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.

中文翻译：

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FOXO1 和 FOXO3 转录因子在衰老和骨关节炎期间的半月板发育和稳态中具有独特的功能。


本研究的目的是检查半月板中 FoxO 的表达和 FoxO 的功能。与年轻和老年正常供体的正常半月板相比，患有骨关节炎（OA）的人膝关节半月板中，FoxO1和3的表达显着降低。在衰老过程中以及手术半月板不稳定或机械过度使用引起的 OA 期间，小鼠半月板中 FoxO1 和 3 的表达也显着降低。 FoxO1 缺失以及 FoxO1、3 和 4 的组合缺失会诱导小鼠产后半月板发育异常，这些突变小鼠在 6 个月时自发表现出半月板病理。 Col2Cre 介导的 FoxO3 或 FoxO4 缺失的小鼠半月板发育正常，但具有更严重的衰老相关损伤。在成熟的 AcanCreERT2 小鼠中，FoxO1、3 和 4 的缺失加重了所有实验性 OA 模型中的半月板损伤。 FoxO 缺失抑制了自噬和抗氧化防御基因，并改变了几个半月板特异性基因。这些基因的表达在培养的人半月板细胞中受到腺病毒 FoxO1 的调节。这些结果表明 FoxO1 在半月板发育和成熟中起着关键作用，FoxO1 和 3 都支持稳态并防止半月板因机械过度使用以及衰老和 OA 过程中而受损。