title: Hispidulin attenuates bone resorption and osteoclastogenesis via the RANKL-induced NF-κB and NFATc1 pathways.
abstract: Hispidulin, a flavonoid that is known to have anti-inflammatory and anti-oxidant effects, attenuates osteoclastogenesis and bone resorption. To investigate the molecular mechanism of its inhibitory effect on osteoclastogenesis, we employed the receptor activator of the nuclear factor κB (NF-κB) ligand (RANKL)-induced murine monocyte/macrophage RAW 264.7 cells and bone marrow-derived macrophages (BMMs) for osteoclastic differentiation in vitro. The inhibitory effect on in vitro osteoclastogenesis was evaluated by counting the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and by measuring the expression levels of osteoclast-specific genes such as matrix metalloproteinase 9 (MMP9), TRAP and cathepsin K. Similarly, hispidulin significantly inhibited osteoclast activity in RAW 264.7 cell as well as stimulated the ALP activity of MC3T3E1 cells. Furthermore, the in vivo suppressive effect on bone loss was assessed quantitatively in a lipopolysaccharide (LPS)-induced mouse model using microcomputational tomography (μCT) and histochemical analyses. Hispidulin was found to inhibit RANKL-induced activation of Jun N-terminal kinase (JNK) and p38, in addition to NF-κB in vitro experiment. Additionally, hispidulin decreased NFATc1 transcriptional activity in RANKL-induced osteoclastogenesis. This study identifies hispidulin as a potent inhibitor of osteoclastogenesis and bone resorption and provides evidence for its therapeutic potential to treat diseases involving abnormal bone lysis.
authors.affiliation: Department of Dental Pharmacology, School of Dentistry and Institute of Oral Bioscience, Brain Korea 21 project, Chonbuk National University, Jeonju 561-756, Republic of Korea.
authors.forename: Manoj
authors.initials: M
authors.lastname: Nepal
authors.forename: Hwa Jung
authors.initials: HJ
authors.lastname: Choi
authors.forename: Bo-Yun
authors.initials: BY
authors.lastname: Choi
authors.forename: Moon-Shik
authors.initials: MS
authors.lastname: Yang
authors.forename: Jung-Il
authors.initials: JI
authors.lastname: Chae
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: Yunjo
authors.initials: Y
authors.lastname: Soh
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001862:Bone Resorption / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D047309:Flavones / Q000494:pharmacology* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D053245:RANK Ligand / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D047309:Flavones; D008070:Lipopolysaccharides; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D000469:Alkaline Phosphatase; C055957:hispidulin
keywords: Bone resorption; Hispidulin; Osteoclastogenesis; RANKL; μCT