Arctiin abrogates osteoclastogenesis and bone resorption via suppressing RANKL-induced ROS and NFATc1 activation. (September 2020)

• Record Type: Journal Article
• Authors: Chen, Delong; Ye, Zhen; Wang, Chao; Wang, Qingqing; Wang, Haibin; Kuek, Vincent; Wang, Ziyi; Qiu, Heng; Yuan, Jinbo; Kenny, Jacob; Yang, Fan; He, Jianbo; Liu, Yun; Wang, Gang; Zhang, Meng; Zhang, Gangyu; Wang, Junjian; Chen, Peng; Xu, Jiake
• Is Part Of: Pharmacological research. Volume 159(2020)
• Publication Date: 2020-09
• Subjects: α-MEM Alpha modified minimal essential medium -- ARC Arctiin -- ARE antioxidant response element -- Atp6V0d2 encoding the vacuolar H + ATPase V0 subunit d2 [V-ATPase-d2] -- BMMs bone marrow-derived monocytes -- BSA bovine serum albumin -- BV/TV bone volume/tissue volume -- Ct.Ar cortical bone area -- Ct.Ar/Tt.Ar cortical area fraction -- Ct.Th cortical thickness -- Ctsk encoding cathepsin K -- DMSO dimethyl sulfoxide -- EDTA ethylenediaminetetraacetic -- FBS fetal bovine serum -- Gsr glutathione-disulfide reductase -- H&E hematoxylin and eosin -- Ho-1 heme oxygenase-1 -- IL-1 interleukin-1 -- Keap1 kelch-like ECH-associated protein-1 -- MAPK mitogen-activated protein kinase -- M-CSF macrophage colony-stimulating factor -- Mmp9 encoding matrix metalloproteinase 9 -- MTS tetrazolium salt -- NFATc1 nuclear factor of activated T cells 1 -- NF-κB nuclear factor-κB -- Nrf2 NF-E2-related factor 2 -- N.Oc/BS osteoclast number/bone surface -- OVX ovariectomy -- Oc.S/BS osteoclast surface/bone surface -- PFA paraformaldehyde -- qRT-PCR Quantitative real-time PCR -- RANK activator of nuclear factor-κB -- RANKL receptor activator of nuclear factor-κB ligand -- RIPA radioimmune precipitation assay -- ROS reactive oxygen species -- SDS-PAGE sodium dodecyl sulfate-polyacrylamide gel electrophoresis -- Tb.Th trabecular thickness -- Tb.Sp trabecular spacing -- Tb.N trabecular number -- Tt.Ar total tissue area -- TGF-β transforming growth factor-beta -- TRAcP tartrate-resistant acid phosphatase -- TRAF6 tumor necrosis factor receptor-associated factor 6; Arctiin -- Osteoclast -- Bone resorption -- RANKL-induced NFATc1 activation -- ROS; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.104944
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Note: ARC inhibits osteoclastogenesis by suppressing RANKL-induced MAPK (including JNKs and ERKs), calcium, and NFATc1 signaling pathway, as well as by promoting the expression of ROS scavenging enzymes in Nrf2/Keap1/ARE signaling pathway. Abstract: Osteoporosis, characterized by disrupted bone resorption and formation, is viewed as a global health challenge. Arctiin (ARC) is a main component of Arctium lappa L, which exerts chemopreventive effects against various tumor cells. However, the role of ARC in bone remodeling is still unclear. Here, we first demonstrated that ARC inhibits osteoclast formation and bone resorption function induced by the receptor activator of nuclear factor-κB ligand (RANKL) in a dose- and time-dependent manner without exerting cytotoxic effects. Mechanistic analysis revealed that ARC not only suppresses RANKL-induced mitogen-activated protein kinase (MAPK) and calcium signaling pathways, but also enhances the expression of cytoprotective enzymes that are involved in scavenging reactive oxygen species (ROS). Further, ARC inhibits the activation of the major transcription factor nuclear factor of activated T cells 1 (NFATc1) during RANKL-induced osteoclast formation. Preclinical studies showed that ARC protects bone loss in an ovariectomy (OVX) mouse model. Conclusively, our data confirmed that ARC could potentially inhibit osteoclastogenesis by abrogating RANKL-induced MAPK, calcium, and NFATc1 signaling pathway, as well as by promoting the expression of ROS scavenging enzymes in Nrf2/Keap1/ARE signaling pathway, thereby 2 preventing OVX-induced bone loss. Thus, ARC may serve as a novel therapeutic agent for the treatment of osteoporosis.