The Mechanism Study On α7 Nicotinic Acetylcholine Receptors Intervening Osteoarthritis By Regulating Macrophage Activity

Background: Osteoarthritis(OA)is a degenerative joint disease that causes chronic disability among the elderly.Despite recent advances in symptomatic management of OA by pharmacological and surgical approaches,there remains a lack of optimal approaches to manage inflammation in the joints,which causes cartilage degradation and joint pain.In this study,we investigated the efficacy and underlying mechanisms of nicotine exposure in attenuating joint inflammation,cartilage degradation and pain in a mouse model of OA.Methods:(1)A mouse model of OA was induced by injection of monosodium iodoacetate(MIA)0.1 mg/10 μL into the knee joint.(2)Their mechanical allodynia was assessed with Von Frey Hairs and intraperitoneal injection of nicotine to evaluate the analgesia effect of osteoarthritis pain.(3)Gelatin zymography was used to evaluate the effect of nicotine to activity of metalloproteinase-9(MMP-9)in OA mice’s knee joints.(4)The macrophage line RAW264.7 cells and bone marrow-derived macrophages were used to investigate the pharmacological effects and the mechanism of nicotine on LPS-induced joint inflammation.(5)PI3K/Akt/NF-κB/MMP-9 signaling pathways were assessed by western blot,immunofluorescence staining and gelatin zymography.Results: Consecutive administration of nicotine(0.5,1 mg/kg,i.p.)for 28 days sigificantly reduced mechanical allodynia,cartilage degradation and the upregulation of metalloproteinase-9(MMP-9),a hallmark of joint inflammation in OA,in mice treated with MIA.The effects of nicotine were abolished by the selective α7 nicotinic acetylcholine receptor(α7-nAChR)blocker MLA.In RAW264.7 cells and murine primary bone marrow-derived macrophages,nicotine significantly inhibited MMP-9 production induced by LPS.In addition,nicotine significantly enhanced PI3K/Akt and inhibited NF-κB translocation from the cytosol to the nucleus in an α7-nAChR-dependent manner,suggesting that nicotine acts on α7-nAChRs to inhibit MMP-9 production by macrophages through modulation of the PI3K/Akt-NF-κB pathway.Conclusion: Our results provide novel evidence that nicotine can attenuate joint inflammation and pain in experimental OA via α7-nAChRs.α7-nAChR could thus serve as a highly promising target to manage joint inflammation and pain in OA.