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

Significance Meniscus damage is a common musculoskeletal injury and a major risk factor for knee osteoarthritis (OA). An important knowledge gap exists about meniscus cell homeostasis mechanisms and how their impairment contributes to meniscus pathology following trauma and in aging. Forkhead Box O (FoxO) transcription factors are essential regulators of cellular homeostasis. We performed analysis of expression patterns and function of FoxO in human and mouse menisci. Our results show that FoxOs are suppressed in degenerated meniscus and that FoxO1 regulates meniscus growth and maturation, while both FoxO1 and 3 have protective functions in meniscus during aging and OA. These discoveries provide insight into mechanisms of meniscus degeneration and targets for therapeutic intervention. 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.