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Dual targeting of SREBP2 and ERRα by carnosic acid suppresses RANKL-mediated osteoclastogenesis and prevents ovariectomy-induced bone loss.
- Source :
-
Cell death and differentiation [Cell Death Differ] 2020 Jul; Vol. 27 (7), pp. 2048-2065. Date of Electronic Publication: 2020 Jan 06. - Publication Year :
- 2020
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Abstract
- Osteoporosis develops because of impaired bone formation and/or excessive bone resorption. Several pharmacological treatment of osteoporosis has been developed; however, new treatments are still necessary. Cholesterol and estrogen receptor-related receptor alpha (ERRα) promote osteoclasts formation, survival, and cellular fusion and thus become high risk factors of osteoporosis. In this study, we identified that carnosic acid (CA) suppressed bone loss by dual-targeting of sterol regulatory element-binding protein 2 (SREBP2, a major regulator that regulates cholesterol synthesis) and ERRα. Mechanistically, CA reduced nuclear localization of mature SREBP2 and suppressed de novo biogenesis of cholesterol. CA subsequently decreased the interaction between ERRα and peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1β), resulting in decreased the transcription activity of ERRα and its target genes expression. Meanwhile, CA directly bound to the ligand-binding domain of ERRα and significantly promoted its ubiquitination and proteasomal degradation. Subsequently, STUB1 was identified as the E3 ligase of ERRα. The lysine residues (K51 and K68) are essential for ubiquitination and proteasomal degradation of ERRα by CA. In conclusion, CA dually targets SREBP2 and ERRα, thus inhibits the RANKL-induced osteoclast formation and improves OVX-induced bone loss. CA may serve as a lead compound for pharmacological control of osteoporosis.
- Subjects :
- Animals
Bone Resorption diagnostic imaging
Bone Resorption etiology
Bone Resorption pathology
Cell Differentiation drug effects
Cell Line
Cholesterol metabolism
Female
Humans
Luciferases metabolism
Lysine metabolism
Mice, Inbred C57BL
Nuclear Proteins metabolism
Osteoclasts drug effects
Osteoporosis blood
Osteoporosis diagnostic imaging
Osteoporosis etiology
Proteasome Endopeptidase Complex metabolism
Proteolysis drug effects
Tartrate-Resistant Acid Phosphatase metabolism
Transcription Factors metabolism
Ubiquitin-Protein Ligases
Ubiquitination drug effects
ERRalpha Estrogen-Related Receptor
Abietanes pharmacology
Bone Resorption prevention & control
Osteoclasts metabolism
Osteogenesis drug effects
Ovariectomy
RANK Ligand pharmacology
Receptors, Estrogen metabolism
Sterol Regulatory Element Binding Protein 2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5403
- Volume :
- 27
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cell death and differentiation
- Publication Type :
- Academic Journal
- Accession number :
- 31907393
- Full Text :
- https://doi.org/10.1038/s41418-019-0484-5