Reduction of Smad2 caused by oxidative stress leads to necrotic death of hypertrophic chondrocytes associated with an endemic osteoarthritis

Author:

He Ying12,Fan Lihong3,Aaron Nicole4,Feng Yiping1,Fang Qian1,Zhang Ying1,Zhang Dan1,Wang Hui1,Ma Tianyou1,Sun Jian1,Chen Jinghong1

Affiliation:

1. Institute of Endemic Diseases, Xi'an, Shaanxi, China

2. Graduate Students Teaching Experiment Center, School of Public Health, Xi'an Jiaotong University Health Science Center, Key Laboratory of Trace Elements and Endemic Diseases, Xi'an, Shaanxi, China

3. Department of Cardiology, The First Affiliated Hospital of Xi’an Jiao Tong University, Xi'an, Shaanxi, China

4. Department of Pharmacology, Columbia University, New York, NY, USA

Abstract

Abstract Objective The occurrence and development of an endemic OA, Kashin–Beck disease (KBD), is closely related to oxidative stress induced by free radicals. The aim of the study was to find the key signalling molecules or pathogenic factors as a potential treatment strategy for KBD. Methods Real-time PCR and western blotting were performed to detect the mRNA and protein expression levels in cells and tissues. Immunohistochemical staining was assayed in rat models and human samples obtained from children. The type of cell death was identified by annexin V and propidium iodide staining with flow cytometry. Results Oxidative stress decreased levels of Smad2 and Smad3 in hypertrophic chondrocytes both in vitro and in vivo. In the cartilage of KBD patients, the expression of Smad2 and Smad3 proteins in the middle and deep zone was significantly decreased with an observed full deletion in the deep zone of some samples. Reduction of Smad2 protein induced necrotic death of hypertrophic chondrocytes, while reduction of Smad3 protein induced apoptosis. The reduction of Smad2 protein was not accompanied by Smad3 protein reduction in hypertrophic chondrocyte necrosis. Furthermore, the reduction of Smad2 also impaired the construction of tissue-engineered cartilage in vitro. Conclusion These studies reveal that oxidative stress causes necrosis of hypertrophic chondrocytes by downregulating Smad2 protein, which increases the pathogenesis of KBD cartilage. The importance of Smad2 in the development of KBD provides a new potential target for the treatment of KBD.

Funder

National Natural Science Foundation of China

Publisher

Oxford University Press (OUP)

Subject

Pharmacology (medical),Rheumatology

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