title: Leonurine hydrochloride inhibits osteoclastogenesis and prevents osteoporosis associated with estrogen deficiency by inhibiting the NF-κB and PI3K/Akt signaling pathways.
abstract: Osteoclasts, the primary bone resorbing cells, are responsible for destructive bone diseases such as postmenopausal osteoporosis, rheumatoid arthritis, and periodontitis. Many plant-derived traditional medicines that might suppress the formation and/or function of osteoclasts are promising treatments for osteoclast-related diseases. In this study, we investigated the effects of leonurine hydrochloride (LH) on receptor activator NF-κB ligand (RANKL)-induced osteoclastogenesis and ovariectomy-induced bone loss. LH is a synthetic chemical compound based on the structure of leonurine, which is found in motherwort and has been reported to exhibit phytoestrogenic activity. In RAW 264.7 cells and mouse bone marrow monocytes (BMMs), LH suppressed RANKL-induced osteoclastogenesis and actin ring formation in a dose-dependent manner. LH targeted RANKL-induced osteoclastogenesis and bone resorption at an early stage. Molecular analysis demonstrated that LH attenuated RANKL-induced NF-κB signaling by inhibiting the phosphorylation and degradation of IκBα and NF-κB p65 nuclear translocation. LH inhibited the RANK-TRAF6 association triggered by RANKL binding and the phosphatidylinositol 3-kinase (PI3K)/Akt axis, without significantly affecting the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and AP-1 signaling pathways. LH attenuated the RANKL-stimulated expression of osteoclast-related genes including NFATc1, tartrate resistant acid phosphatase (TRAP), cathepsin K, and osteoclast-associated receptor (OSCAR). Consistent with the in vitro results, LH administration attenuated osteoclast activity, thus preventing bone loss caused by estrogen deficiency in mice. In this study, LH suppressed RANKL-induced osteoclastogenesis via RANK-TRAF6, NF-κB, and PI3K/Akt signaling. These data provide the first evidence that LH might be a promising therapeutic compound to treat osteoclast-related diseases, such as osteoporosis.
authors.affiliation: Department of Orthopaedics and Central Laboratory, The third Hospital Affiliated to Nantong University, Wuxi, Jiangsu 214041, China.
authors.forename: Feng-Lai
authors.initials: FL
authors.lastname: Yuan
authors.affiliation: Department of Orthopaedics and Central Laboratory, The third Hospital Affiliated to Nantong University, Wuxi, Jiangsu 214041, China.
authors.forename: Rui-Sheng
authors.initials: RS
authors.lastname: Xu
authors.affiliation: Department of Orthopaedics and Central Laboratory, The third Hospital Affiliated to Nantong University, Wuxi, Jiangsu 214041, China.
authors.forename: Dong-Lin
authors.initials: DL
authors.lastname: Jiang
authors.affiliation: Department of Orthopaedics and Central Laboratory, The third Hospital Affiliated to Nantong University, Wuxi, Jiangsu 214041, China.
authors.forename: Xing-Long
authors.initials: XL
authors.lastname: He
authors.affiliation: Department of Orthopaedics and Central Laboratory, The third Hospital Affiliated to Nantong University, Wuxi, Jiangsu 214041, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Su
authors.affiliation: Department of Orthopaedics and Central Laboratory, The third Hospital Affiliated to Nantong University, Wuxi, Jiangsu 214041, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Jin
authors.affiliation: Department of Orthopaedics and Central Laboratory, The third Hospital Affiliated to Nantong University, Wuxi, Jiangsu 214041, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D015663:Osteoporosis, Postmenopausal / Q000378:metabolism*; D010052:Ovariectomy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016328:NF-kappa B; C013587:leonurine; D005707:Gallic Acid; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Leonurine hydrochloride; NF-κB; Osteoclastogenesis; Osteoporosis; PI3K/Akt signaling