Background/Purpose: The synovial inflammation observed in Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA) is characterised by synovial fibroblast hyperplasia, leukocyte infiltration, neoangiogenesis and hypoxia. These features cause the inflamed synovium to adopt a tumour-like phenotype which facilitates the invasion of adjacent cartilage. Pathogenic differences between RA and PsA are observed in the vascular morphology pattern, synovial tissue (ST) cellular infiltrates and lining-layer thickness. While synovial fibroblasts (FLS) have generally been considered as a heterogeneous population of cells with specific functions, recent studies have identified distinct FLS subsets which differentially contribute to disease pathogenesis. CD34^–THY1⁺ FLS are increased in RA synovial sublining compared to that of OA, and are reported to sustain synovitis. In contrast, CD34^–THY1^– FLS were elevated in the OA synovial lining layer and are thought to contribute to cartilage and bone degradation. The aim of this study was to compare the phenotypic, metabolic and functional profiles of PsA-FLS compared to RA-FLS.

Methods: Single cell analysis of PsA and RA ST cell suspensions were analysed for specific synovial fibroblast subsets and metabolic markers by 14-colour flow cytometry. Fibroblasts were defined as CD45-CD146-CD31-podoplanin+. Subsets were further defined according to CD34 and THY1 expression and analysed for pmTOR, pS6, GLUT1 and pSTAT3 expression. The metabolic profiles of primary RA- and PsA-FLS were analysed using the XFe96-Extracellular Flux Analyzer. Gene expression for metabolic and inflammatory mediators was determined by quantitative-PCR. Cell migration and invasion were determined by wound repair scratch assays and Transwell Matrigel™ invasion chambers. All patients satisfy ACR classification criteria for RA and CASPAR criteria for PsA.

Results: A significant increase in the podoplanin⁺CD34^–THY1⁺ FLS subset was demonstrated in RA synovial tissue single cell suspensions compared to that of PsA (p=0.0003). In contrast, a significant increase in podoplanin⁺CD34^–THY1^– FLS subset was observed in PsA (p< 0.0001). In both RA and PsA, GLUT1 and pSTAT3 were slightly elevated in the THY1⁺ subset, while pmTOR and pS6 were slightly elevated in the THY1^– subset. Expression of glycolytic genes HK2, GAPDH, PKM2 and LDHA and the glucose receptors GLUT-1 and GLUT-3 were significantly increased in cultured RA-FLS compared to PsA-FLS. This was paralleled by an overall increase in the ECAR:OCR ratio in RA-FLS compared to PsA-FLS, demonstrating a shift to a more glycolytic phenotype in RA, an effect associated with an increase in disease activity score, DAS28. Finally, a significant increase ICAM-1 and MMP-1 expression was demonstrated in RA-FLS compared to PsA-FLS, in addition to an increase in their migratory and invasive capacity.

Conclusion: This study demonstrates, for the first time, distinct differences in FLS subsets in RA synovial biopsies compared to PsA, with an increase in the more invasive, podoplanin⁺CD34^–THY1⁺ FLS observed in RA. This was consistent with an increase in their metabolic profile and functional capacity and reflects the clinical observations of disease activity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/characterisation-of-rheumatoid-and-psoriatic-arthritis-synovial-fibroblasts/