Abstract
IntroductionOsteoclasts 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).ResultsImmunohistochemical 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).ConclusionsOver-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.
Highlights
Osteoclasts are responsible for the bone loss associated with rheumatoid arthritis (RA)
Immunohistochemical analysis revealed that bone-apposing osteoclasts within the rheumatoid synovium express both angiopoietin-like 4 (ANGPTL4) and hypoxia-inducible factor-1 alpha (HIF-1a)
ANGPTL4 was strongly expressed in synovial lining cells, endothelial cells, stromal cells, CD68+ macrophages and plasma cells within RA synovium
Summary
Osteoclasts are responsible for the bone loss associated with rheumatoid arthritis (RA). We have investigated expression of ANGPTL4 and its regulatory transcription factor, hypoxia-inducible factor-1 alpha (HIF-1a), in osteoclasts and other cells within rheumatoid synovium. Bone loss in RA, comprising both juxta-articular bone erosions and systemic osteoporosis, is associated with progressive disability and is predictive of poor prognosis [1,2]. Both types of bone loss are mediated by osteoclasts [3,4], multinucleated cells specialised to carry out lacunar bone resorption. Endothelial cells, fibroblasts, lymphocytes, plasma cells and CD68+ macrophages within the RA synovium express the hypoxia-inducible transcription factor, HIF [9,10,11]. Hypoxic accumulation and activation of HIF-alpha allows transcription of genes involved in processes including angiogenesis, inflammation, apoptosis and regulation of immune function [12]
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