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: Zhi-feng Wei, Qi Lv, Ying Xia, Meng-fan Yue, Can Shi, Yu-feng Xia, Gui-xin Chou, Zheng-tao Wang, Yue Dai
• Journal: International journal of biological sciences (Int J Biol Sci) Vol. 11 Issue 9 Pg. 1113-26 ( 2015) ISSN: 1449-2288 [Electronic] Australia
• PMID: 26221077 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Alkaloids
• Plant Extracts
• RANK Ligand
• Receptors, Aryl Hydrocarbon
• norisoboldine

Topics

• Alkaloids (pharmacology, therapeutic use)
• Animals
• Arthritis (drug therapy, metabolism)
• Cell Differentiation (drug effects)
• Cell Line
• Inflammation (drug therapy, metabolism)
• Lindera (chemistry)
• Male
• Mice
• Osteoclasts (cytology, drug effects)
• Plant Extracts (pharmacology, therapeutic use)
• RANK Ligand (pharmacology)
• Rats
• Rats, Wistar
• Receptors, Aryl Hydrocarbon (genetics, metabolism)
• Signal Transduction (drug effects)