TGFβ1 signaling protects chondrocytes against oxidative stress via FOXO1-autophagy axis.
TGFβ1 signaling protects chondrocytes against oxidative stress via FOXO1-autophagy axis.
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DOI：
10.1016/j.joca.2021.07.015
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发表时间：
2021-11
影响因子：
7
通讯作者：
Nakashima Y
中科院分区：
文献类型：
--
作者：
Kurakazu I;Akasaki Y;Tsushima H;Sueishi T;Toya M;Kuwahara M;Uchida T;Lotz MK;Nakashima Y
叉头盒O1(FOXO1)转录因子是自噬的关键调控因子。在软骨细胞中，FOXO1的表达随着年龄的增长而减少，由于自噬功能障碍而导致骨关节炎，但FOXO1表达的调节以及随着年龄的增长而表达减少的机制尚不清楚。我们研究了转化生长因子β-1(转化生长因子-β-1)信号调节FOXO-1-自噬轴的机制。用转化生长因子β-1处理后的软骨细胞检测FOXO1的表达。免疫组织化学方法检测幼年、中年和老年小鼠膝关节中激活素受体样激酶5(ALK5)和FOXO1的表达。观察Alk5抑制剂和Smad3或Smad2基因敲除对FOXO1表达的影响。分析转化生长因子β-1在过氧化氢(H_2O_2)处理后自噬中的作用。用细胞存活率和TUNEL法检测转化生长因子β1对过氧化氢损伤的保护作用。转化生长因子β-1促进FOXO1mRNA和蛋白的表达。Alk5和FOXO1的表达均随增龄而降低。Alk5抑制和Smad3基因敲除可抑制转化生长因子β1诱导的FOXO1表达，而Smad2基因敲除可增强FoxO1的表达。转化生长因子β1通过Smad3-FOXO1途径促进微管相关蛋白1A/1B轻链3B(Lc3)-I蛋白的表达。此外，在H_2O_2处理下，转化生长因子β_1促进了LC_3-II的表达。转化生长因子β-1可抑制H_2O_2诱导的软骨细胞死亡，这种保护作用可被FOXO_1基因敲除。转化生长因子β1通过FoxO1-自噬轴保护软骨细胞免受氧化应激，随着年龄的增长，Alk5表达的减少可能导致FoxO1的表达减少。
The forkhead box O1 (FOXO1) transcription factor is a key regulator of autophagy. In chondrocytes, reduced FOXO1 expression with aging causes osteoarthritis due to dysfunction of autophagy, but the mechanisms underlying regulation of FOXO1 expression and the reduction in expression with aging remain unclear. We investigated the mechanism by which transforming growth factor β1 (TGFβ1) signaling regulates the FOXO1–autophagy axis. Expression of FOXO1 was measured in chondrocytes after TGFβ1 treatment. Immunohistochemistry was performed to estimate the levels of activin receptor-like kinase 5 (ALK5) and FOXO1 in the knee joints of young, middle-aged and old mice. The effects of the ALK5 inhibitor and SMAD3 or SMAD2 knockdown on FOXO1 expression were evaluated. The role of TGFβ1 in autophagy after hydrogen peroxide (H2O2) treatment was analyzed. The protective effect of TGFβ1 against H2O2 treatment was assessed by cell viability assay and TUNEL assay. TGFβ1 promoted the expression of FOXO1 mRNA and protein. Both ALK5 and FOXO1 expression decreased with aging. ALK5 inhibition and SMAD3 knockdown suppressed induction of FOXO1 expression by TGFβ1, whereas SMAD2 knockdown increased it. TGFβ1 promoted the expression of microtubule-associated proteins 1A/1B light chain 3B (LC3)-I protein via the SMAD3–FOXO1 pathway. Furthermore, under H2O2 treatment, TGFβ1 promoted expression of LC3-II. TGFβ1 pretreatment suppressed cell death of chondrocytes following H2O2 treatment, but this protective effect was abolished by FOXO1 knockdown. TGFβ1 protects chondrocytes against oxidative stress via the FOXO1–autophagy axis, and a reduction in ALK5 expression might cause reduced FOXO1 expression with aging.
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影响因子：
7
作者：
Ansari MY;Khan NM;Ahmad I;Haqqi TM
通讯作者：
Haqqi TM
影响因子：
7.3
作者：
Gellibert, FO;Woolven, J;Hartley, D
通讯作者：
Hartley, D
DOI：
10.1073/pnas.0502738102
发表时间：
2005-08-09
影响因子：
11.1
作者：
Matsuzaki, H;Daitoku, H;Fukamizu, A
通讯作者：
Fukamizu, A
影响因子：
4.8
作者：
Ding, Yan;Kim, Jin Kuk;Choi, Mary E.
通讯作者：
Choi, Mary E.
影响因子：
11.2
作者：
Kiyono, Kunihiko;Suzuki, Hiroshi I.;Miyazono, Kohei
通讯作者：
Miyazono, Kohei