The long non-coding RNA HOTAIR contributes to joint-specific gene expression in rheumatoid arthritis

Muriel Elhai, Raphael Micheroli, Miranda Houtman, Masoumeh Mirrahimi, Larissa Moser, Chantal Pauli, Kristina Bürki, Andrea Laimbacher, Gabriela Kania, Kerstin Klein, Philipp Schätzle, Mojca Frank Bertoncelj, Sam G. Edalat, Leandra Keusch, Alexandra Khmelevskaya, Melpomeni Toitou, Celina Geiss, Thomas Rauer, Maria Sakkou, George Kollias, Marietta Armaka, Oliver Distler and Caroline Ospelt ()
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Muriel Elhai: University Hospital of Zurich, University of Zurich
Raphael Micheroli: University Hospital of Zurich, University of Zurich
Miranda Houtman: University Hospital of Zurich, University of Zurich
Masoumeh Mirrahimi: University Hospital of Zurich, University of Zurich
Larissa Moser: University Hospital of Zurich, University of Zurich
Chantal Pauli: University Hospital Zurich
Kristina Bürki: University Hospital of Zurich, University of Zurich
Andrea Laimbacher: University Hospital of Zurich, University of Zurich
Gabriela Kania: University Hospital of Zurich, University of Zurich
Kerstin Klein: University Hospital of Zurich, University of Zurich
Philipp Schätzle: University of Zurich
Mojca Frank Bertoncelj: University Hospital of Zurich, University of Zurich
Sam G. Edalat: University Hospital of Zurich, University of Zurich
Leandra Keusch: University Hospital of Zurich, University of Zurich
Alexandra Khmelevskaya: University Hospital of Zurich, University of Zurich
Melpomeni Toitou: University Hospital of Zurich, University of Zurich
Celina Geiss: University Hospital of Zurich, University of Zurich
Thomas Rauer: University Hospital Zurich
Maria Sakkou: Biomedical Sciences Research Center (BSRC) ‘Alexander Fleming’
George Kollias: Biomedical Sciences Research Center (BSRC) ‘Alexander Fleming’
Marietta Armaka: Biomedical Sciences Research Center “Alexander Fleming”
Oliver Distler: University Hospital of Zurich, University of Zurich
Caroline Ospelt: University Hospital of Zurich, University of Zurich

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Although patients with rheumatoid arthritis (RA) typically exhibit symmetrical joint involvement, some patients develop alternative disease patterns in response to treatment, suggesting that different molecular mechanism may underlie disease progression depending on joint location. Here, we identify joint-specific changes in RA synovium and synovial fibroblasts (SF) between knee and hand joints. We show that the long non-coding RNA HOTAIR, which is only expressed in knee SF, regulates more than 50% of this site-specific gene expression in SF. HOTAIR is downregulated after stimulation with pro-inflammatory cytokines and is expressed at lower levels in knee samples from patients with RA, compared with osteoarthritis. Knockdown of HOTAIR in knee SF increases PI-Akt signalling and IL-6 production, but reduces Wnt signalling. Silencing HOTAIR inhibits the migratory function of SF, decreases SF-mediated osteoclastogenesis, and increases the recruitment of B cells by SF. We propose that HOTAIR is an important epigenetic factor in joint-specific gene expression in RA.

Date: 2023
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DOI: 10.1038/s41467-023-44053-w

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