Dysregulated FOXO transcription factors in articular cartilage in aging and osteoarthritis

被引：123

作者：

Akasaki, Y. ^{[1
]}

Hasegawa, A. ^{[1
]}

Saito, M. ^{[1
]}

Asahara, H. ^{[1
,3
,4
]}

Iwamoto, Y. ^{[2
]}

Lotz, M. K. ^{[1
]}

机构：

[1] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA

[2] Kyushu Univ, Grad Sch Med Sci, Dept Orthopaed Surg, Fukuoka 812, Japan

[3] Natl Res Inst Child Hlth & Dev, Tokyo, Japan

[4] Tokyo Med & Dent Univ, Dept Syst Bio Med, Tokyo, Japan

来源：

OSTEOARTHRITIS AND CARTILAGE | 2014年 / 22卷 / 01期

基金：

美国国家卫生研究院;

关键词：

FoxO; Cartilage; Osteoarthritis; Aging; OXIDATIVE STRESS; DOWN-REGULATION; LIFE-SPAN; GROWTH; AUTOPHAGY; ACTIVATION; CELLS; PROLIFERATION; AGGREGATION; DEGRADATION;

D O I：

10.1016/j.joca.2013.11.004

中图分类号：

R826.8 [整形外科学]; R782.2 [口腔颌面部整形外科学]; R726.2 [小儿整形外科学]; R62 [整形外科学（修复外科学）];

学科分类号：

摘要：

Objective: Aging is a major risk factor for osteoarthritis (OA). Forkhead-box class O (FoxO ) transcription factors regulate mechanisms of cellular aging, including protein quality control, autophagy and defenses against oxidative stress. The objective of this study was to analyze FoxO transcription factors in normal, aging and OA cartilage. Design: Knee joints from humans ages 23-90 and from mice at the age of 4-24 months and following surgically induced OA were analyzed for expression of FoxO proteins. Regulation of FoxO protein expression and activation was analyzed in cultured chondrocytes. Results: Human cartilage expressed FOXO1 and FOXO3 but not FOXO4 proteins. FOXO1 and FOXO3 were more strongly expressed the superficial and mid zone as compared to the deep zone and were mainly localized in nuclei. During human joint aging, expression of FOXO1 and FOXO3 was markedly reduced in the superficial zone of cartilage regions exposed to maximal weight bearing. In OA cartilage, chondrocyte clusters showed strong FOX phosphorylation and cytoplasmic localization. Similar patterns of FOXO expression in normal joints and changes in aging and OA were observed in mouse models. In cultured chondrocytes, IL-1 beta and TNF-alpha suppressed FOXO1, while TGF-beta and PDGF increased FOXO1 and FOXO3 expression. FOXO1 and FOXO3 phosphorylation was increased by IL-1 beta, PDGF, bFGF, IGF-1, and the oxidant t-BHP. Conclusions: Normal articular cartilage has a tissue specific signature of FoxO expression and activation and this is profoundly altered in aging and OA in humans and mice. Changes in FoxO expression and activation may be involved in cartilage aging and OA. (C) 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

引用

页码：162 / 170

页数：9

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