The tumour-associated glycoprotein podoplanin is expressed in fibroblast-like synoviocytes of the hyperplastic synovial lining layer in rheumatoid arthritis

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.

Altered Dermal Fibroblasts in Systemic Sclerosis Display Podoplanin and CD90

“…29e32 Synovial fibroblasts in the joints of rheumatoid arthritis patients also display Pdpn, suggesting that this transition accompanies inflammation. 67,68 Herein, we demonstrate that fibroblasts in vitro can transition in response to inflammatory stimuli that have NF-kB activation as a common element and, likewise, as noted in an acute mouse ear model of inflammation, Tolllike receptor and interferon signaling pathways did not contribute to Pdpn induction. 66 Pdpn is constitutively expressed in lymphoid reticular stroma; however, when the lymph node becomes reactive or effectively inflamed, Pdpn levels increase even further.…”

New Insights into the Role of Podoplanin in Epithelial–Mesenchymal Transition

“…These authors showed induction of podoplanin by treatment 14 -mechanism involving the induction of the IL-3 receptor. In an interesting report , Ekwall et al (2011) showed that podoplanin is up-regulated in patients with rheumatoid arthritis, but not in patients with osteoarthritis. In another report, were shown to induce podoplanin expression; however only IL-7 was able to induce also Prox1, and to stimulate endothelial cell growth (Al-Rawi et al, 2005).…”

Human Synovial Lubricin Expresses Sialyl Lewis x Determinant and Has L-selectin Ligand Activity

“…Immunofluorescence and Confocal Microscopy-Human synovial tissue specimens from five RA patients were processed for immunohistochemical staining as described previously (45). In brief, paraformaldehyde-fixed paraffin-embedded 4-m sections of human synovial tissue were deparaffinized and rehydrated and subjected to an antigen retrieval procedure.…”