Abstract
IntroductionActivated fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA) share many characteristics with tumour cells and are key mediators of synovial tissue transformation and joint destruction. The glycoprotein podoplanin is upregulated in the invasive front of several human cancers and has been associated with epithelial-mesenchymal transition, increased cell migration and tissue invasion. The aim of this study was to investigate whether podoplanin is expressed in areas of synovial transformation in RA and especially in promigratory RA-FLS.MethodsPodoplanin expression in human synovial tissue from 18 RA patients and nine osteoarthritis (OA) patients was assessed by immunohistochemistry and confirmed by Western blot analysis. The expression was related to markers of synoviocytes and myofibroblasts detected by using confocal immunofluoresence microscopy. Expression of podoplanin, with or without the addition of proinflammatory cytokines and growth factors, in primary human FLS was evaluated by using flow cytometry.ResultsPodoplanin was highly expressed in cadherin-11-positive cells throughout the synovial lining layer in RA. The expression was most pronounced in areas with lining layer hyperplasia and high matrix metalloproteinase 9 expression, where it coincided with upregulation of α-smooth muscle actin (α-sma). The synovium in OA was predominantly podoplanin-negative. Podoplanin was expressed in 50% of cultured primary FLSs, and the expression was increased by interleukin 1β, tumour necrosis factor α and transforming growth factor β receptor 1.ConclusionsHere we show that podoplanin is highly expressed in FLSs of the invading synovial tissue in RA. The concomitant upregulation of α-sma and podoplanin in a subpopulation of FLSs indicates a myofibroblast phenotype. Proinflammatory mediators increased the podoplanin expression in cultured RA-FLS. We conclude that podoplanin might be involved in the synovial tissue transformation and increased migratory potential of activated FLSs in RA.
Highlights
Activated fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA) share many characteristics with tumour cells and are key mediators of synovial tissue transformation and joint destruction
The most prominent feature of RA is the progressive destruction of articular cartilage and bone, which is orchestrated by activated RA fibroblast-like synoviocytes (RA-FLSs) [5,6]
Podoplanin is expressed in the human synovial lining layer in RA By carrying out IHC on paraffin sections of human synovia, we found that podoplanin was highly expressed in rounded cells of the epithelium-like synovial lining layer in 17 of the 18 RA specimens (Figures 1A-D and 1L-M)
Summary
Activated fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA) share many characteristics with tumour cells and are key mediators of synovial tissue transformation and joint destruction. Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease predominantly affecting joints, leading to tissue destruction and functional disability [1,2]. Both genetic and environmental factors are believed to contribute to the dysregulated immune responses seen in this. RA-FLSs mediate tissue destruction and are considered to play a major role in initiating and driving RA in concert with inflammatory cells [7]. Apart from being a marker of FLSs, cadherin-11 has been shown to be essential for the formation of synovial lining structures in vitro and for the development of inflammatory arthritis in mice [14,15]
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