ADAMTS-7 forms a positive feedback loop with TNF-α in the pathogenesis of osteoarthritis.
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.
Department of Orthopaedic Surgery, New York University Medical Center, New York, New York, USA Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong, China.
Yongjie
Y
Lai
Department of Orthopaedic Surgery, New York University Medical Center, New York, New York, USA.
Xiaohui
X
Bai
Department of Orthopaedic Surgery, New York University Medical Center, New York, New York, USA.
Yunpeng
Y
Zhao
Department of Orthopaedic Surgery, New York University Medical Center, New York, New York, USA.
Qingyun
Q
Tian
Department of Orthopaedic Surgery, New York University Medical Center, New York, New York, USA.
Ben
B
Liu
Department of Orthopaedic Surgery, New York University Medical Center, New York, New York, USA.
Edward A
EA
Lin
Department of Molecular and Human Genetics, Baylor College of Medicine, Howard Hughes Medical Institute, Houston, Texas, USA.
Yuqing
Y
Chen
Department of Molecular and Human Genetics, Baylor College of Medicine, Howard Hughes Medical Institute, Houston, Texas, USA.
Brendan
B
Lee
Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Alberta, Canada.
C Thomas
CT
Appleton
Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Alberta, Canada.
Frank
F
Beier
Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong, China.
Xiu-Ping
XP
Yu
Department of Orthopaedic Surgery, New York University Medical Center, New York, New York, USA Department of Cell Biology, New York University School of Medicine, New York, New York, USA.
Chuan-Ju
CJ
Liu
D051722:ADAM Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000071118:ADAMTS7 Protein; D000375:Aging / Q000276:immunology; D000818:Animals; D002356:Cartilage / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D025461:Feedback, Physiological; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010003:Osteoarthritis / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D000071118:ADAMTS7 Protein; C496264:Adamts7 protein, mouse; C539627:Adamts7 protein, rat
Arthritis; Chondrocytes; Osteoarthritis; TNF-alpha