P2X4 promotes interleukin-1β production in osteoarthritis via NLRP1

Interleukin-1 (IL-1) has a significant role in osteoarthritis (OA). The purinergic receptor, P2X4, has previously been implicated in IL-1 secretion. The NLRP1 inflammasome mediates the production of IL-1 in inflammatory disorders. However, it is unknown whether P2X4 modulates NLRP1-mediated IL-1 release. In the present study, the correlation between the P2X4 receptor and NLRP1 was investigated in OA fibroblast-like synoviocytes (OAFLS). The expression of P2X4 and NLRP1 was detected in the OAFLS. The OAFLS were stimulated with P2X4 and the levels of IL-1 and matrix metalloproteinases (MMPs) were measured. To determine whether P2X4 is involved in NLRP1-triggered IL-1 production, NLRP1 small interfering RNA (siRNA) was used. In the OAFLS, a markedly higher expression of P2X4 and NLRP1 was revealed compared with that in the normal FLS. OAFLS stimulated by P2X4 resulted in concentration-dependent increases in the production of IL-1, MMP-3 and MMP-9. Furthermore, P2X4-mediated IL-1 production was attenuated by the NLRP1 siRNA. The results of the present study indicate that P2X4 induced IL-1, MMP-3 and MMP-9 production in the OAFLS. IL-1 induced by P2X4 is mediated via NLRP1. P2X4/NLRP1 may be important in the pathogenesis of OA and may represent a novel therapeutic target.