OA.