Triterpenoids from Celastrus orbiculatus Thunb. inhibit RANKL-induced osteoclast formation and bone resorption via c-Fos signaling

초록

Fourteen triterpenes, lup-20(29)-ene-3 beta,6 beta-diol (1), betulin (2), lupeol caffeate (3), 3 beta-caffeoyloxylup-20(29)-en-6 alpha-ol (4), betulin-3 beta-yl-caffeate (5), 3 beta-trans-feruloylbetulin (6), betulinaldehyde 3-caffeate (7), 3-O-trans-caffeoylbetulinic acid (8), dammarenediol II 3-caffeate (9), 12-oleanene-3 beta,6 alpha-diol (10), 11 alpha-hydroxy-3 beta-amyrin (11), nivadiol (12), 29-hydroxyfriedelin (13), and celastrusin A (14) were isolated fromCelastrus orbiculatusThunb. and evaluated for their activity on receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclast differentiation in bone marrow macrophages (BMMs). Compounds betulin (2), betulin-3 beta-yl-caffeate (5), 3 beta-trans-feruloylbetulin (6), and 3-O-trans-caffeoylbetulinic acid (8) significantly inhibited osteoclast formation in a dose-dependent manner. Among these, betulin-3 beta-yl-caffeate (5) exhibited the most potent inhibitory activity. We demonstrated that betulin-3 beta-yl-caffeate (5) suppressed F-actin-ring formation and bone resorption activity. At the molecular level, betulin-3 beta-yl-caffeate (5) inhibited RANK-induced expression of c-Fos and the induction of nuclear factor of activated T cells 1 (NFATc1), a key transcription factor for osteoclast formation, and it also downregulated mRNA expression of osteogenesis-associated marker genes including tartrate-resistant acid phosphatase (TRAP), dendritic cell-specific transmembrane protein (DC-STAMP), and matrix metalloprotein (MMP). These results indicate that betulin-3 beta-yl-caffeate (5) may be a promising candidate for the treatment of osteoclast-related diseases such as osteoporosis. [GRAPHICS] .

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