Dysregulated circadian rhythm pathway in human osteoarthritis: NR1D1 and BMAL1 suppression alters TGF-β signaling in chondrocytes

被引：73

作者：

Akagi, R. ^{[1
,2
]}

Akatsu, Y. ^{[1
,2
]}

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

Alvarez-Garcia, O. ^{[1
]}

Teramura, T. ^{[1
]}

Muramatsu, Y. ^{[1
]}

Saito, M. ^{[1
,3
]}

Sasho, T. ^{[2
]}

Su, A. I. ^{[1
]}

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

机构：

[1] Scripps Res Inst, Dept Mol & Expt Med, MEM 161,10550 North Torrey Pines Rd, La Jolla, CA 92037 USA

[2] Chiba Univ, Sch Med, Dept Orthopaed Surg, 1-8-1 Inohana, Chiba 2608677, Japan

[3] Toho Univ, Sakura Med Ctr, Dept Orthopaed Surg, 564-1 Shimoshizu, Sakura, Chiba 2858741, Japan

来源：

OSTEOARTHRITIS AND CARTILAGE | 2017年 / 25卷 / 06期

基金：

美国国家卫生研究院;

关键词：

Circadian rhythm; NR1D1; BMAL1; Osteoarthritis; TGF-beta; REV-ERB-ALPHA; ORPHAN NUCLEAR RECEPTOR; GENE-EXPRESSION; TIMING SYSTEM; CLOCK; CARTILAGE; TRANSCRIPTION; SERUM; HOMEOSTASIS; DISRUPTION;

D O I：

10.1016/j.joca.2016.11.007

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：

100224 [整形外科学];

摘要：

Objectives: Circadian rhythm (CR) was identified by RNA sequencing as the most dysregulated pathway in human osteoarthritis (OA) in articular cartilage. This study examined circadian rhythmicity in cultured chondrocytes and the role of the CR genes NR1D1 and BMAL1 in regulating chondrocyte functions. Methods: RNA was extracted from normal and OA-affected human knee cartilage (n = 14 each). Expression levels of NR1D1 and BMAL1 mRNA and protein were assessed by quantitative PCR and immunohistochemistry. Human chondrocytes were synchronized and harvested at regular intervals to examine circadian rhythmicity in RNA and protein expression. Chondrocytes were treated with small interfering RNA (siRNA) for NR1D1 or BMAL1, followed by RNA sequencing and analysis of the effects on the transforming growth factor beta (TGF-beta) pathway. Results: NR1D1 and BMAL1 mRNA and protein levels were significantly reduced in OA compared to normal cartilage. In cultured human chondrocytes, a clear circadian rhythmicity was observed for NR1D1 and BMAL1. Increased BMAL1 expression was observed after knocking down NR1D1, and decreased NR1D1 levels were observed after knocking down BMAL1. Sequencing of RNA from chondrocytes treated with NR1D1 or BMAL1 siRNA identified 330 and 68 significantly different genes, respectively, and this predominantly affected the TGF-beta signaling pathway. Conclusions: The CR pathway is dysregulated in OA cartilage. Interference with circadian rhythmicity in cultured chondrocytes affects TGF-beta signaling, which is a central pathway in cartilage homeostasis. (C) 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

引用

页码：943 / 951

页数：9

共 61 条

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