title: Progranulin protects against osteoarthritis through interacting with TNF-α and β-Catenin signalling.
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.
authors.affiliation: Department of Orthopaedic Surgery, Hospital for Joint Diseases, New York University, New York, New York, USA.|Department of Orthopaedic Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China.
authors.forename: Yun-Peng
authors.initials: YP
authors.lastname: Zhao
authors.affiliation: Department of Orthopaedic Surgery, Hospital for Joint Diseases, New York University, New York, New York, USA.|Department of Orthopaedic Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China.
authors.forename: Ben
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Orthopaedic Surgery, Hospital for Joint Diseases, New York University, New York, New York, USA.
authors.forename: Qing-Yun
authors.initials: QY
authors.lastname: Tian
authors.affiliation: Department of Orthopaedic Surgery, Hospital for Joint Diseases, New York University, New York, New York, USA.
authors.forename: Jian-Lu
authors.initials: JL
authors.lastname: Wei
authors.affiliation: Department of Orthopaedic Surgery, Hospital for Joint Diseases, New York University, New York, New York, USA.
authors.forename: Brendon
authors.initials: B
authors.lastname: Richbourgh
authors.affiliation: Department of Orthopaedic Surgery, Hospital for Joint Diseases, New York University, New York, New York, USA.|Department of Cell Biology, New York University School of Medicine, New York, New York, USA.
authors.forename: Chuan-Ju
authors.initials: CJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010003:Osteoarthritis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077153:Progranulins; D011498:Protein Precursors; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D011498:Protein Precursors; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin
keywords: Chondrocytes; Osteoarthritis; TNF-alpha