Foxo transcription factors in meniscus development, aging and osteoarthritis

Purpose: Meniscus damage is one of the most common musculoskeletal injuries. Although new methods for arthroscopic meniscal repair are being applied, these are mainly indicated in young patients with a traumatic tear within, or close to, the vascular zone, and failure rates are high. Only limited information in available on mechanisms that control meniscus cell homeostasis and how such mechanisms change with aging or after trauma and set the stage for meniscus degeneration. FoxO transcription factors have important functions in regulating cellular defense responses to stress, and influence life span and aging-related diseases in model organisms. The objective of this study was to analyze how FoxO expression in meniscus changes during aging and OA development, to determine the consequences of FoxO gene deletion for meniscus integrity and identify genes and functions that are regulated by FoxO in meniscus cells. Methods: FoxO expression was examined at mRNA and protein levels in young, normal aged and OA-affected human menisci and in mouse models of age-related, surgical-induced and exercise-induced models of OA. FoxO function was examined in vivo by conditional gene deletions in mice. In human meniscus cells, gene expression changes were analyzed following FoxO inhibition and FoxO overexpression. Results: In human OA menisci, FoxO1 and 3 expressions were significantly reduced compared with normal menisci from young and old normal donors. FoxO1 and 3 were also significantly reduced in mouse menisci during aging and in surgical and mechanical overuse models of OA. Mice with Col2Cre-mediated FoxO1 and combined FoxO1, 3, 4 deletions showed abnormal postnatal meniscus development and spontaneously manifested meniscus lesions by 6 months of age. In mice with Col2Cre-mediated deletion of FoxO3 or FoxO4, meniscus development was normal but more severe changes occurred in aging than in control mice. Combined deletion of FoxO1, 3 and 4 in mature AcanCreERT2 mice increased the severity of meniscus damage in the surgical and mechanical overuse and aging models of OA. Expression of autophagy and anti-oxidant defense genes was significantly reduced in menisci from mice with FoxO deletion and several meniscus specific genes were dysregulated. In cultured human meniscus cells, FoxO1 inhibitor suppressed meniscus specific genes, autophagy and anti-oxidant defense genes. These genes were increased in human OA meniscus cells by adenoviral FoxO1. Conclusions: This is the first study of FoxO transcription factors in meniscus and the first detailed study of a transcription factor in mature meniscus. FoxO expression is reduced in meniscus aging and following meniscus injury in humans and mice. FoxO deletion in mice leads to accelerate aging-related and mechanical injury induced meniscus damage, suggesting that the reduced FoxO expression is a factor that contributes to meniscus degeneration. Approaches that increase FoxO expression or activity have potential to protect against aging-related and mechanical injury-related meniscus damage and OA development.View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)