title: Angiopoietin-like 4 is over-expressed in rheumatoid arthritis patients: association with pathological bone resorption.
abstract: BACKGROUND
  Osteoclasts are responsible for the bone loss associated with rheumatoid arthritis (RA). The secreted adipokine angiopoietin-like 4 (ANGPTL4) specifically increases osteoclast-mediated bone resorption. We have investigated expression of ANGPTL4 and its regulatory transcription factor, hypoxia-inducible factor-1 alpha (HIF-1α), in osteoclasts and other cells within rheumatoid synovium. We have also examined whether circulating levels of ANGPTL4 differ in RA patients compared with that in normal controls or patients with osteoarthritis (OA).
  
  
  RESULTS
  Immunohistochemical analysis revealed that bone-apposing osteoclasts within the rheumatoid synovium express both ANGPTL4 and HIF-1α. ANGPTL4 was also strongly expressed in synovial lining cells, endothelial cells, stromal cells, CD68+ macrophages and plasma cells within RA synovium. Little ANGPTL4 was evident in normal synovial tissue. This reflected the over-expression of HIF-1α in rheumatoid versus normal synovial tissue. The concentration of ANGPTL4 was higher in both the serum and the synovial fluid of RA patients than in patients with OA or normal controls. High serum ANGPTL4 associated with elevated levels of the serum marker of bone resorption, receptor activator for nuclear factor κB ligand (RANKL).
  
  
  CONCLUSIONS
  Over-expression of ANGPTL4 in multiple cell types within the rheumatoid synovium potentially provides a local pool of ANGPTL4 to stimulate osteoclast-mediated bone resorption in RA. Additionally, correlation of high serum ANGPTL4 with circulating RANKL suggests that ANGPTL4 may represent a novel marker for bone destruction in RA.
authors.affiliation: Botnar Research Centre, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: Swales
authors.affiliation: Pathology Department, Nuffield Orthopaedic Centre, University of Oxford, Oxford, United Kingdom.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Athanasou
authors.affiliation: Botnar Research Centre, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Knowles
mesh_terms: D000368:Aged; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000097:blood / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D015415:Biomarkers / Q000097:blood; D001862:Bone Resorption / Q000097:blood / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D003937:Diagnosis, Differential; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000097:blood / Q000235:genetics; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000097:blood / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010950:Plasma Cells / Q000378:metabolism / Q000473:pathology; D053245:RANK Ligand / Q000097:blood / Q000235:genetics*; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D013582:Synovial Fluid / Q000737:chemistry / Q000378:metabolism
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D015415:Biomarkers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053245:RANK Ligand; C505688:TNFSF11 protein, human