ADAMTS-7 forms a positive feedback loop with TNF-α in the pathogenesis of osteoarthritis

Authors

Yongjie Lai, New York University
Xiaohui Bai, New York University
Yunpeng Zhao, New York University
Qingyun Tian, New York University
Ben Liu, New York University
Edward A. Lin, New York University
Yuqing Chen, Howard Hughes Medical Institute
Brendan Lee, Howard Hughes Medical Institute
C. Thomas Appleton, Western University
Frank Beier, Western University
Xiu Ping Yu, Shandong University
Chuan Ju Liu, New York University

Document Type

Article

Publication Date

1-1-2014

Journal

Annals of the Rheumatic Diseases

First Page

1575

Last Page

1584

URL with Digital Object Identifier

10.1136/annrheumdis-2013-203561

Abstract

Objective: To examine the expression of ADAMTS-7 during the progression of osteoarthritis (OA), defining its role in the pathogenesis of OA, and elucidating the molecular events involved. Methods: ADAMTS-7 expression in cartilage of a rat OA model was assayed using immunohistochemistry. Cartilage-specific ADAMTS-7 transgenic mice and ADAMTS-7 small interfering (si)RNA knockdown mice were generated and used to analyse OA progression in both spontaneous and surgically induced OA models. Cartilage degradation and OA was evaluated using Safranin-O staining, immunohistochemistry, ELISA and western blotting. In addition, mRNA expression of tumour necrosis factor (TNF)-α and metalloproteinases known to be involved in cartilage degeneration in OA was analysed. Furthermore, the transactivation of ADAMTS-7 by TNF-α and its downstream NF-κB signalling was measured using reporter gene assay. Results: ADAMTS-7 expression was elevated during disease progression in the surgically induced rat OA model. Targeted overexpression of ADAMTS-7 in chondrocytes led to chondrodysplasia characterised by short-limbed dwarfism and a delay in endochondral ossification in 'young mice' and a spontaneous OA-like phenotype in 'aged' mice. In addition, overexpression of ADAMTS-7 led to exaggerated breakdown of cartilage and accelerated OA progression, while knockdown of ADAMTS-7 attenuated degradation of cartilage matrix and protected against OA development, in surgically induced OA models. ADAMTS-7 upregulated TNF-α and metalloproteinases associated with OA; in addition, TNF-α induced ADAMTS-7 through NF-κB signalling. Conclusions: ADAMTS-7 and TNF-α form a positive feedback loop in the regulation of cartilage degradation and OA progression, making them potential molecular targets for prevention and treatment of joint degenerative diseases, including OA.

Notes

Article is openly available from the journal.