title: Norisoboldine, an Anti-Arthritis Alkaloid Isolated from Radix Linderae, Attenuates Osteoclast Differentiation and Inflammatory Bone Erosion in an Aryl Hydrocarbon Receptor-Dependent Manner.
abstract: Norisoboldine (NOR), the primary isoquinoline alkaloid constituent of the root of Lindera aggregata, has previously been demonstrated to attenuate osteoclast (OC) differentiation. Accumulative evidence has shown that aryl hydrocarbon receptor (AhR) plays an important role in regulating the differentiation of various cells, and multiple isoquinoline alkaloids can modulate AhR. In the present study, we explored the role of NOR in the AhR signaling pathway. These data showed that the combination of AhR antagonist resveratrol (Res) or α-naphthoflavone (α-NF) nearly reversed the inhibition of OC differentiation through NOR. NOR could stably bind to AhR, up-regulate the nuclear translocation of AhR, and enhance the accumulation of the AhR-ARNT complex, AhR-mediated reporter gene activity and CYP1A1 expression in RAW 264.7 cells, suggesting that NOR might be an agonist of AhR. Moreover, NOR inhibited the nuclear translocation of NF-κB-p65, resulting in the evident accumulation of the AhR-NF-κB-p65 complex, which could be markedly inhibited through either Res or α-NF. Although NOR only slightly affected the expression of HIF-1α, NOR markedly reduced VEGF mRNA expression and ARNT-HIF-1α complex accumulation. In vivo studies indicated that NOR decreased the number of OCs and ameliorated the bone erosion in the joints of rats with collagen-induced arthritis, accompanied by the up-regulation of CYP1A1 and the down-regulation of VEGF mRNA expression in the synovium of rats. A combination of α-NF nearly completely reversed the effects of NOR. In conclusion, NOR attenuated OC differentiation and bone erosion through the activation of AhR and the subsequent inhibition of both NF-κB and HIF pathways.
authors.affiliation: 1. State Key Laboratory of Natural Medicine, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Zhi-feng
authors.initials: ZF
authors.lastname: Wei
authors.affiliation: 1. State Key Laboratory of Natural Medicine, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Lv
authors.affiliation: 1. State Key Laboratory of Natural Medicine, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
authors.affiliation: 1. State Key Laboratory of Natural Medicine, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Meng-fan
authors.initials: MF
authors.lastname: Yue
authors.affiliation: 1. State Key Laboratory of Natural Medicine, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Can
authors.initials: C
authors.lastname: Shi
authors.affiliation: 1. State Key Laboratory of Natural Medicine, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Yu-feng
authors.initials: YF
authors.lastname: Xia
authors.affiliation: 2. Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Gui-xin
authors.initials: GX
authors.lastname: Chou
authors.affiliation: 2. Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Zheng-tao
authors.initials: ZT
authors.lastname: Wang
authors.affiliation: 1. State Key Laboratory of Natural Medicine, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Dai
mesh_terms: D000470:Alkaloids / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D001168:Arthritis / Q000188:drug therapy / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D027443:Lindera / Q000737:chemistry*; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects*; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D053245:RANK Ligand / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000470:Alkaloids; D010936:Plant Extracts; D053245:RANK Ligand; D018336:Receptors, Aryl Hydrocarbon; C464745:norisoboldine
keywords: Aryl hydrocarbon receptor; Inflammatory bone erosion; Norisoboldine; Osteoclast differentiation; Rheumatoid arthritis