Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Sci Transl Med. 2018 Feb 14;10(428). doi: 10.1126/scitranslmed.aan0746.
Aging is a main risk factor for osteoarthritis (OA). FoxO transcription factors protect against cellular and organismal aging, and FoxO expression in cartilage is reduced with aging and in OA. To investigate the role of FoxO in cartilage, Col2Cre-FoxO1, 3, and 4 single knockout (KO) and triple KO mice (Col2Cre-TKO) were analyzed. Articular cartilage in Col2Cre-TKO and Col2Cre-FoxO1 KO mice was thicker than in control mice at 1 or 2 months of age. This was associated with increased proliferation of chondrocytes of Col2Cre-TKO mice in vivo and in vitro. OA-like changes developed in cartilage, synovium, and subchondral bone between 4 and 6 months of age in Col2Cre-TKO and Col2Cre-FoxO1 KO mice. Col2Cre-FoxO3 and FoxO4 KO mice showed no cartilage abnormalities until 18 months of age when Col2Cre-FoxO3 KO mice had more severe OA than control mice. Autophagy and antioxidant defense genes were reduced in Col2Cre-TKO mice. Deletion of FoxO1/3/4 in mature mice using Aggrecan(Acan)-CreERT2 (AcanCreERT-TKO) also led to spontaneous cartilage degradation and increased OA severity in a surgical model or treadmill running. The superficial zone of knee articular cartilage of Col2Cre-TKO and AcanCreERT-TKO mice exhibited reduced cell density and markedly decreased In vitro, ectopic FoxO1 expression increased and synergized with transforming growth factor-β stimulation. In OA chondrocytes, overexpression of FoxO1 reduced inflammatory mediators and cartilage-degrading enzymes, increased protective genes, and antagonized interleukin-1β effects. Our observations suggest that FoxO play a key role in postnatal cartilage development, maturation, and homeostasis and protect against OA-associated cartilage damage.
衰老是骨关节炎（OA）的主要危险因素。FoxO 转录因子可预防细胞和机体衰老，软骨中 FoxO 的表达随衰老和 OA 而减少。为了研究 FoxO 在软骨中的作用，分析了 Col2Cre-FoxO1、3 和 4 单敲除（KO）和三重 KO 小鼠（Col2Cre-TKO）。Col2Cre-TKO 和 Col2Cre-FoxO1 KO 小鼠的关节软骨在 1 或 2 月龄时比对照小鼠更厚。这与 Col2Cre-TKO 小鼠体内和体外软骨细胞增殖增加有关。Col2Cre-TKO 和 Col2Cre-FoxO1 KO 小鼠的软骨、滑膜和软骨下骨在 4 至 6 月龄时出现类似 OA 的变化。Col2Cre-FoxO3 和 FoxO4 KO 小鼠在 18 月龄时没有软骨异常，而 Col2Cre-FoxO3 KO 小鼠的 OA 比对照小鼠更严重。Col2Cre-TKO 小鼠的自噬和抗氧化防御基因减少。使用 Aggrecan(Acan)-CreERT2（AcanCreERT-TKO）在成熟小鼠中删除 FoxO1/3/4 也导致自发性软骨降解，并在手术模型或跑步机跑步中增加 OA 严重程度。Col2Cre-TKO 和 AcanCreERT-TKO 小鼠膝关节关节软骨的浅层区细胞密度降低，并且显著降低了体外异位 FoxO1 表达增加，并与转化生长因子-β刺激协同作用。OA 软骨细胞中 FoxO1 的过表达减少了炎症介质和软骨降解酶，增加了保护性基因，并拮抗了白细胞介素-1β的作用。我们的观察表明，FoxO 在出生后软骨发育、成熟和稳态中发挥关键作用，并可预防与 OA 相关的软骨损伤。
