Yongjie Lai1, Xiaohui Bai2, Yunpeng Zhao2, Qingyun Tian2, Ben Liu2, Edward A Lin2, Yuqing Chen3, Brendan Lee3, C Thomas Appleton4, Frank Beier4, Xiu-Ping Yu5, Chuan-Ju Liu6. 1. 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. 2. Department of Orthopaedic Surgery, New York University Medical Center, New York, New York, USA. 3. Department of Molecular and Human Genetics, Baylor College of Medicine, Howard Hughes Medical Institute, Houston, Texas, USA. 4. Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Alberta, Canada. 5. Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong, China. 6. 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.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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-7transgenic 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: Philipp G Maass; Jutta Wirth; Atakan Aydin; Andreas Rump; Sigmar Stricker; Sigrid Tinschert; Miguel Otero; Kaneyuki Tsuchimochi; Mary B Goldring; Friedrich C Luft; Sylvia Bähring Journal: Hum Mol Genet Date: 2009-12-16 Impact factor: 6.150
Authors: C Thomas G Appleton; David D McErlain; Vasek Pitelka; Neil Schwartz; Suzanne M Bernier; James L Henry; David W Holdsworth; Frank Beier Journal: Arthritis Res Ther Date: 2007 Impact factor: 5.156