title: Licorice isoliquiritigenin suppresses RANKL-induced osteoclastogenesis in vitro and prevents inflammatory bone loss in vivo.
abstract: Osteoclasts, bone-specialized multinucleated cells, are responsible for bone destructive diseases such as osteoporosis, periodontitis, and rheumatoid arthritis. Natural plant-derived products have received substantial attention given their potential therapeutic and preventive activities against human diseases. In the present study, we investigated the effects of isoliquiritigenin (ISL), a natural flavonoid isolated from licorice, on receptor activator of nuclear factor-κB ligand (RANKL)-induced in vitro osteoclastogenesis and inflammation-mediated bone destruction in vivo. We observed that ISL dose-dependently inhibited RANKL-induced osteoclast formation from RAW 264.7 and primary mouse bone marrow-derived macrophages (BMMs), as well as decreased the extent of lacunar resorption. Specifically, ISL targeted RANKL-induced osteoclastogenesis and F-actin rings formation at an early stage. The RANKL-stimulated mRNA expression of osteoclast-related genes and transcription factors were also diminished by ISL. Mechanistically, ISL blocked the RANKL-triggered RANK-TRAF6 association, phosphorylation of mitogen-activated protein kinases (MAPKs), inhibitor of κBα (IκBα) phosphorylation and degradation, nuclear factor-κB (NF-κB) p65 nuclear translocation, as well as activator protein (AP)-1 activation. ISL almost abrogated the nuclear factor of activated T cells (NFATc1) expression and inhibited its nuclear translocation specifically in pre-osteoclasts. Furthermore, the ectopic introduction of NFATc1 into osteoclast precursors almost reversed the ISL-elicited anti-osteoclastogenic effects. Consistent with the in vitro results, administration of ISL prevented inflammatory bone loss in mice by attenuating osteoclast activity. Taken together, our results demonstrated that ISL suppresses RANKL-induced osteoclastogenesis and inflammatory bone loss via RANK-TRAF6, MAPK, IκBα/NF-κB, and AP-1 signaling pathways. Therefore, ISL may be considered as a novel therapeutic and/or preventive strategy against lytic bone diseases.
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
authors.forename: Lingxin
authors.initials: L
authors.lastname: Zhu
authors.forename: Hongxia
authors.initials: H
authors.lastname: Wei
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Shasha
authors.initials: S
authors.lastname: Yang
authors.forename: Lan
authors.initials: L
authors.lastname: Xiao
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Bin
authors.initials: B
authors.lastname: Peng
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000302:isolation & purification / Q000494:pharmacology*; D006035:Glycyrrhiza / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000276:immunology / Q000378:metabolism; D014162:Transfection
chemical_list: D000199:Actins; D000906:Antibodies; D047188:Chalcones; D053245:RANK Ligand; D048029:TNF Receptor-Associated Factor 6; C040920:isoliquiritigenin