Background and Objectives In contrast to normal synovial tissue, rheumatoid synovium is hypoxic, and expresses the hypoxia-inducible transcription factors HIF-1α and HIF-2α which allow the transcription of genes involved in angiogenesis, inflammation, apoptosis and regulation of immune function. Hypoxia also stimulates osteoclast differentiation and causes a HIF-1α-dependent 3-fold increase in bone resorption. Angiopoietin-like 4 (ANGPTL4) is a hypoxia- and HIF-inducible pro-angiogenic adipokine that is induced in fibroblast-like synoviocytes in rheumatoid arthritis. This study sought to investigate whether ANGPTL4 is expressed in osteoclasts and other cells within rheumatoid synovial tissue, and to compare serum and synovial fluid levels of ANGPTL4 with those in normal controls and patients with osteoarthritis.
Materials and Methods Serum, synovial fluid and synovial tissue samples were derived from patients with osteoarthritis (OA) and rheumatoid arthritis (RA); serum was obtained from aged-matched normal controls. All donors were recruited from the Nuffield Orthopaedic Centre, Oxford, UK and gave written informed consent. ANGPTL4 and HIF-1α expression was assessed in OA and RA synovial sections by immunohistochemistry and immunofluorescence. Serum and synovial fluid levels of ANGPTL4 were measured by ELISA. Osteoclasts were differentiated from circulating RA monocytes using M-CSF and RANKL, and hypoxic induction of ANGPTL4 mRNA was measured by real-time PCR.
Results Bone-apposing osteoclasts within the rheumatoid synovium expressed ANGPTL4 and its regulating transcription factor HIF-1α. ANGPTL4 was strongly expressed in synovial lining cells, endothelial cells, stromal cells, CD68 + macrophages and plasma cells within the RA synovium. Little ANGPTL4 was evident in normal synovium, mirroring the expression pattern of HIF-1α in rheumatoid versus normal synovial tissue. ANGPTL4 concentrations were higher in the serum and synovial fluid of RA patients than in OA patients or normal controls. High serum ANGPTL4 correlated with elevated levels of the serum bone resorption marker sRANKL. Finally, ANGPTL4 mRNA was induced 5.5-fold by hypoxia in monocyte-derived osteoclasts from RA patients.
Conclusions ANGPTL4 is over-expressed in both the serum and the synovial fluid and tissue of RA patients. Expression of ANGPTL4 in bone-apposing osteoclasts and correlation of high serum ANGPTL4 with circulating sRANKL suggests ANGPTL4 as a marker for bone destruction, and a potential target for inhibition of osteoclast-mediated bone resorption in RA.
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