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Progranulin protects against osteoarthritis through interacting with TNF-α and β-Catenin signalling
  1. Yun-peng Zhao1,2,
  2. Ben Liu1,2,
  3. Qing-yun Tian1,
  4. Jian-lu Wei1,
  5. Brendon Richbourgh1,
  6. Chuan-ju Liu1,3
  1. 1Department of Orthopaedic Surgery, Hospital for Joint Diseases, New York University, New York, New York, USA
  2. 2Department of Orthopaedic Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
  3. 3Department of Cell Biology, New York University School of Medicine, New York, New York, USA
  1. Correspondence to Chuan-ju Liu, Rm 1608, HJD, Department of Orthopaedic Surgery, New York University Medical Center, 301 East 17th Street, New York, NY 10003, USA; chuanju.liu{at}med.nyu.edu

Abstract

Objective Progranulin (PGRN) was previously isolated as an osteoarthritis (OA)-associated growth factor. Additionally, PGRN was found to play a therapeutic role in inflammatory arthritis mice models through antagonising tumour necrosis factor α (TNF-α). This study was aimed at investigating the role of PGRN in degradation of cartilage and progression of OA.

Methods Progression of OA was analysed in both spontaneous and surgically induced OA models in wild type and PGRN-deficient mice. Cartilage degradation and OA were evaluated using Safranin O staining, immunohistochemistry and ELISA. Additionally, mRNA expression of degenerative factors and catabolic markers known to be involved in cartilage degeneration in OA were analysed. Furthermore, the anabolic effects and underlying mechanisms of PGRN were investigated by in vitro experiments with primary chondrocytes.

Results Here, we found that deficiency of PGRN led to spontaneous OA-like phenotype in ‘aged’ mice. Additionally, PGRN-deficient mice exhibited exaggerated breakdown of cartilage structure and OA progression, while local delivery of recombinant PGRN protein attenuated degradation of cartilage matrix and protected against OA development in surgically induced OA models. Furthermore, PGRN activated extracellular signal-regulated kinases (ERK) 1/2 signalling and elevated the levels of anabolic biomarkers in human chondrocyte, and the protective function of PGRN was mediated mainly through TNF receptor 2. Additionally, PGRN suppressed inflammatory action of TNF-α and inhibited the activation of β-Catenin signalling in cartilage and chondrocytes.

Conclusions Collectively, this study provides new insight into the pathogenesis of OA, and also presents PGRN as a potential target for the treatment of joint degenerative diseases, including OA.

  • Osteoarthritis
  • Chondrocytes
  • TNF-alpha

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