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转化生长因子β1信号通路通过FOXO1-自噬轴保护软骨细胞免受氧化应激。

TGFβ1 signaling protects chondrocytes against oxidative stress via FOXO1-autophagy axis.

作者信息

Kurakazu I, Akasaki Y, Tsushima H, Sueishi T, Toya M, Kuwahara M, Uchida T, Lotz M K, Nakashima Y

机构信息

Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka city, Fukuoka, 812-8582, Japan.

Department of Molecular Medicine, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

出版信息

Osteoarthritis Cartilage. 2021 Nov;29(11):1600-1613. doi: 10.1016/j.joca.2021.07.015. Epub 2021 Aug 20.

DOI:10.1016/j.joca.2021.07.015
PMID:34419603
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8789330/
Abstract

OBJECTIVE: 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. METHODS: 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 (HO) treatment was analyzed. The protective effect of TGFβ1 against HO treatment was assessed by cell viability assay and TUNEL assay. RESULTS: 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 HO treatment, TGFβ1 promoted expression of LC3-II. TGFβ1 pretreatment suppressed cell death of chondrocytes following HO treatment, but this protective effect was abolished by FOXO1 knockdown. CONCLUSIONS: TGFβ1 protects chondrocytes against oxidative stress via the FOXO1-autophagy axis, and a reduction in ALK5 expression might cause reduced FOXO1 expression with aging.

摘要

目的：叉头框O1（FOXO1）转录因子是自噬的关键调节因子。在软骨细胞中，随着衰老FOXO1表达降低，由于自噬功能障碍导致骨关节炎，但FOXO1表达调控的机制以及衰老过程中表达降低的原因仍不清楚。我们研究了转化生长因子β1（TGFβ1）信号通路调节FOXO1-自噬轴的机制。 方法：检测TGFβ1处理后软骨细胞中FOXO1的表达。进行免疫组织化学以评估年轻、中年和老年小鼠膝关节中激活素受体样激酶5（ALK5）和FOXO1的水平。评估ALK5抑制剂以及SMAD3或SMAD2基因敲低对FOXO1表达的影响。分析TGFβ1在过氧化氢（HO）处理后对自噬的作用。通过细胞活力测定和TUNEL测定评估TGFβ1对HO处理的保护作用。 结果：TGFβ1促进FOXO1 mRNA和蛋白的表达。ALK5和FOXO1的表达均随衰老而降低。抑制ALK5和敲低SMAD3可抑制TGFβ1对FOXO1表达的诱导作用，而敲低SMAD2则增强这种诱导作用。TGFβ1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HO处理下，TGFβ1促进LC3-II的表达。TGFβ1预处理可抑制HO处理后软骨细胞的死亡，但FOXO1基因敲低可消除这种保护作用。 结论：TGFβ1通过FOXO1-自噬轴保护软骨细胞免受氧化应激，ALK5表达降低可能是衰老过程中FOXO1表达降低的原因。

相似文献

[1]
TGFβ1 signaling protects chondrocytes against oxidative stress via FOXO1-autophagy axis.

Osteoarthritis Cartilage. 2021-11

[2]
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J Biol Chem. 2019-10-10

[3]
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[4]
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[5]
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[6]
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Arthritis Res Ther. 2017-5-31

[7]
Knockdown of SGK1 alleviates the IL-1β-induced chondrocyte anabolic and catabolic imbalance by activating FoxO1-mediated autophagy in human chondrocytes.

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[8]
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[10]
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引用本文的文献

[1]
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[2]
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J Orthop Translat. 2025-8-10

[3]
Chinese Massage (Tuina) Attenuates Knee Osteoarthritis by Modulating Autophagy-Related Cytokines: A Multidisciplinary Methodological Investigation.

J Inflamm Res. 2025-8-2

[4]
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BMC Vet Res. 2025-8-6

[5]
Inhibition of CHI3L1 attenuates excessive autophagy in intestinal epithelial cells to reduce the severity of necrotizing enterocolitis.

Cell Death Discov. 2025-4-5

[6]
Traditional Chinese Manual Therapy (Tuina) Improves Knee Osteoarthritis by Regulating Chondrocyte Autophagy and Apoptosis via the PI3K/AKT/mTOR Pathway: An in vivo Rat Experiment and Machine Learning Study.

J Inflamm Res. 2024-9-17

[7]
ADPN Regulates Oxidative Stress-Induced Follicular Atresia in Geese by Modulating Granulosa Cell Apoptosis and Autophagy.

Int J Mol Sci. 2024-5-15

[8]
Uncovering the shared neuro-immune-related regulatory mechanisms between spinal cord injury and osteoarthritis.

Heliyon. 2024-4-25

[9]
Aging and the emerging role of cellular senescence in osteoarthritis.

Osteoarthritis Cartilage. 2024-4

[10]
FOXO 1 deletion in chondrocytes rescues diabetes-impaired fracture healing by restoring angiogenesis and reducing apoptosis.

Front Endocrinol (Lausanne). 2023

本文引用的文献

[1]
TGFβ attenuates cartilage extracellular matrix degradation via enhancing FBXO6-mediated MMP14 ubiquitination.

Ann Rheum Dis. 2020-5-14

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FOXO1 transcription factor regulates chondrogenic differentiation through transforming growth factor β1 signaling.

J Biol Chem. 2019-10-10

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Osteoarthritis Cartilage. 2017-8-8

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Osteoarthritis Cartilage. 2017-7-14

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Suppression of Sestrins in aging and osteoarthritic cartilage: dysfunction of an important stress defense mechanism.

Osteoarthritis Cartilage. 2017-2

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