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Repurposing the multiple sclerosis drug Siponimod for osteoporosis treatment.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 2024 Jul 05; Vol. 974, pp. 176630. Date of Electronic Publication: 2024 Apr 30. - Publication Year :
- 2024
-
Abstract
- Osteoporosis is the most common bone disorder, in which an imbalance between osteoclastic bone resorption and osteoblastic bone formation disrupts bone homeostasis. Osteoporosis management using anti-osteoclastic agents is a promising strategy; however, this remains an unmet need. Sphingosine-1-phosphate (S1P) and its receptors (S1PRs) are essential for maintaining bone homeostasis. Here, we identified that Siponimod, a Food and Drug Administration-approved S1PR antagonist for the treatment of multiple sclerosis, shows promising therapeutic effects against osteoporosis by inhibiting osteoclast formation and function. We found that Siponimod inhibited osteoclast formation in a dose-dependent manner without causing cytotoxicity. Podosome belt staining and bone resorption assays indicated that Siponimod treatment impaired osteoclast function. Western blot and qPCR assays demonstrated that Siponimod suppressed the expression of osteoclast-specific markers, including C-Fos, Nftac1, and Ctsk. Mechanistically, we validated that Siponimod downregulated receptor activator of nuclear factor kappa B ligand (RANKL)-induced Mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) signaling pathways during osteoclastogenesis. Moreover, in a preclinical mouse model, Siponimod prevented ovariectomy-induced bone loss by suppressing osteoclast activity in vivo. Collectively, these results suggest that Siponimod could serve as an alternative therapeutic agent for the treatment of osteoporosis.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Mice
Female
Sphingosine 1 Phosphate Receptor Modulators pharmacology
Sphingosine 1 Phosphate Receptor Modulators therapeutic use
Osteogenesis drug effects
NF-kappa B metabolism
Mice, Inbred C57BL
RAW 264.7 Cells
Bone Resorption drug therapy
Signal Transduction drug effects
RANK Ligand metabolism
Humans
Osteoporosis drug therapy
Osteoporosis metabolism
Osteoclasts drug effects
Osteoclasts metabolism
Drug Repositioning
Benzyl Compounds pharmacology
Benzyl Compounds therapeutic use
Azetidines pharmacology
Azetidines therapeutic use
Multiple Sclerosis drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0712
- Volume :
- 974
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 38692426
- Full Text :
- https://doi.org/10.1016/j.ejphar.2024.176630