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ADAMTS-7 forms a positive feedback loop with TNF-α in the pathogenesis of osteoarthritis
  1. Yongjie Lai1,2,
  2. Xiaohui Bai1,
  3. Yunpeng Zhao1,
  4. Qingyun Tian1,
  5. Ben Liu1,
  6. Edward A Lin1,
  7. Yuqing Chen3,
  8. Brendan Lee3,
  9. C Thomas G Appleton4,
  10. Frank Beier4,
  11. Xiu-Ping Yu2,
  12. Chuan-ju Liu1,5
  1. 1Department of Orthopaedic Surgery, New York University Medical Center, New York, New York, USA
  2. 2Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong, China
  3. 3Department of Molecular and Human Genetics, Baylor College of Medicine, Howard Hughes Medical Institute, Houston, Texas, USA
  4. 4Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Alberta, Canada
  5. 5Department of Cell Biology, New York University School of Medicine, New York, New York, USA
  1. Correspondence to Professor Xiu-Ping Yu, Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong 250012, PR China; yuxp{at}sdu.edu.cn; or Dr Chuan-Ju Liu, Department of Orthopaedic Surgery, New York University School of Medicine, 301 East 17th Street, New York, NY 10003, USA; chuanju.liu{at}nyumc.org

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.

  • Arthritis
  • Chondrocytes
  • Osteoarthritis
  • TNF-alpha

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