FoxO transcription factors modulate autophagy and proteoglycan 4 in cartilage homeostasis and osteoarthritis.
FoxO transcription factors modulate autophagy and proteoglycan 4 in cartilage homeostasis and osteoarthritis.
复制标题
DOI：
10.1126/scitranslmed.aan0746
复制
发表时间：
2018-02-14
影响因子：
17.1
通讯作者：
Lotz MK
中科院分区：
文献类型：
--
作者：
Matsuzaki T;Alvarez-Garcia O;Mokuda S;Nagira K;Olmer M;Gamini R;Miyata K;Akasaki Y;Su AI;Asahara H;Lotz MK
衰老是骨关节炎（OA）的主要危险因素。FoxO转录因子保护细胞和生物体老化，软骨中FoxO表达随着老化和OA而减少。为了研究软骨功能中的FoxO，将单和三重FoxO 1/3/4 floxed小鼠与Col 2-Cre小鼠杂交以产生Col 2Cre-FoxO 1、3和4单敲除（KO）和三重KO小鼠（Col 2Cre-TKO）。在1或2个月时，Col 2Cre-TKO和Col 2Cre-FoxO 1 KO小鼠的关节软骨显著厚于对照小鼠。这与体内和体外Col 2Cre-TKO小鼠软骨细胞增殖增加有关。在Col 2Cre-TKO和Col 2Cre-FoxO 1 KO小鼠中，软骨、滑膜和软骨下骨在4至6月龄之间发生OA样变化。Col 2 Cre-FoxO 3和FoxO 4 KO小鼠直到18个月时才显示出软骨异常，此时Col 2 Cre-FoxO 3 KO小鼠出现更严重的自发性OA。自噬和抗氧化防御基因在Col 2Cre-TKO小鼠中减少。使用聚集蛋白聚糖（Acan）-CreERT 2（AcanCreERT-TKO）在成熟小鼠中缺失三重FoxO 1/3/4也导致自发性软骨降解和由手术膝关节不稳定或跑步机跑步诱导的OA严重程度增加。Col 2Cre-TKO和AcanCreERT-TKO小鼠的浅表区表现出细胞密度降低和Prg 4显著降低。在体外，异位FoxO 1表达增加Prg 4，并与TGFβ刺激协同作用。在OA软骨细胞中，FoxO 1的过表达减少了炎症介质、软骨降解酶，增加了保护基因并拮抗了IL-1β的作用。我们的观察表明，FoxOs在出生后软骨发育，成熟和体内平衡中起着关键作用，并保护免受OA相关的软骨损伤。FoxO在出生后软骨发育、成熟、稳态和骨关节炎发病机制中起关键作用。
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 FoxO in cartilage function, single and triple FoxO1/3/4 floxed mice were crossed with Col2-Cre mice to generate Col2Cre-FoxO1, 3, and 4 single knockout (KO) and triple KO mice (Col2Cre-TKO). Articular cartilage in Col2Cre-TKO and Col2Cre-FoxO1 KO mice was significantly thicker than in control mice at 1 or 2 months. 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 when Col2Cre-FoxO3 KO mice had more severe spontaneous OA. Autophagy and anti-oxidant defense genes were reduced in Col2Cre-TKO mice. Deletion of triple FoxO1/3/4 in mature mice using Aggrecan(Acan)-CreERT2 (AcanCreERT-TKO) also led to spontaneous cartilage degradation and increased severity of OA induced by surgical knee instability or treadmill running. The superficial zone of Col2Cre-TKO and AcanCreERT-TKO mice exhibited reduced cell density and markedly decreased Prg4. In vitro, ectopic FoxO1 expression increased Prg4 and synergized with TGFβ stimulation. In OA chondrocytes, overexpression of FoxO1 reduced inflammatory mediators, cartilage-degrading enzymes, increased protective genes and antagonized IL-1β effects. Our observations suggest that FoxOs play a key role in postnatal cartilage development, maturation and homeostasis and protects against OA-associated cartilage damage. FoxOs play a key role in postnatal cartilage development, maturation, homeostasis, and osteoarthritis pathogenesis.
登录
查看更多内容
影响因子：
9.9
作者：
Eijkelenboom, Astrid;Mokry, Michal;Burgering, Boudewijn M. T.
通讯作者：
Burgering, Boudewijn M. T.
影响因子：
2.8
作者：
Krenn, V;Morawietz, L;König, A
通讯作者：
König, A
影响因子：
2.9
作者：
JAY, GD;HONG, BS
通讯作者：
HONG, BS
影响因子：
4.1
作者：
Cuellar, Araceli;Reddi, A. Hari
通讯作者：
Reddi, A. Hari
影响因子：
7
作者：
Glasson, S. S.;Blanchet, T. J.;Morris, E. A.
通讯作者：
Morris, E. A.