Aenea Brugman1, Órla Tynan2, Dumitru Anton3, Carl Orr4, Viviana Marzaioli5, Douglas Veale6 and Ursula Fearon7, 1Molecular Rheumatology Department, Trinity Biomedical Sciences Institute, Trinity College Dublin; EULAR Centre for Arthritis and Rheumatic Diseases, St Vincent University Hospital, University College Dublin, Dublin, Ireland, 2Molecular Rheumatology Department, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland, EULAR Centre for Arthritis and Rheumatic Diseases, St Vincent University Hospital, University College Dublin, Dublin, Ireland, 3Molecular Rheumatology Department, Trinity Biomedical Sciences Institute, Trinity College Dublin, EULAR Centre for Arthritis and Rheumatic Diseases, St Vincent University Hospital, University College Dublin, Dublin, Ireland, 4Saint Vincent's University Hospital, Dublin, Ireland, 5Trinity College Dublin and University College Dublin, Dublin, Ireland, 6St.Vincent's University Hosp, Dublin, Ireland, 7Trinity College Dublin, Dublin, Ireland
Background/Purpose: While common pathogenic mechanisms exist between PsA and RA, distinct vascular morphology has been observed, with PsA displaying a tortuous, dilated, irregular shaped morphology compared to a straight regular branching pattern observed in RA. The aim of this study is to examine the effect of the PsA and RA joint microenvironment on endothelial cell function.
Methods: PsA and RA patients underwent key-hole joint arthroscopy and synovial biopsies were obtained. PsA and RA synovial fibroblasts (FLS) were isolated and grown to passage 1-5. PsA and RA FLS supernatants were harvested and referred to as conditioned media (CM). Endothelial cells (EC) were cocultured with PsA FLS/RA FLS or PsA CM/RA CM, and pro-inflammatory mediators (cytokines, matrix-metalloproteinases, angiogenic growth factors, chemokines and adhesion molecules) were quantified by ELISA, real-time PCR and flow cytometry.
Results: Co-culture of PsA and RA FLS with EC induced IL-6 secretion, with no effect observed for MCP-1 or Ang2. PsA FLS CM induced MCP-1, Ang2, ICAM-1, MMP2 and MMP3 expression in EC, with only MMP-2 increasing in response to RA FLS CM. Both PsA FLS CM and RA FLS CM decreased VCAM-1 expression, an effect that was more pronounced for RA FLS CM. Either co-culture of PsA FLS/RA FLS or PsA FLS CM/RA FLS CM with EC induced the frequency and/or MFI of key chemokine receptors CXCR3 and CXCR4 on EC, an effect that was more pronounced for FLS CM vs FLS co-culture, particularly for PsA CM. Both PsA FLS/RA FLS coculture or PsA/RA CM decreased the frequency of CXCR5, however induced CXCR5 MFI. Only co-culture with PsA FLS and RA FLS induced the expression of ICAM-1, with no effect observed for PsA or RA FLS CM. No effect was observed for VCAM-1 expression. In contrast, the effect of coculture on FLS led to a reduction in the expression of ICAM-1 on both PsA and RA FLS, with increased expression of VCAM-1 observed for PsA FLS. No effect was observed for chemokine receptor expression on either PsA FLS or RA FLS when co-cultured with EC.
Conclusion: PsA and RA FLS/CM induce angiogenic, chemokine and adhesion molecule expression on EC, with differential effects for some mediators observed in response to PsA vs RA joint microenvironments. Furthermore, differences were observed between EC-FLS cocultures vs EC FLS CM co-cultures, suggesting cell-cell contact and soluble mediators both influence the EC pathogenic phenotype.
A. Brugman: None; Ó. Tynan: None; D. Anton: None; C. Orr: None; V. Marzaioli: None; D. Veale: None; U. Fearon: None.