FOXO1 and FOXO3 transcription factors have unique functions in meniscus development and homeostasis during aging and osteoarthritis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 6; pp. 3135 - 3143
• Main Authors: Lee, Kwang Il, Choi, Sungwook, Matsuzaki, Tokio, Alvarez-Garcia, Oscar, Olmer, Merissa, Grogan, Shawn P., D’Lima, Darryl D., Lotz, Martin K.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11.02.2020
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Aging (artificial); Animals; Antioxidants; Arthritis; Autophagy; Biological Sciences; Biomedical materials; Clonal deletion; Damage; Deletion; Destabilization; Disease Models, Animal; Female; Forkhead Box Protein O1 - analysis; Forkhead Box Protein O1 - genetics; Forkhead Box Protein O1 - metabolism; Forkhead Box Protein O3 - analysis; Forkhead Box Protein O3 - genetics; Forkhead Box Protein O3 - metabolism; Forkhead protein; FOXO1 protein; FOXO3 protein; FOXO4 protein; Gene expression; Genes; Homeostasis; Humans; Knee; Knee Joint - metabolism; Male; Maturation; Meniscus; Meniscus - growth & development; Meniscus - metabolism; Mice; Mice, Knockout; Middle Aged; Mutants; Osteoarthritis; Osteoarthritis - metabolism; Phagocytosis; Transcription factors; Young Adult; FoxO; fibroblasts; chondrocytes; meniscus; osteoarthritis
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1918673117

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.