Rheumatoid arthritis (RA), an autoimmune disease, contributes to progressive articular destruction and comorbidities in vascular, metabolic, bone, and psychological fields (McInnes and Schett, 2017). The clinical status of RA patients has improved recently because of medical progresses in diagnosis and treatment, thereby making reducing disease severity and preventing systemic complications a possibility (Radu and Bungau, 2021). The synovium converts into a hyperplastic invasive tissue during RA, and fibroblast-like synoviocytes (FLS) are epigenetically bestowed with an aggressive phenotype in RA (Nygaard and Firestein, 2020). There are no available therapies that specifically target FLS (Ganesan and Rasool, 2017), which makes it an attracting target for RA.

Transcriptional mechanisms of imprinting and epigenetic alterations result in a chronic phenotype of FLS in RA (Korb-Pap et al., 2016). The implication of non-coding RNAs (ncRNAs) in various biological processes have receiving increasing attention, and ncRNAs can be allocated into two major subtypes: long ncRNAs (lncRNAs) with more than 200 nucleotides and small ncRNAs (Liang et al., 2019). Many ncRNAs have been validated as possible markers for the diagnosis and treatment of RA (Wang et al., 2019). For one of them, lncRNA H19 expression has been reported to be enhanced in the synovial tissues of osteoarthritis and RA patients relative to normal/joint trauma controls (Stuhlmuller et al., 2003). H19 is abundantly expressed during embryonic development and downregulated after birth (Gabory et al., 2010). More importantly, the depletion of H19 repressed the proliferation of FLS and weakened collagen-induced arthritis (CIA) in mice (Fu et al., 2021). Therefore, we set to find out the downstream effector of H19 in regulating FLS phenotype during the progression of RA. Interestingly, the relevance of the interaction between H19 and RNA-binding proteins to Paneth cell function (Chung et al., 2021) has drawn our attention. Transcription factors are sequence-specific DNA binding proteins that upregulate or downregulate the transcription of genes, and a large number of transcription factors has been reported to interact with RNAs (Long et al., 2017). Our preliminary microarray analysis showed that sorting nexin (SNX)10 was the most upregulated gene in FLS extracted from RA patients and overexpressing H19 artificially. SNX10 is expressed in osteoclasts and is required for osteoclast differentiation (C. H. Zhu et al., 2012), indicating its close relation to the skeletal system. Therefore, we sought to describe the role of H19 in joint damage by evaluating its contribution to the aggressive phenotype of RA-FLS and to expound the transcription mechanism behind.