Triterpenoids from Potentilla chinensis inhibit RANKL‐induced osteoclastogenesis in vitro and lipopolysaccharide‐induced osteolytic bone loss in vivo

Abstract In this study, a phytochemical investigation on the methanol extract of Potentilla chinensis led to the isolation of eleven triterpenoids including ursolic acid ( 1 ), pomolic acid ( 2 ), tormentic acid ( 3 ), 2‐epi‐corosolic acid ( 4 ), 3‐epi‐corosolic acid (ECA, 5 ), 3 β ‐hydroxyurs‐11‐en‐13 β (28)‐olide ( 6 ), euscaphic acid ( 7 ), 2‐epi‐tormentic acid ( 8 ), corosolic acid ( 9 ), uvaol ( 10 ), and 3‐ O ‐acetylpomolic acid ( 11 ). Among them, ECA ( 5 ) showed potential anti‐osteoclastogenic activity. To the best of our knowledge, this represents the first isolation of ECA ( 5 ) from P. chinensis as well as the first investigation of its effects on osteoclast formation. Further study revealed that ECA inhibited RANKL‐induced mature osteoclast formation in vitro without compromising cell viability. Mechanistically, ECA attenuated RANKL‐induced mitogen‐activated protein kinases (MAPKs) and nuclear factor‐κB (NF‐κB) activation, leading to the inhibition of c‐Fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) activation. Moreover, ECA protected against LPS‐induced inflammatory bone loss and osteoclast formation in a mouse model. However, ECA did not inhibit LPS‐induced inflammatory responses in macrophages. Our findings suggest that ECA mitigates LPS‐induced inflammatory bone loss in mice by inhibiting RANKL‐induced activation of key osteoclastogenic transcription factors, including c‐Fos and NFATc1, and may be a potential natural triterpenoid for preventing or treating osteolytic diseases.