Alpinetin ameliorates bone loss in LPS-induced inflammation osteolysis via ROS mediated P38/PI3K signaling pathway. (October 2022)

• Record Type: Journal Article
• Authors: Wei, Linhua; Chen, Weiwei; Huang, Linke; Wang, Hui; Su, Yuangang; Liang, Jiamin; Lian, Haoyu; Xu, Jiake; Zhao, Jinmin; Liu, Qian
• Is Part Of: Pharmacological research. Volume 184(2022)
• Publication Date: 2022-10
• Subjects: Alp Alpinetin -- AKT protein kinase B -- BMMs bone marrow macrophages -- BV/TV bone volume per tissue volume -- c-fos Proto-oncogene C-Fos -- Ctsk cathepsin K -- DAPI 4, 6-diamidino-2-phenylindole -- DCF 2', 7'-dichlorofluorescein -- DHE dihydroethidium -- FBS fetal bovine serum -- GSK3-β Glycogen synthase kinase-3β -- CAT catalase -- HO-1 heme oxygenase-1 -- IKK IκB kinase -- MAPK mitogen-activated protein kinases -- M-CSF macrophage-colony stimulating factor -- Mmp9 matrix metallopeptidase 9 -- NFATc1 nuclear factor of activated T cells 1 -- NF-κB nuclear factor-κB -- NOX NADPH oxidase -- PBS phosphate-buffered saline -- PCR polymerase chain reaction -- PI3K phosphoinositide 3-kinase -- RANKL receptor activator of the nuclear factor‐κB ligand -- ROS reactive oxygen species -- TNF tumor necrosis factor -- TRAcP tartrate-resistant acid phosphatase; Alpinetin -- Inflammation -- ROS -- Osteolysis; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106400
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Background and objective: Bone loss occurs in several inflammatory diseases because of chronic persistent inflammation that activates osteoclasts (OCs) to increase bone resorption. Currently available antiresorptive drugs have severe side effects or contraindications. Herein, we explored the effects and mechanism of Alpinetin (Alp) on receptor activator of nuclear factor κB ligand (RANKL)-mediated OCs differentiation, function, and in inflammatory osteolysis of mice. Method: Primary mouse bone marrow-derived macrophages (BMMs) induced by RANKL and macrophage colony-stimulating factor (M-CSF) were utilized to test the impact of Alp on OCs differentiation, function, and intracellular reactive oxygen species (ROS) production, respectively. Expression of oxidant stress relevant factors and OCs specific genes were assessed via real-time quantitative PCR. Further, oxidative stress-related factors, NF-κB, MAPK, PI3K/AKT/GSK3-β, and NFATc1 pathways were examined via Western blot. Finally, LPS-induced mouse calvarial osteolysis was used to investigate the effect of Alp on inflammatory osteolysis in vivo . Result: Alp suppressed OCs differentiation and resorption function, and down-regulated the ROS production. Alp inhibited IL-1β, TNF-α and osteoclast-specific gene transcription. It also blocked the gene and protein expression of Nox1 and Keap1, but enhanced Nrf2, CAT, and HO-1 protein levels. Additionally, Alp suppressed the phosphorylation of PI3K and P38, and restrained the expression of osteoclast-specific gene Nfatc1 and its auto-amplification, hence minimizing LPS-induced osteolysis in mice. Conclusion: Alp is a novel candidate or therapeutics for the osteoclast-associated inflammatory osteolytic ailment. Graphical Abstract: Alpinetin ameliorates bone loss in LPS-induced inflammation osteolysis of mice via suppressing RANKL-induced osteoclastogenesis through inhibiting inflammation and down-regulating ROS-mediated P38/PI3K signaling pathway. ga1 Highlights: Bone loss occurs in various inflammatory diseases, and osteoclasts are the only bone resorbing cells. Alpinetin inhibits inflammation and intracellular ROS generation in osteoclastogenesis. Alpinetin suppresses osteoclasts differentiation and function via down-regulating P38 and PI3K-NFATc1 signaling axis. Alpinetin plays a therapeutic effect on inflammatory osteolysis in mice.