Angiopoietin-like 4 is over-expressed in rheumatoid arthritis patients: association with pathological bone resorption

• Published in: PloS one 2014-10, Vol.9 (10), p.e109524-e109524
• Main Authors: Swales, Catherine, Athanasou, Nicholas A, Knowles, Helen J
• Format: Article
• Language: English
• Subjects: Age; Aged; Angiogenesis; Angiopoietin; Angiopoietin-Like Protein 4; Angiopoietins - blood; Angiopoietins - genetics; Arthritis; Arthritis, Rheumatoid - blood; Arthritis, Rheumatoid - diagnosis; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - pathology; B cells; Biocompatibility; Biology and Life Sciences; Biomarkers - blood; Biomedical materials; Bone loss; Bone resorption; Bone Resorption - blood; Bone Resorption - diagnosis; Bone Resorption - genetics; Bone Resorption - pathology; Case-Control Studies; Cloning; Comparative analysis; Diagnosis, Differential; Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - pathology; Ethics; Female; Gene expression; Gene Expression Regulation; Humans; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1, alpha Subunit - blood; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-inducible factor 1a; Hypoxia-inducible factors; Macrophages; Macrophages - metabolism; Macrophages - pathology; Male; Medicine and Health Sciences; Middle Aged; Osteoarthritis; Osteoarthritis - blood; Osteoarthritis - diagnosis; Osteoarthritis - genetics; Osteoarthritis - pathology; Osteoclasts; Osteoclasts - metabolism; Osteoclasts - pathology; Overexpression; Patients; Plasma cells; Plasma Cells - metabolism; Plasma Cells - pathology; RANK Ligand - blood; RANK Ligand - genetics; Research and Analysis Methods; Rheumatoid arthritis; Rheumatoid factor; Rheumatoid synovitis; Rheumatoid synovium; Rheumatology; Signal Transduction; Stromal cells; Stromal Cells - metabolism; Stromal Cells - pathology; Synovial fluid; Synovial Fluid - chemistry; Synovial Fluid - metabolism; TRANCE protein
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0109524

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). 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). 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.