FOXO1 and FOXO3 transcription factors have unique functions in meniscus development and homeostasis during aging and osteoarthritis.
FoxO
chondrocytes
fibroblasts
meniscus
osteoarthritis
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
11 02 2020
11 02 2020
Historique:
pubmed:
26
1
2020
medline:
12
5
2020
entrez:
26
1
2020
Statut:
ppublish
Résumé
The objective of this study was to examine FoxO expression and FoxO function in meniscus. In menisci from human knee joints with osteoarthritis (OA), FoxO1 and 3 expression were significantly reduced compared with normal menisci from young and old normal donors. The expression of FoxO1 and 3 was also significantly reduced in mouse menisci during aging and OA induced by surgical meniscus destabilization or mechanical overuse. Deletion of FoxO1 and combined FoxO1, 3, and 4 deletions induced abnormal postnatal meniscus development in mice and these mutant mice spontaneously displayed meniscus pathology at 6 mo. Mice with Col2Cre-mediated deletion of FoxO3 or FoxO4 had normal meniscus development but had more severe aging-related damage. In mature AcanCreERT2 mice, the deletion of FoxO1, 3, and 4 aggravated meniscus lesions in all experimental OA models. FoxO deletion suppressed autophagy and antioxidant defense genes and altered several meniscus-specific genes. Expression of these genes was modulated by adenoviral FoxO1 in cultured human meniscus cells. These results suggest that FoxO1 plays a key role in meniscus development and maturation, and both FoxO1 and 3 support homeostasis and protect against meniscus damage in response to mechanical overuse and during aging and OA.
Identifiants
pubmed: 31980519
pii: 1918673117
doi: 10.1073/pnas.1918673117
pmc: PMC7022148
doi:
Substances chimiques
Forkhead Box Protein O1
0
Forkhead Box Protein O3
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3135-3143Subventions
Organisme : NIA NIH HHS
ID : R01 AG049617
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG062533
Pays : United States
Organisme : NIA NIH HHS
ID : R37 AG059418
Pays : United States
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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