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.

Norisoboldine, a natural AhR agonist, promotes Treg differentiation and attenuates colitis via targeting glycolysis and subsequent NAD+/SIRT1/SUV39H1/H3K9me3 signaling pathway

“… 14 demonstrate that inflammatory hypoxia is observed in colons of mice with chronic colitis. Norisoboldine (NOR), the primary isoquinoline alkaloid of Radix Linderae, possesses well ability to activate aryl hydrocarbon receptor (AhR) 15 . In addition, it can effectively inhibit systemic inflammation in rats with adjuvant-induced arthritis or collagen-induced arthritis through a gut-dependent manner 16 .…”

Herbal compounds for rheumatoid arthritis: Literatures review and cheminformatics prediction

“…In RA, osteoclasts formation and differentiation are closely associated with local bone erosion (Wei et al, ). The previous study has showed that IL‐10 and transforming growth factor‐β1, the cytokines secreted from regulatory T cells, play a key role in suppressing osteoclast differentiation and bone resorption (Xu et al, ).…”

“…Triptolide enhances these suppressive effects by promoting the production of IL‐10 and transforming growth factor‐β1 (Xu et al, ). The aryl hydrocarbon receptor participates in the activation and differentiation of osteoclasts (Wei et al, ). Norisoboldine attenuates osteoclast differentiation and bone erosion in an aryl hydrocarbon receptor‐dependent manner (Wei et al, ).…”

“…The aryl hydrocarbon receptor participates in the activation and differentiation of osteoclasts (Wei et al, ). Norisoboldine attenuates osteoclast differentiation and bone erosion in an aryl hydrocarbon receptor‐dependent manner (Wei et al, ). Receptor activator of nuclear factor κB ligand (RANKL) is a key factor for osteoclasts formation and differentiation.…”

Unfractionated Heparin Promotes Osteoclast Formation in Vitro by Inhibiting Osteoprotegerin Activity

“…This cell line can support osteoclast formation in vitro , by secreting RANKL, OPG, and M-CSF, without supplementation from any other regulatory factors [ 20 ]. The RAW 264.7 monocyte cell line is the most commonly used osteoclast precursor; it is widely used to examine osteoclast formation in vitro [ 21 , 22 , 23 , 24 , 25 ].…”