Desloratadine inhibits heterotopic ossification by suppression of BMP2-Smad1/5/8 signaling.
Animals
Bone Morphogenetic Protein 2
/ physiology
Cell Differentiation
/ drug effects
Loratadine
/ analogs & derivatives
Male
Mice
Mice, Inbred C57BL
Ossification, Heterotopic
/ prevention & control
Osteogenesis
/ drug effects
Receptor, Platelet-Derived Growth Factor alpha
/ analysis
Signal Transduction
/ drug effects
Smad Proteins
/ physiology
Achilles tenotomy mice
BMP-Smad signaling
PDGFRα+ cells
bone QCT/μCT
heterotopic ossification
Journal
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
ISSN: 1554-527X
Titre abrégé: J Orthop Res
Pays: United States
ID NLM: 8404726
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
20
05
2019
accepted:
30
01
2020
pubmed:
12
2
2020
medline:
3
9
2021
entrez:
12
2
2020
Statut:
ppublish
Résumé
Heterotopic ossification (HO) is a pathological condition in which ectopic bone forms within soft tissues such as skeletal muscle. Human platelet-derived growth factor receptor α positive (PDGFRα+) cells, which were proved to be the original cells of HO were incubated in osteogenic differentiation medium with Food and Drug Administration-approved compounds. Alkaline phosphatase activity was measured as a screening to inhibit osteogenic differentiation. For the compounds which inhibited osteogenic differentiation of PDGFRα+ cells, we examined dose dependency of its effect using alizarin red S staining and its cell toxicity using WST-8. In addition, regulation of bone morphogenetic proteins (BMP)-Smad signaling which is the major signal of osteogenic differentiation was investigated by Western blotting to elucidate the mechanism of osteogenesis inhibitory effect by the compound. In vivo experiment, complete transverse incision of Achilles tendons in mice was made and mice were fed the compound by mixing with drinking water after operation. Ten weeks after operation, we assessed and quantified HO by micro-computed tomography scan. Intriguingly, we discovered desloratadine inhibited osteogenic differentiation of PDGFRα+ cells using the drug repositioning method. Desloratadine inhibited osteogenic differentiation of the cells dose dependently without cell toxicity. Desloratadine suppressed phosphorylation of Smad1/5/8 induced by BMP2 in PDGFRα+ cells. In Achilles tenotomy mice model, desloratadine treatment significantly inhibited ectopic bone formation compared with control. In conclusion, we discovered desloratadine inhibited osteogenic differentiation using human PDGFRα+ cells and proved its efficacy using Achilles tenotomy ectopic bone formation model in vivo. Our study paved the way to inhibit HO in early clinical use because of its guaranteed safety.
Substances chimiques
Bone Morphogenetic Protein 2
0
Smad Proteins
0
Loratadine
7AJO3BO7QN
Receptor, Platelet-Derived Growth Factor alpha
EC 2.7.10.1
desloratadine
FVF865388R
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1297-1304Informations de copyright
© 2020 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.
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