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

• Published in: Journal of natural medicines 2021, Vol.75 (1), p.56-65
• Main Authors: Vu, Thi Oanh, Tran, Phuong Thao, Seo, Wonyoung, Lee, Jeong Hyung, Min, Byung Sun, Kim, Jeong Ah
• Format: Article
• Language: English
• Subjects: Acid phosphatase (tartrate-resistant); Actin; Animals; Antifungal agents; Biomedical and Life Sciences; Biomedicine; Bone growth; Bone marrow; Bone resorption; Bone Resorption - drug therapy; Bone Resorption - metabolism; Bone Resorption - pathology; c-Fos protein; Celastrus - chemistry; Celastrus orbiculatus; Cell Differentiation - drug effects; Complementary & Alternative Medicine; DC-STAMP protein; Dendritic cells; Gene expression; Macrophages; Male; Medicinal Chemistry; Mice; Mice, Inbred ICR; NF-AT protein; Original Paper; Osteoclastogenesis; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteoclasts - pathology; Osteogenesis; Osteoporosis; Pharmacology/Toxicology; Pharmacy; Phytochemicals; Plant Extracts - isolation & purification; Plant Extracts - pharmacology; Plant Sciences; Proto-Oncogene Proteins c-fos - metabolism; RANK Ligand - antagonists & inhibitors; RANK Ligand - metabolism; Signal Transduction - drug effects; TRANCE protein; Transcription factors; Triterpenes; Triterpenes - isolation & purification; Triterpenes - pharmacology; Triterpenoids
• ISSN: 1340-3443; 1861-0293
• DOI: 10.1007/s11418-020-01444-3

Fourteen triterpenes, lup-20(29)-ene-3β,6β-diol ( 1 ), betulin ( 2 ), lupeol caffeate ( 3 ), 3β-caffeoyloxylup-20(29)-en-6α-ol ( 4 ), betulin-3β-yl-caffeate ( 5 ), 3β- trans -feruloylbetulin ( 6 ), betulinaldehyde 3-caffeate ( 7 ), 3- O - trans -caffeoylbetulinic acid ( 8 ), dammarenediol II 3-caffeate ( 9 ), 12-oleanene-3β,6α-diol ( 10 ), 11α-hydroxy-3β-amyrin ( 11 ), nivadiol ( 12 ), 29-hydroxyfriedelin ( 13 ), and celastrusin A ( 14 ) were isolated from Celastrus orbiculatus Thunb. and evaluated for their activity on receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation in bone marrow macrophages (BMMs). Compounds betulin ( 2 ), betulin-3β-yl-caffeate ( 5 ), 3β- trans -feruloylbetulin ( 6 ), and 3- O - trans -caffeoylbetulinic acid ( 8 ) significantly inhibited osteoclast formation in a dose-dependent manner. Among these, betulin-3β-yl-caffeate ( 5 ) exhibited the most potent inhibitory activity. We demonstrated that betulin-3β-yl-caffeate ( 5 ) suppressed F-actin-ring formation and bone resorption activity. At the molecular level, betulin-3β-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-3β-yl-caffeate ( 5 ) may be a promising candidate for the treatment of osteoclast-related diseases such as osteoporosis.