The role of synovial fibroblasts in RA

Synovial fibroblasts are the major stromal cells in the joint synovium and play a crucial part in inflammation and joint destruction in RA.

Synovial fibroblasts from patients with RA exhibit an intrinsically activated phenotype, which is maintained under cell culture conditions and is characterised by increased expression of matrix-degrading enzymes and pro-inflammatory cytokines and chemokines. This aggressive phenotype is believed to be sustained by alterations in epigenetic modifications, such as DNA methylation and non-coding RNA. In our work, we look at different aspects of fibroblast biology to decipher how these cells are activated in RA, how they contribute to disease and how they can be therapeutically targeted.

Current projects

Genetic factors contribute 50% to the risk of RA and the heritability of RA is estimated to be approximately 60%. Genome-wide association studies (GWAS) have identified over 100 genetic susceptibility loci for RA. However, only a small proportion of RA risk loci have been functionally analysed to date. In this project, we align genetic data with in depth analysis of the epigenetic landscape of synovial fibroblasts to determine which genetic risk loci lie within active, regulatory DNA regions in synovial fibroblasts. We then further analyse these DNA regions in synovial fibroblasts to see the molecular and functional impact of the genetic risk loci on fibroblast biology.

Involved team members

  • Miranda Houtman
  • Larissa Moser

Funded by

  • Swiss National Science Foundation

Collaborators

Prof Stephen Eyre, Arthritis Research UK Centre for Genetics and Genomics, University of Manchester, UK

Relevant Publications

We could show that synovial fibroblasts significantly differ between different joint locations in their epigenome, transcriptome and function. We hypothesize that the differences in these local cells of the joints substantially influence the inflammatory response, the influx of immune cells, the resolution of inflammation and thus disease outcome and therapeutic response. To test this hypothesis, we analyze joint-specific differences in the inflammatory and anti-inflammatory response using histological and single cell molecular analysis and try to identify the key regulators of joint-specific inflammatory signaling pathways.

Involved team members

  • Eva Camarillo
  • Muriel Elhai
  • Miranda Houtman
  • Raphael Micheroli

Funded by

  • Iten-Kohaut-Foundation
  • Novartis Foundation for medical-biological research
  • MLR Foundation

Relevant publications

We have shown that synovial fibroblasts isolated from different joints substantially differ in gene expression and functional properties. In particular, the expression of genes that are involved in embryonic limb development, namely HOX genes, substantially differs between joint regions. Also in skin and cartilage, the expression of HOX transcription factors is strongly related to the anatomical localisation. Based on this data, we hypothesize that the joint-specific phenotypes shaped during embryonic development and maintained during adult life, significantly contribute to the pathognomic patterns of joint affection in chronic inflammatory arthritis such as RA. However, little is known about the function of HOX genes in synovial fibroblasts. Therefore, we analyse the properties of various HOX transcription factors and non-coding RNAs in synovial fibroblasts with knock-down and overexpression experiments.

Involved team members

  • Eva Camarillo
  • Muriel Elhai
  • Masoumeh Mirrahimi
  • Larissa Moser

Funded by

  • Foundation for Research in Science and the Humanities at the University of Zurich
  • EMDO Foundation
  • Hartmann-Müller Foundation
  • Kurt-und-Senta-Herrmann Foundation
  • Carigest

Relevant publications

Group Members

Caroline Ospelt, Prof. Dr. med.

Forschungsgruppenleiterin, Klinik für Rheumatologie

Tel. +41 43 253 31 71
Spezialgebiete: The role of synovial fibroblasts in RA, Forschungsgebiete: Synoviale Fibroblasten in Arthritiden, Funktionelle Genomik, Expertise: Genetics, Epigenetics, scRNAseq, functional fibroblasts analysis

Muriel Danièle Elhai, PD Dr. Dr. med.

Oberärztin, Klinik für Rheumatologie

Tel. +41 44 255 26 87
Spezialgebiete: Systemische Sklerose, Kollagenosen, Systemerkrankungen

Raphael Micheroli-Konuk, MPH, PD Dr. med.

Leitender Arzt, Klinik für Rheumatologie

Tel. +41 44 255 26 87
Spezialgebiete: Psoriasisarthritis, Axiale Spondyloarthritis, Rheumatoide Arthritis

Celina Geiss

Doktorandin, Klinik für Rheumatologie

Tel. +41 43 253 31 74
Spezialgebiete: Rheumatoid arthritis / Systemic sclerosis - Group Ospelt / Elhai

Masoume Halsadat Mirrahimi

Doktorandin, Klinik für Rheumatologie

Tel. +41 43 253 31 74
Spezialgebiete: Rheumatoid arthritis - Group Ospelt

Alexandra Khmelevskaya

Doktorandin, Klinik für Rheumatologie

Tel. +41 43 253 31 74
Spezialgebiete: Rheumatoid arthritis / Psoriatic arthritis - Group Ospelt / Micheroli

Ege Ezen

Doktorand, Klinik für Rheumatologie

Phatthamon Laphanuwat

Postdoktorandin, Klinik für Rheumatologie

Jingyi Wang

Akademischer Gast, Klinik für Rheumatologie

Aikaterini Apostolopoulou

Doktorandin, Klinik für Rheumatologie