AUTHOR=Hong Guoju , Zhou Lin , Han Xiaorui , Sun Ping , Chen Zhenqiu , He Wei , Tickner Jennifer , Chen Leilei , Shi Xuguang , Xu Jiake 

TITLE=Asiatic Acid Inhibits OVX-Induced Osteoporosis and Osteoclastogenesis Via Regulating RANKL-Mediated NF-κb and Nfatc1 Signaling Pathways

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.00331

DOI=10.3389/fphar.2020.00331

ISSN=1663-9812

ABSTRACT=<p><italic>Asiatic acid</italic> is a triterpenoid compound extracted from a medicinal plant <italic>Centella asiatica</italic>. It has been used as a highly efficient compound for the treatment of cancer and hyperlipidemia, as well as possessing potential antiinflammatory properties. However, its effects on bone metabolism and osteoporosis haven’t been reported. The purpose of our research were to reveal the biomolecular effects of <italic>asiatic acid</italic> on osteoclasts, and its underlying molecular mechanisms regulating its effects on receptor activator of NF-κB ligand (RANKL)-induced signaling pathways. We found that <italic>asiatic acid</italic> inhibited multinucleated tartrate-resistant acid phosphatase (TRAcP)-positive osteoclast differentiation and osteoclast induced bone loss. Real time PCR showed that <italic>asiatic acid</italic> reduced the expression of down-cascade target genes including <italic>Ctsk</italic>, <italic>Nfatc1</italic>, <italic>Calcr</italic>, and <italic>Atp6v0d2</italic>. Western blot and luciferase reporter gene assays revealed that <italic>asiatic acid</italic> inhibits RANKL mediated NF-κB and NFATc1 signalings. Further, <italic>in vivo</italic> study demonstrated <italic>asiatic acid</italic> attenuates estrogen deficiency-induced bone loss in ovariectomized mice. MicroCT and histology analyses revealed that osteoclast numbers were significantly suppressed in <italic>asiatic acid</italic> treated groups. Furthermore, serum levels of TRAcP and CTX-1 were downregulated in treated groups. Taken together, our data show that <italic>asiatic acid</italic> can inhibit osteoclastic formation and reduce OVX-induced bone resorption through RANKL-activated NF-κB or NFATc1 signaling, suggesting that <italic>asiatic acid</italic> may be a potential and effective natural compound for the therapy of excessive RANKL-related osteolytic diseases.</p>