Herbacetin inhibits RANKL-mediated osteoclastogenesis in vitro and prevents inflammatory bone loss in vivo

• Published in: European journal of pharmacology Vol. 777; pp. 17 - 25
• Main Authors: Li, Liang, Sapkota, Mahesh, Kim, Se-woong, Soh, Yunjo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15-04-2016
• Subjects: Animals; Bone loss; Bone Resorption - complications; Bone Resorption - metabolism; Bone Resorption - physiopathology; Bone Resorption - prevention & control; Flavonoids - pharmacology; Gene Expression Regulation - drug effects; Herbacetin; Inflammation - complications; Lipopolysaccharides - pharmacology; MAP Kinase Signaling System - drug effects; Mice; NF-kappa B - metabolism; NFATc1; Osteoclast; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteoclasts - pathology; Osteogenesis - drug effects; RANK Ligand - metabolism; RANKL; RAW 264.7 Cells; RNA, Messenger - genetics; RNA, Messenger - metabolism; Time Factors; Transcription Factors - genetics; Transcription Factors - metabolism; RANKL; Herbacetin; Osteoclast; NFATc1; Bone loss
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2016.02.057

Herbacetin is an active flavonol (a type of flavonoid) that has various biologic effects such as antioxidant, antitumor, and anti-inflammatory activities. However, one of its novel effects remains to be investigated, that is, the induction of osteoclastogenesis by the receptor activator of nuclear factor-κB ligand (RANKL). In this study, we examined the effects and mechanisms of action of herbacetin on osteoclastogenesis in RANKL-treated bone marrow–derived macrophages (BMMs) and murine macrophage RAW264.7 cells in vitro and on lipopolysaccharide (LPS)-induced bone destruction in vivo. Herbacetin significantly inhibited RANKL-induced osteoclast formation and differentiation in BMMs and RAW264.7 cells in a dose-dependent manner. Moreover, the suppressive effect of herbacetin resulted in a decrease in osteoclast-related genes, including RANK, tartrate-resistant acid phosphatase, cathepsin K, and matrix metalloproteinase-2 and -9 (MMP-9). Consistent with mRNA results, we confirmed that herbacetin treatment downregulated protein expression of MMP-9 and cathepsin K. Herbacetin also decreased induction of the osteoclastogenic transcription factor c-Fos and nuclear factor of activated T cells c1 (NFATc1) and blocked RANKL-mediated activation of Jun N-terminal kinase (JNK) and nuclear factor-κB. Herbacetin clearly inhibited the bone resorption activity of osteoclasts on plates coated with fluorescein-labeled calcium phosphate. More importantly, the application of herbacetin significantly reduced LPS-induced inflammatory bone loss in mice in vivo. Taken together, our results indicate that herbacetin has potential for use as a therapeutic agent in disorders associated with bone loss.