Rheumatoid arthritis (RA) is a chronic systemic disease, mainly characterized by synovitis, synovial hyperplasia, pannus formation, and osteochondral destruction (Muraki et al., 2018; Shiraishi et al., 2017). Due to the joint dysfunction caused by RA, patients often have limited activities, and the quality of life is seriously reduced (Wang et al., 2020a). Although many effective drugs have been developed, the long treatment cycle of RA significantly increases the incidence of adverse drug reactions. Therefore, to provide the basis for individualized therapy, it is vital to elicit the molecular mechanisms of RA pathogenesis.

MicroRNAs (miRNAs) are small, non-coding RNA molecules consisting of 21–24 base pairs that specifically bind to target genes through the 3' untranslated region (3'-UTR) and control the expression of multiple genes at the post-transcriptional level (Zhang et al., 2019). In recent years, cumulative evidences have shown that miRNAs play crucial roles in the development of RA by regulating cell viability, apoptosis, and invasion (Lai et al., 2017; Stanczyk et al., 2008). In synovial tissue of patients with RA, miRNA expression was significantly altered compared with those of healthy individuals. The abnormal miRNAs promote the expression of proinflammatory cytokine and enzymes that erodes the cartilage matrix by interfering Wnt, NF-κB, and JAK/STAT signaling pathways (Han et al., 2022).

The Mir204 and Mir211 have similar nucleotide sequences and share the same seed sequence. There are only two nucleotide differences in humans and one nucleotide difference in mice. These structural similarity and homology between these two miRNAs allow them to have the same gene targeting spectrum (Lee et al., 2016). In breast cancer, Mir204 acts as a tumor suppressor. The expression of Mir204 induced apoptosis while the deletion of Mir204 gene led to abnormal cell invasion (Imam et al., 2012). MiRNA has also become an indispensable regulatory factor in bone pathophysiology (Asahara, 2016). We have previously reported that homologous miRNAs, Mir204 and Mir211, together protecting joint from osteoarthritis development. The loss of Mir204/211 led to the upregulation of matrix degradation enzymes in articular chondrocytes, resulting in articular cartilage destruction and synovial hyperplasia (Huang et al., 2019). Since synovial inflammation is now considered as the major pathology of RA and hyperplasia of fibroblast-like synoviocyte (FLS) displayed tumor-like behaviors that contribute to pannus growth, inflammation, and cartilage damage, here we aimed to investigate whether Mir204/211 play an indispensable role in RA synovial inflammation and hyperplasia (Winchester et al., 2015).

Structure-specific recognition protein 1 (SSRP1) is a subunit of the histone chaperone transcription (FACT) complex and is involved in almost all chromatin-related processes. As a transcription factor, Ssrp1 regulates multiple cell processes, including cell cycle regulation and DNA repair (Gao and Xiong, 2018; Wang et al., 2019). In addition, Ssrp1 expression was significantly upregulated in a variety of tumors, such as breast and ovarian cancer, and was strongly associated with poorer prognosis. The knockdown of Ssrp1 expression by siRNA technique depressed the proliferation of glioma cells (Liao et al., 2017). SSRP1 inhibitor, CBL0137, induced cell death by down-regulating gene expression in the NF-κB signaling pathway (Barone et al., 2017). Wu et al. suggested that Ssrp1 modulates P53 pathway and its downstream molecules, and Ssrp1 may be involved in the cell cycle progression through regulation of P53 pathway (Wu et al., 2019a). Although Ssrp1 has been shown to stimulate proliferation through cell cycle regulation in a variety of human cancers, the role, mechanism, and clinical significance of Ssrp1 in RA remain unclear.

Collagen-induced arthritis (CIA) shares similar characteristics with RA, including synovial hyperplasia and inflammatory articular cartilage destruction, and has been extensively used in RA research (Song et al., 2018; Bas et al., 2016). Multiple lines of evidence have shown that RA FLSs are the principal cells in participation in the initiation, development, and deterioration of joint inflammation in RA disease (Xiao et al., 2021). In this study, we determined the effects of Mir204/211 on the inflammatory response and proliferation of primary CIA FLS by overexpression or knockdown of Mir204/211, as well as the downstream mechanisms of Mir204/211 in mitigation of synovial inflammation and excessive proliferation. We determined the relationship between Mir204/211 and Ssrp1 and revealed their effects on CIA-induced synovial cell proliferation in Mir204/211 double knockout (dKO) mice. Our findings suggest that Mir204/211 suppressed synovial inflammation and proliferation in RA by targeting Ssrp1.

RA is a chronic inflammatory disease, and genetic and environmental factors are involved during the disease initiation and progression. It is characterized by synovial inflammation leading to abnormal synovial hyperplasia, which eventually invades cartilage and leads to joint destruction (Li et al., 2018). The structural similarity and homology between Mir204 and Mir211 allow them to have the same gene targeting spectrum (Lee et al., 2016). Since the roles of Mir204 and Mir211 in RA are still unclear, here we will discuss the key role of Mir204/211 in RA from two aspects, synovial inflammation and abnormal synovial proliferation. It has been reported that Mir204 is down-regulated in synovial tissues of RA patients, and Mir204 regulates RA FLS survival by regulating STAT3 protein (Xiao et al., 2021; Li et al., 2018). Consistent with these findings, we found that expression levels of Mir204 and Mir211 in FLS of CIA mice were significantly reduced compared with those of normal mice. As demonstrated in this study that Mir204/211 suppress RA progression and play a protective role in RA, in our in vitro cell culture studies, we transfected CIA FLS with Mir204 mimics (or Mir204 inhibitor) and Mir211 mimics (or Mir211 inhibitor) simultaneously, to verify the important roles of Mir204/211 in RA.

In in vitro cell culture experiments, simultaneous overexpression of Mir204/211 was found to alleviate synovial inflammation-associated cell phenotypes in RA. We also performed cell scratching assay and cell apoptosis assay using flow cytometry method. The results suggest that simultaneous overexpression of Mir204/211 inhibited the migration of CIA FLS and promoted their apoptosis whereas simultaneous knockdown of Mir204/211 caused opposite phenomena. In RA, inflammatory FLS is the main source of inflammatory cytokines, and these pro-inflammatory mediators will further aggravate synovial inflammation and lead to the RA deterioration (Wu et al., 2016; Wu et al., 2019a; Hong et al., 2018). Yuan et al. reported that the expressions of pro-inflammatory cytokines, such as Il1b, Il6, and Il23, were all up-regulated in synovial tissues of CIA mice (Yuan et al., 2019). While other cytokines, such as Il4, Il10, and Tgfb1, played an implicit part in the anti-inflammatory response (Fabbrini and Magkos, 2015). In our assays, simultaneous overexpression of Mir204/211 decreased the expression of inflammatory cytokines (Il1b, Il6, Il8, and Il23) in CIA FLS and promoted the synthesis of anti-inflammatory cytokines (Il4, Il10, and Tgfb1), while knockdown of both Mir204 and Mir211 resulted in absolute opposite outcomes. Our results demonstrated that Mir204/211 treatment suppressed the abnormal migration and apoptotic behavior of RA FLS, as well as inflammatory factor-mediated disease deterioration.

NF-κB is a crucial transcription factors family and acts as a pro-inflammatory mediator to induce the production of cytokines, chemokines, and cell adhesion molecules in inflammatory cells (Umezawa et al., 2000; Imbert and Peyron, 2017; Chen et al., 2021). The translocation of p65 promotes the generation of numerous inflammatory factors (e.g. Il1b, Il6, Il23) and matrix metalloproteinases (MMPs) (Baldwin, 2012; Morgan and Liu, 2011; Yang et al., 2017). The expressions of these inflammatory factors and MMPs will eventually lead to synovial inflammation and joint destruction, thereby becoming one of the indispensable pathogenic factors of RA (Xu et al., 2018). We found decreased expression levels of P65 and IKKα, increased I-κBα protein expression in the Mir204 + Mir211 mimics group, while there were promoted P65 and IKKα protein expressions and declined I-κBα expression level in the Mir204 + Mir211 inhibitor group. Simultaneous overexpression or knockdown of Mir204/211 had no significant effect on the protein expression of IKKβ, and it seemed Mir204/211 might regulate the activity of NF-κB signaling pathway through modulation of IKKα. Later, IF assays also confirmed the results of western blotting. Above all, we found that Mir204/211 attenuated inflammation-mediated exacerbation by regulation of NF-κB p65 translocation in RA.

In terms of cell proliferation, CCK-8 analysis and flow cytometry were both conducted. Cell cycle regulatory proteins include cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (CKIs). Ccnd1 and Cdkn1c (CKI) both regulate the cell cycle through regulation of the G1/S phase (Wang et al., 2020b). Both Cdkn2a and Cdkn1a genes are crucial modulators in the regulation of cell senescence and are CDK inhibitors that lead to cell cycle stagnation in the G1 phase (Fernandez et al., 2015; Zhang et al., 2018). Simultaneous overexpression of Mir204/211 blocked cell cycle in G0/G1 phase, notably reduced Ccnd1 expression, and greatly increased Cdkn2a, Cdkn1a, and Cdkn1c mRNA expression, whereas simultaneous knockdown of Mir204/211 led to a significant increase in Ccnd1 expression and a significant decrease in Cdkn2a, Cdkn1a, and Cdkn1c expressions. Mir204/211 influenced the cell cycle by regulating Ccnd1, Cdkn2a, Cdkn1a, and Cdkn1c expression, thus inhibited cell proliferation.

PI3K/AKT is a classical signaling pathway participating in cell proliferation, migration, survival, and angiogenesis. Recent studies have shown that activation of PI3K/AKT signaling promotes the migration of RA FLS and plays an indispensable role in the pathogenesis of RA (Wang et al., 2020cWang et al., 2020a; Jiao et al., 2018). PI3K regulates cell proliferation, apoptosis, and metabolism. Lin et al. reported increased expression level of PI3K in RA synovial tissue, and the elevated PI3K promoted AKT phosphorylation and activated the PI3K/AKT signaling pathway. Activated AKT phosphorylates a variety of proteins and mediates cell proliferation (Lin et al., 2019). Western blotting results revealed that expression of PI3K and P-AKT protein was suppressed in the Mir204 + Mir211 mimics group, while upregulations of PI3K and P-AKT were observed in the Mir204 + Mir211 inhibitor group, revealing that Mir204/211 inhibited aberrant proliferation of CIA FLS by regulating the PI3K/AKT signaling pathway.

Based on the results of bio-informative analysis, PCR assay, and western blot analysis, we found that Ssrp1 was the downstream target gene of Mir204/211. We proposed that the abnormal expression of Ssrp1 in CIA may be caused by the dysregulation of the upstream miRNAs, Mir204 and Mir211. Trp53 is a vital tumor suppressor gene, which plays a role in initiating cell death and leads to the inhibition of Cdkn1a in cancer cells (Zhang et al., 2021). Wu et al. reported that NF-κB and P53 pathways could be regulated by FACT complex, and activation of NF-κB pathway and inhibition of P53 pathway might play the regulatory role of Ssrp1 in colorectal cancer (Wu et al., 2019b). Ding et al. found that in hepatocellular carcinoma, high expression of Ssrp1 activated the NF-κB pathway and suppressed the P53 pathway. Cyclins, such as Cdkn1a and Cdkn1b, are downstream signaling factors and can be regulated by Trp53. The expression level of Ccnd1 could also be negatively regulated by Cdkn1a (Vogelstein et al., 2000). Woksepp et al. demonstrated that knockdown of Ssrp1 by siRNA enhanced the phosphorylation of P53 and resulted in P53 activation, indicating that Ssrp1 had an inhibitory effect on Trp53. Over-activated NF-κB pathway is a common cause of the inhibition of P53 pathway in tumors, and P53 pathway is negatively regulated by NF-κB pathway (Gasparian et al., 2011). Liao et al. reported that low expression of Ssrp1 depressed p65 expression and a series of proliferation-related genes (such as Ccnd1) (Liao et al., 2017). Furthermore, Wang et al. also found that Ssrp1 promoted cell proliferation and apoptosis by activating AKT pathway (Wang et al., 2019). Thus, we hypothesized that Ssrp1 might regulate cell proliferation in RA by cell cycle.

Ki-67 is a widely used proliferation marker, highly expressed in cyclonic cells and significantly down-regulated in dormant cells. Ki-67 is an important proliferation marker for various cancer grades (Sun and Kaufman, 2018). Ki-67 is well recognized to identify aberrant synovial cells, which display a characteristic of excessive proliferation. Pessler et al. have quantified a strong correlation between Ki-67 expression and the histological degree of synovitis (Pessler et al., 2008). Through cell transfection and IF assay, we observed significantly declined expression of Ki-67 in cells with overexpression of Mir204/211 and prominently promoted Ki-67 expression in cells with overexpression of Mir204/211 and SSRP1, revealing that Mir204/211 suppressed cell proliferation by manipulating Ssrp1 expression.

To further test our hypothesis, we performed the in vivo experiments in the following studies. Severe arthritis, as manifested by synovial hyperplasia along with angiogenesis and cartilage destruction was more significant in mice of the CIA dKO group as compared with mice in the CIA WT group. IHC staining of SSRP1 showed evidently increased SSRP1 positive cells in the knee joint sections of CIA dKO mice as compared with those in CIA WT mice, confirming that Ssrp1 was the downstream target gene of Mir204/211, and the expression of Ssrp1 was elevated in RA. Lastly, we found that Ssrp1 knockdown exerts an anti-arthritis effect in CIA dKO mice by regulating proliferation and inflammation. CIA dKO mice received AAV-shSsrp1 displayed alleviated paw swelling, arthritis scores, synovial inflammation, and articular cartilage destruction compared with the AAV-shRNA Ctrl CIA dKO mice. Our study revealed that Ssrp1knockdown exerted an anti-arthritis effect in RA by suppressing cell proliferation and inflammation.

Mir204/211 suppress RA progression by regulating both inflammation and cell proliferation, and Mir204/211 affect cell proliferation and inflammation in RA by regulating downstream target gene Ssrp1 (Figure 10).

Figure 10

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All data generated or analysed during this study are included in the manuscript and supporting file.

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Author details

1. Qi-Shan Wang

   Department of Pharmacy, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

   Contribution

   Conceptualization, Data curation, Software, Formal analysis, Investigation, Methodology, Writing - original draft

   Contributed equally with

   Kai-Jian Fan

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0985-3993

2. Kai-Jian Fan

   Department of Pharmacy, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

   Contribution

   Conceptualization, Data curation, Software, Formal analysis, Investigation, Methodology, Writing - original draft

   Contributed equally with

   Qi-Shan Wang

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5295-3175

3. Hui Teng

   Department of Pharmacy, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

   Contribution

   Data curation, Software, Investigation, Methodology

   Competing interests

   No competing interests declared

4. Sijia Chen

   Department of Pharmacy, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

   Contribution

   Data curation, Software, Methodology

   Competing interests

   No competing interests declared

5. Bing-Xin Xu

   Department of Pharmacy, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

   Contribution

   Data curation, Software, Formal analysis, Methodology

   Competing interests

   No competing interests declared

6. Di Chen

   Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China

   Contribution

   Data curation, Project administration, Writing - review and editing

   For correspondence

   di.chen@siat.ac.cn

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4258-3457

7. Ting-Yu Wang

   Department of Pharmacy, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

   Contribution

   Funding acquisition, Project administration, Writing - review and editing

   For correspondence

   drtywang@163.com

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5000-7890

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