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

Elhai, M;Micheroli, R;Houtman, M;Mirrahimi, M;Moser, L;Pauli, C;Bürki, K;Laimbacher, A;Kania, G;Klein, K;Schätzle, P;Bertoncelj, MF;Edalat, SG;Keusch, L;Khmelevskaya, A;Toitou, M;Geiss, C;Rauer, T;Sakkou, M;Kollias, G;Armaka, M;Distler, O;Ospelt, C;

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.