title: Anti-osteoclastogenic activity of isoliquiritigenin via inhibition of NF-κB-dependent autophagic pathway.
abstract: Previous studies, including those from our laboratory, have demonstrated that the natural flavonoid isoliquiritigenin (ISL) is a promising agent for bone destructive diseases. However, the mechanisms underlying its anti-osteoclastogenic effects are still far from clear. Here, we evaluated the potential alterations of autophagy and nuclear factor-κB (NF-κB) during anti-osteoclastogenic effects by ISL in vitro and in vivo. We observed that ISL inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis and suppressed autophagic microtubule-associated protein light chain 3 (LC3)-II and Beclin 1 accumulation. ISL treatment resulted in the interruption of several specific features for autophagy in osteoclast precursors, including acidic vesicular organelle formation, LC3-II accumulation, and appearance of autophagic vacuoles. The RANKL-stimulated expression levels of autophagy-related genes and proteins also diminished in ISL-treated osteoclast precursors. The reactivation of autophagy by rapamycin almost reversed the ISL-elicited anti-osteoclastogenic effects. Interestingly, ISL inhibited the RANKL-stimulated NF-κB expression and nuclear translocation, whereas the NF-κB inhibitor Bay 11-7082 markedly suppressed the RANKL-induced autophagic activation. Consistent with the in vitro results, the administration of ISL could attenuate osteoclastogenic cathepsin K, autophagic LC3, and NF-κB expression to protect against inflammatory calvarial bone erosion in vivo. Our findings highlight the inhibition of NF-κB-dependent autophagy as an important mechanism of ISL-mediated anti-osteoclastogenic activity.
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: Shan
authors.initials: S
authors.lastname: Liu
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.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: Jie
authors.initials: J
authors.lastname: Zhang
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: Jingjing
authors.initials: J
authors.lastname: Yu
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: Xue
authors.initials: X
authors.lastname: Cheng
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. Electronic address: phs301@vip.163.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Peng
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D050071:Bone Density Conservation Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001862:Bone Resorption / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D047188:Chalcones / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D012886:Skull / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013450:Sulfones / Q000494:pharmacology
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D050071:Bone Density Conservation Agents; D047188:Chalcones; D008070:Lipopolysaccharides; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D009570:Nitriles; D053245:RANK Ligand; D013450:Sulfones; C505689:Tnfsf11 protein, mouse; C040920:isoliquiritigenin; D056657:Cathepsin K; C534132:Ctsk protein, mouse; D020123:Sirolimus
keywords: Autophagy; Isoliquiritigenin; Lipopolysaccharide; Nuclear factor-κB; Osteoclastogenesis