BioMed Research International

BioMed Research International / 2019 / Article

Review Article | Open Access

Volume 2019 |Article ID 6920281 |

Chong Chen, Tianhua Rong, Zheng Li, Jianxiong Shen, "Noncoding RNAs Involved in the Pathogenesis of Ankylosing Spondylitis", BioMed Research International, vol. 2019, Article ID 6920281, 8 pages, 2019.

Noncoding RNAs Involved in the Pathogenesis of Ankylosing Spondylitis

Academic Editor: Peyman Björklund
Received03 Apr 2019
Accepted25 Jun 2019
Published07 Jul 2019


Ankylosing spondylitis (AS) is a form of arthritis that can lead to fusion of vertebrae and sacroiliac joints following syndesmophyte formation. The etiology of this painful disease remains poorly defined due to its complex genetic background. There are no commonly accepted methods for early diagnosis of AS, nor are there any effective or efficient clinical treatments. Several noncoding RNAs (ncRNAs) have been linked to AS pathogenesis and inflammation via selective binding of their downstream targets. However, major gaps in knowledge remain to be filled before such findings can be translated into clinical treatments for AS. In this review, we outline recent findings that demonstrate essential roles of ncRNAs in AS mediated via multiple signaling pathways such as the Wnt, transforming growth factor-β/bone morphogenetic protein, inflammatory, T-cell prosurvival, and nuclear factor-κB pathways. The summary of these findings provides insight into the molecular mechanisms by which ncRNAs can be targeted for AS diagnosis and the development of therapeutic drugs against a variety of autoimmune diseases.

1. Introduction

Ankylosing spondylitis (AS) is a type of arthritis most commonly affecting the spine that is characterized by back pain, syndesmophyte formation, fusion of the spine and sacroiliac joints, and disability. In AS, inflammation in various regions of the skeletal system induces new bone formation [1].

Through transcriptional analysis and RNA-labeled sequencing, the Australo-Anglo-American Spondyloarthritis Consortium has identified all of the RNA labels from each long noncoding RNA (lncRNA; >200 nucleotides) transcript isolated from AS-associated gene deserts in peripheral blood monocytes [2]. Now further research is needed to explore the roles of the identified ncRNAs in the pathogenesis of AS. Moreover, analysis of sequence variation in ncRNAs has never been properly conducted to determine independent risk factors for AS among those common for human diseases. Recently, the contributions of microRNAs (miRNAs), a subfamily of small ncRNAs that regulate target gene transcripts, to autoimmune diseases have been recognized [3]. These miRNAs target several signaling pathways that are potentially involved in the specific mechanisms underlying AS pathogenesis, whereas lncRNAs have been reported to have important roles in major cellular processes such as chromatin remodeling and subsequent transcription, posttranscriptional processing, and integrity of the nucleus [47]. Ultimately, lncRNAs, through various functions, regulate cellular proliferation, migration, and differentiation as well as organogenesis [8].

Furthermore, previous research suggests that lncRNAs maintain body homeostasis and contribute to rheumatic and autoimmune diseases.

In the present review, we summarize the literature describing the emerging roles of ncRNAs in multiple signaling pathways that contribute to several autoimmune diseases, with an emphasis on AS (Tables 1 and 2). We also illustrate the role of ncRNAs in the pathogenesis of AS (Figure 1). Specifically, we discuss the function of ncRNAs in the Wnt, transforming growth factor-β (TGFβ)/bone morphogenetic protein (BMP), inflammatory, T-cell prosurvival, and nuclear factor-κB (NF-κB) signaling pathways. ncRNAs are capable of targeting members of these signaling pathways, and we suggest that ncRNAs represent molecular targets for AS diagnosis and the development of therapeutic drugs against autoimmune diseases.

ncRNASignaling pathway(s)Key signaling  

miR-29aWntDKK1 and GSK3βhFOB cellsRegulates TNFα and  
pathogenic bone metabolism
miR-29aWntDKK1PBMCsDiagnostic marker of new  
bone formation
miR-29a/miR-29cWntDKK1osteoblastsPost-transcriptional mechanisms for  
osteonectin regulation
miR-130aTNFHDAC3PBMCsHDAC3 forms a negative feedback loop with  
miR-130a and enhances  
TNF-1α expression
miR-10bTNF/T cell-mediated prosurvivalIL-17A/MAP3K7Th17 cellsmiR-10b acts in a feedback loop to suppress IL-17A by targeting  
lnc-LIN54-1/ lnc-FRG2C-3/ lnc-USP50-2
TGFβ-BMPsTGFβMSCsPathological osteogenesis[14]
hsa-miR-20a/ hsa-miR-300/ hsa-miR-185/ hsa-miR-30d/  
hsa-miR-320a/ hsamiR- 130b/ hsa-miR-33a/  
TGFβ-BMPsBMP2/osteocalcin/ Runx2osteoclasts/ fibroblastsRegulation of cell-cell interaction between osteoclasts and fibroblasts[15]
miR-199a-5pmTOR/T cell-mediated  
RhebTh17 cellInduces autophagy[16]
miR-16/miR-221 /let-7iT cell-mediated prosurvivalTLR-4/IFN-γT cellsIncreased let-7i expression  
facilitates immune response
miR-124T cell-mediated  
ANTXR2Th1 cellsInduces autophagy[18]
miR-155NF-κBIFN-βosteoclastsSelectively interacts with  
both SOCS1 and MITF
miR-146a/ miR-155serum samplesNovel complementary  
hsa-miR-29/ hsa-miR-126-3pPBMCsBiomarkers and  
provocative therapeutic targets
miR-21PDCD4whole bloodDevelopment of AS[22]

Abbreviations: PBMCs, peripheral blood mononuclear cells; MSCs, mesenchymal stem cells

ncRNASNP No.Key signaling  
Associated or notAssociated  

miR-146ars2910164IRAK1 (rs3027898)Yespolymorphisms[23]
miR-146ars2431697/ rs2910164/  
miR-196ars11614913Bach1, IL-1β and  
miR-146a/ miR-9-3/
miR-205/Yescopy number variants[27]

2. Wnt Signaling Pathway

Wnt signaling is evolutionarily conserved in metazoans and essential for cellular processes including cell fate determination, migration, and polarization as well as neural patterning, organogenesis, tissue homeostasis, and tissue repair after stroke or traumatic injury [28, 29]. Accumulating evidence indicates that Wnt signaling has clinical implications in the pathogenesis of autoimmune diseases, including AS, via its role in bone morphogenesis and homeostasis through the induction of mesenchymal cell osteoblastogenesis. This process may be an important contributor to the anabolic metabolism involved in joint remodeling in patients with AS and/or osteoarthritis [30].

Dickkopf-1 (DKK1), a potent inhibitor of the canonical Wnt signaling pathway, is required during Drosophila embryonic head development and interacts with its coreceptor LRP5. LRP5 dysfunction and/or deficiency can result in erosive arthritis [9]. Additionally, some studies have reported that promotion of Wnt/β-catenin signaling, e.g., by antagonism of DKK1, is a promising therapeutic option for patients with bone pathologies [31].

DKK1 is considered a biomarker for the early detection of new bone formation in AS patients [32, 33]. However, another study reported a compensatory increase in circulating endogenous factors that promote new bone formation, which they attribute to a decrease in DKK-1-mediated inhibition in AS patients [34]. Huang et al. [10] reported higher expression of miR-29a in AS patients than in patients with rheumatoid arthritis (RA) or healthy individuals, which suggests the potential of miR-29a as a novel biomarker for AS. Functionally, one study showed that miR-29a mediates tumor necrosis factor-α (TNFα)-induced bone loss via selective suppression of DKK1 and glycogen synthase kinase 3β (GSK3β), which activates the canonical Wnt/β-catenin signaling pathway [9]. Nevertheless, increased miR-29a expression was not found to correlate with the Bath Ankylosing Spondylitis Functional Index (BASFI), an index that reflects the degree of functional limitations in AS patients. Moreover, the expression levels of both miR-29a and miR-29c were decreased in osteoblasts following treatment with DKK-1, revealing that miR-29 expression is induced by an increase in canonical Wnt signaling during osteoblastic differentiation [11]. In brief, these results indicate that miR-29a is essential for the regulation of TNFα-mediated osteogenic differentiation, at least in part through the regulation of DKK1 and GSK3β, and thereby enhances canonical Wnt signaling [9].

3. TNF Signaling Pathway

Over the last two decades, the use of TNF inhibitors has improved AS treatment by reducing inflammation, leading to significant reductions in clinical symptoms in AS patients that were not achieved with conventional treatments.

TNF inhibitors have a recognized ability to inhibit spinal radiographic progression in AS patients [35, 36]. We hypothesize that this process may occur through the interaction of these inhibitors with DKK-1, given that neutralization of DKK-1 with antibodies has been widely used to reverse bone-destructive patterns in mouse models of RA, inevitably resulting in hyperosteogeny in patients with osteoarthritis [37]. In addition, Adalimumab, a monoclonal antibody to human TNFα, is an effective anti-inflammatory agent in AS patients, but its effect is also accompanied by reduced expression of DKK-1 in serum and increased focal fat deposition in the lumbar spine [38]. We hypothesize that the TNF-induced release of DKK1 inhibits Wnt signaling, which in turn reduces osteoblastogenesis and osteoprotegerin (OPG) expression and instead increases osteoclast activity and erosion. This is consistent with the observed reductions in serum DKK1 levels in RA patients treated with TNF inhibitors [37]. Furthermore, a study in a genetically engineered AS mouse model showed that treatment with DKK1-blocking antibodies promoted fusion of the sacroiliac joints [39].

Histone acetyltransferases (HATs) and histone deacetylases (HDACs), the master regulators of acetylation and deacetylation, respectively, modulate the expression levels of various genes, including those that encode inflammatory cytokines [40]. HDAC inhibitors have been administered to reduce the release of proinflammatory cytokines such as TNFα [41], which in turn reduces the expression of SIRT1 that is activated by the TNFα/NF-κB signaling pathway [42]. Recently, HDAC3 was reported to modulate a negative feedback loop involving miR-130a expression through the upregulation of TNFα in peripheral blood monocytes, suggesting a potential molecular mechanism underlying the pathology of AS [12]. Further, TNFα upregulates miR-10b, which in turn suppresses IL-17A production, revealing an essential role for miR-10b in a negative feedback loop that inhibits the Th17-mediated inflammatory response in AS [43].

IL-1R-associated kinase (IRAK1) is a member of the signaling cascade that induces TNF expression and plays a critical role in providing negative feedback for TNFα-induced inflammation. IRAK1 is regulated by miR146a, a miRNA that inhibits osteoclastogenesis and has received attention for its potential use in the diagnosis of juvenile idiopathic arthritis [23, 44, 45].

4. TGFβ-BMP Signaling Pathway

The BMPs, members of the TGFβ superfamily, are released by various cell types including osteoblasts, chondrocytes, and endothelial cells [46]. Proosteogenic BMPs such as BMP2/4/7 bind cognate membrane-bound receptors, and these binding events induce phosphorylation of SMAD1/5/8, respectively. Phosphorylated SMAD1/5/8 then associate with SMAD4 and translocate to the nucleus to initiate transcription of BMP-responsive genes. Several secreted oligopeptides, such as Noggin (NOG) and Sclerostin, sequester BMPs via a competitive inhibition approach and prevent binding with TGFβ receptors [13]. In the clinic, dysregulation of BMP signaling pathway is correlated with several skeletal disorders, including low- or high-bone mass diseases, heterotopic ossification, and osteoporosis [46].

BMP signaling is involved in the pathological osteogenesis that occurs in AS [47]. An imbalance between BMP2 and NOG contributes to BMP2-mediated increases in osteogenic differentiation of mesenchymal stem cells in AS patients. Xie et al. [14] performed microarray analyses with mesenchymal stem cells from both AS patients and healthy control individuals after 10 days in conditions promoting osteogenic differentiation. Their findings demonstrated differences in lncRNA and mRNA expression between these two groups. For example, analysis of coexpression networks, also known as protein-coding and noncoding gene expression analysis, revealed that several lncRNAs, including lnc-ZNF354A-1, lnc-LIN54-1, lnc-FRG2C-3, and lnc-USP50-2, contribute to osteogenesis in AS patients. Furthermore, bioinformatic predictions of a number of miRNAs from Homo sapiens suggest a suppressive influence on several genes such as osteocalcin, BMP2, and Runx2, which are generally related to osteogenic differentiation. Those Homo sapiens microRNAs (hsa-miRs) include hsa-miR-20a, hsa-miR-30d, hsa-miR-33a, has-miR-130b, hsa-miR-155, hsa-miR-185, hsa-miR-222, hsa-miR-300, and hsa-miR-320a. Additionally, another study demonstrated that osteoclasts could induce the osteogenic differentiation of fibroblasts in vitro, and therefore, miRNAs may play key roles via their modulation of cellular interactions between osteoclasts and fibroblasts [15].

5. T-Cell-Mediated Prosurvival Signaling Pathway

Wang et al. [16] observed significant downregulation of autophagy-related genes such as LC3, Beclin1, ATG5, and miRNA-199a-5p in T cells of AS patients. They also observed higher concentrations of TNFα, interleukin (IL)-17, and IL-23 in the serum of AS patients relative to healthy persons. When Rheb, a known target of miRNA-199a-5p, was inhibited, strikingly different outcomes were observed due to the loss of Rheb-induced inactivation of the phosphorylating mechanistic target of rapamycin (mTOR), and the result was enhanced T-cell autophagy. Thus, miRNA-199a-5p overexpression represents a potentially useful therapeutic strategy for enhancing autophagy and inhibiting the pathogenesis of AS based on the selective modulation of Rheb expression and mTOR signaling.

Additionally, proinflammatory cytokines upregulate miR-10b expression, which functions as a negative autocrine/paracrine feedback inhibitor of IL-17A expression via interaction with MAP3K7. We posit that miR-10b is a potential therapeutic agent for AS treatment according to its ability to suppress pathogenic Th17 cell function, but further research focused on miR-10b is needed [43].

Among several ncRNAs, such as miR-16, miR-221, and let-7i, that are upregulated in T cells of AS patients, a recent study using the Bath Ankylosing Spondylitis Radiology Index (BASRI) test in the lumbar spine of AS patients revealed that miR-221 and let-7i are correlated with alterations in the BASRI [17]. Moreover, increased let-7i expression may facilitate the induction of interferon (IFN)-γ release by T helper type 1 cells, which facilitates immune responses [17]. Furthermore, following the overexpression of let-7i in vitro, insulin-like growth factor 1 receptor (IGF1R) expression is significantly decreased to levels similar to those observed with IGF1R siRNA treatment in Jurkat cells. Inhibition of IGF1R-mediated signaling reduces phosphorylation of mTOR/Akt and Bcl-2 expression levels and reduces negative modulation of Bax/caspase-3/PARP, thereby subsequently inducing autophagy. Similarly, let-7i overexpression induces autophagy, thereby protecting against T-cell apoptosis. This study revealed that let-7i is involved in the cellular decision-making process during the apoptosis/autophagy paradox via selective modulation of IGF1R in T cells from AS patients [48]. Additionally, genetic polymorphisms of IL-1R-associated kinase (IRAK1) have been correlated with AS susceptibility and predicted to impact miR-146’s actions in the 3’ untranslated region; however, no alteration of the miR-146a rs2910164 distribution was observed in AS patients [23]. Th1 cell differentiation and activation are considered to be, at least partially, mediated by the anthrax toxin receptor 2, ANTXR2 [49], which is selectively targeted by miR-124, and overexpression of ANTXR2 induces autophagy during bacterial infection in patients with AS [18].

6. NF-κB Signaling Pathway

Receptor activator of NF-κB ligand (RANKL) functions synergistically with proinflammatory cytokines to promote monocyte differentiation into osteoclasts in synovial tissues [50]. Inflamed synovial tissues contain lymphocytes and fibroblast-like synoviocytes that produce RANKL under various pathological conditions. miR-155, a member of the IFN-β-induced miRNAs, mediates the suppression of IFN-β in osteoclast differentiation through selective interaction with two proteins, suppressor of cytokine signaling 1 (SOCS1) and microphthalmia-associated transcription factor (MITF), that are critical regulators of osteoclastogenesis [19]. Upregulation of miR-155 leads to increases in the release of proinflammatory cytokines IL-6 and IL-23, which promote the maturation of autoreactive Th17 cells and release of TNFα, a well-established mediator of chronic inflammation [51]. Furthermore, miR-155 expression is closely correlated with the BASFI as well as severity indices of thoracolumbar kyphosis secondary to AS [20].

Upregulation of miR-146a has been reported in various autoimmune diseases such as psoriasis, RA, lupus nephritis, and Sjögren’s syndrome [5255]. Xu et al. [24] discovered a correlation between the miR-146a SNP rs2910164 and AS in Chinese patients, and Qian et al. [20] also reported that miR-146a is a novel biomarker for AS. However, when Niu et al. [25] conducted a frequency analysis of three common SNPs in miR-146a, i.e., rs2431697, rs2910164, and rs57095329, in Chinese AS patients, no significant correlations were observed between these three SNPs and AS. However, their findings still indicated the potential involvement of these SNPs in the progression of certain autoimmune diseases and even their potential value in corresponding treatment strategies. Moreover, miR-146a acts as an effective and efficient modulator to prevent overwhelming inflammatory reactions. Reductions in miR-146 expression contribute to the prolonged release of inflammatory cytokines that occurs after the NF-κB signaling pathway is activated by lipopolysaccharide and other proinflammatory mediators [24, 56]. Two downstream targets of miR-146a, TNF receptor-associated protein 6 (TRAF6) and IRAK1, are downregulated by miR-146a when NF-κB activity is reduced during inflammation, and in turn, expression of NF-κB signaling downstream genes, such as IL-1β, IL-6, IL-8, and TNFα, is suppressed [56, 57].

7. Conclusion

Research in recent years has revealed the roles of ncRNAs as essential regulators of vital cellular processes under both normal and pathological conditions. However, our understanding of their functions as regulators of gene expression remains incomplete. Importantly, several ncRNAs have been identified that represent not only potential biomarkers for the diagnosis of AS in an early stage but also promising therapeutic targets for AS treatment. These ncRNAs include hsa-miR-29, hsa-miR-126-3p, and miR-196a [21, 26]. Moreover, both low-copy number ncRNA transcripts, e.g., miR-9-3, miR-143, miR-146a, miR-205, and high-copy number ncRNA transcripts, e.g., miR-23a and miR-301a, are associated with susceptibility to acute anterior uveitis combined with AS [27]. Additionally, miR-21 expression is closely associated with levels of programmed cell death 4 mRNA and collagen crosslinked C-telopeptide protein during AS progression [22].

lncRNA-AK001085 expression in serum is significantly decreased in AS patients compared with healthy individuals, indicating that it is a potential endogenous suppressor of AS. Notably, lncRNA-AK001085 expression can be induced by occupational hazards, cigarette smoking, and even lack of physical exercise. Based on the results of receiver operating curve analyses, lncRNA-AK001085 expression is an independent factor for the diagnosis of AS as well as in the BASFI test to determine disease activity [58].

Complex signaling networks including the Notch/Wnt, Hedgehog/Wnt, MAPK/Wnt, Wnt/BMP, Wnt/TNF, and TNF/NF-κB pathways receive regulatory crosstalk from ncRNAs. ncRNA regulation of these pathways is essential in the process of new bone formation via inflammatory cascades. However, the roles of circular RNA and competing endogenous RNA networks remain to be investigated.

Conflicts of Interest

The authors declare no conflicts of interest.

Authors’ Contributions

Chong Chen, Tianhua Rong, and Zheng Li contributed equally to this work.


Our study was supported by the National Natural Science Foundation of China (no. 81330044 and no. 81772424).


  1. H. Colineaux, A. Ruyssen-Witrand, and A. Cambon-Thomsen, “Genetic markers as a predictive tool based on statistics in medical practice: ethical considerations through the analysis of the use of HLA-B(*)27 in rheumatology in France,” Frontiers in Genetics, vol. 6, article no 299, 2015. View at: Google Scholar
  2. J. D. Reveille, A.-M. Sims, P. Danoy et al., “Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci,” Nature Genetics, vol. 42, no. 2, pp. 123–127, 2010. View at: Publisher Site | Google Scholar
  3. Z. Li, X. Yu, J. Shen, M. T. V. Chan, and W. K. K. Wu, “MicroRNA in intervertebral disc degeneration,” Cell Proliferation, vol. 48, no. 3, pp. 278–283, 2015. View at: Publisher Site | Google Scholar
  4. K. S. Pollard, S. R. Salama, N. Lambert et al., “An RNA gene expressed during cortical development evolved rapidly in humans,” Nature, vol. 443, no. 7108, pp. 167–172, 2006. View at: Publisher Site | Google Scholar
  5. Y. Yu, J. Yang, Q. Li, B. Xu, Y. Lian, and L. Miao, “LINC00152: A pivotal oncogenic long non-coding RNA in human cancers,” Cell Proliferation, vol. 50, no. 4, 2017. View at: Google Scholar
  6. Y. Xin, Z. Li, J. Shen, M. T. V. Chan, and W. K. K. Wu, “CCAT1: A pivotal oncogenic long non-coding RNA in human cancers,” Cell Proliferation, vol. 49, no. 3, pp. 255–260, 2016. View at: Publisher Site | Google Scholar
  7. K. Tano and N. Akimitsu, “Long non-coding RNAs in cancer progression,” Frontiers in Genetics, vol. 3, article no 219, 2012. View at: Google Scholar
  8. T. R. Mercer, M. E. Dinger, and J. S. Mattick, “Long non-coding RNAs: insights into functions,” Nature Reviews Genetics, vol. 10, no. 3, pp. 155–159, 2009. View at: Publisher Site | Google Scholar
  9. C. Li, P. Zhang, and J. Gu, “miR-29a modulates tumor necrosis factor-α-induced osteogenic inhibition by targeting Wnt antagonists,” Development, Growth & Differentiation, vol. 57, no. 3, pp. 264–273, 2015. View at: Publisher Site | Google Scholar
  10. J. Huang, G. Song, Z. Yin, X. Luo, and Z. Ye, “Elevated miR-29a expression is not correlated with disease activity index in PBMCs of patients with ankylosing spondylitis,” Modern Rheumatology, vol. 24, no. 2, pp. 331–334, 2014. View at: Publisher Site | Google Scholar
  11. K. Kapinas, C. B. Kessler, and A. M. Delany, “miR-29 suppression of osteonectin in osteoblasts: Regulation during differentiation and by canonical Wnt signaling,” Journal of Cellular Biochemistry, vol. 108, no. 1, pp. 216–224, 2009. View at: Publisher Site | Google Scholar
  12. Y. Jiang and L. Wang, “Role of histone deacetylase 3 in ankylosing spondylitis via negative feedback loop with microRNA-130a and enhancement of tumor necrosis factor-1α expression in peripheral blood mononuclear cells,” Molecular Medicine Reports, vol. 13, no. 1, pp. 35–40, 2016. View at: Publisher Site | Google Scholar
  13. G. Chen, C. Deng, and Y. P. Li, “TGF-beta and BMP signaling in osteoblast differentiation and bone formation,” International Journal of Biological Sciences, vol. 8, pp. 272–288, 2012. View at: Google Scholar
  14. Z. Xie, J. Li, P. Wang et al., “Differential expression profiles of long noncoding RNA and mRNA of osteogenically differentiated mesenchymal stem cells in ankylosing spondylitis,” The Journal of Rheumatology, vol. 43, no. 8, pp. 1523–1531, 2016. View at: Publisher Site | Google Scholar
  15. F. Yu, Y. Cui, X. Zhou, X. Zhang, and J. Han, “Osteogenic differentiation of human ligament fibroblasts induced by conditioned medium of osteoclast-like cells,” Bioscience Trends, vol. 5, no. 2, pp. 46–51, 2011. View at: Publisher Site | Google Scholar
  16. Y. Wang, J. Luo, X. Wang, B. Yang, and L. Cui, “MicroRNA-199a-5p induced autophagy and inhibits the pathogenesis of ankylosing spondylitis by modulating the mTOR signaling via directly targeting ras homolog enriched in brain (rheb),” Cellular Physiology and Biochemistry, vol. 42, no. 6, pp. 2481–2491, 2017. View at: Publisher Site | Google Scholar
  17. N.-S. Lai, H.-C. Yu, H.-C. Chen, C.-L. Yu, H.-B. Huang, and M.-C. Lu, “Aberrant expression of microRNAs in T cells from patients with ankylosing spondylitis contributes to the immunopathogenesis,” Clinical & Experimental Immunology, vol. 173, no. 1, pp. 47–57, 2013. View at: Publisher Site | Google Scholar
  18. Y. Xia, K. Chen, M.-H. Zhang et al., “MicroRNA-124 involves in ankylosing spondylitis by targeting ANTXR2,” Modern Rheumatology, vol. 25, no. 5, pp. 784–789, 2015. View at: Publisher Site | Google Scholar
  19. J. Zhang, H. Zhao, J. Chen et al., “Interferon-β-induced miR-155 inhibits osteoclast differentiation by targeting SOCS1 and MITF,” FEBS Letters, vol. 586, no. 19, pp. 3255–3262, 2012. View at: Publisher Site | Google Scholar
  20. B. Qian, M. Ji, Y. Qiu et al., “Identification of serum miR-146a and miR-155 as novel noninvasive complementary biomarkers for ankylosing spondylitis,” The Spine Journal, vol. 41, no. 9, pp. 735–742, 2016. View at: Publisher Site | Google Scholar
  21. Q. Lv, Q. Li, P. Zhang et al. et al., “Disorders of MicroRNAs in peripheral blood mononuclear cells: as novel biomarkers ofankylosing spondylitis and provocative therapeutic targets,” BioMed Research International, vol. 2015, Article ID 504208, 7 pages, 2015. View at: Publisher Site | Google Scholar
  22. C.-H. Huang, J. C.-C. Wei, W.-C. Chang et al., “Higher expression of whole blood microRNA-21 in patients with ankylosing spondylitis associated with programmed cell death 4 mRNA expression and collagen cross-linked C-telopeptide concentration,” The Journal of Rheumatology, vol. 41, no. 6, pp. 1104–1111, 2014. View at: Publisher Site | Google Scholar
  23. A. Chatzikyriakidou, P. V. Voulgari, I. Georgiou, and A. A. Drosos, “The role of microRNA-146a (miR-146a) and its target IL-1R-associated kinase (IRAK1) in psoriatic arthritis susceptibility,” Scandinavian Journal of Immunology, vol. 71, no. 5, pp. 382–385, 2010. View at: Publisher Site | Google Scholar
  24. H. Y. Xu, Z. Y. Wang, J. F. Chen et al., “Association between ankylosing spondylitis and the miR-146a and miR-499 polymorphisms,” PLoS ONE, vol. 10, no. 4, Article ID e0122055, 2015. View at: Publisher Site | Google Scholar
  25. Z. Niu, J. Wang, H. Zou, C. Yang, W. Huang, and L. Jin, “common MIR146A polymorphisms in chinese ankylosing spondylitis subjects and controls,” PLoS ONE, vol. 10, no. 9, Article ID e0137770, 2015. View at: Publisher Site | Google Scholar
  26. J. Qi, S. Hou, Q. Zhang et al., “A functional variant of pre-miRNA-196a2 confers risk for Behcet's disease but not for Vogt-Koyanagi-Harada syndrome or AAU in ankylosing spondylitis,” Human Genetics, vol. 132, no. 12, pp. 1395–1404, 2013. View at: Publisher Site | Google Scholar
  27. L. Yang, L. Du, Y. Yue et al., “miRNA copy number variants confer susceptibility to acute anterior uveitis with or without ankylosing spondylitis,” Investigative Opthalmology & Visual Science, vol. 58, no. 4, pp. 1991–2001, 2017. View at: Publisher Site | Google Scholar
  28. Y. Komiya, N. Mandrekar, A. Sato, I. B. Dawid, and R. Habas, “Custos controls β-catenin to regulate head development during vertebrate embryogenesis,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 111, no. 36, pp. 13099–13104, 2014. View at: Publisher Site | Google Scholar
  29. R. T. Moon, A. D. Kohn, G. V. de Ferrari, and A. Kaykas, “WNT and β-catenin signalling: diseases and therapies,” Nature Reviews Genetics, vol. 5, no. 9, pp. 691–701, 2004. View at: Publisher Site | Google Scholar
  30. M. Corr, “Wnt signaling in ankylosing spondylitis,” Clinical Rheumatology, vol. 33, pp. 759–762, 2014. View at: Google Scholar
  31. C.-G. Miao, Y.-Y. Yang, X. He et al., “Wnt signaling pathway in rheumatoid arthritis, with special emphasis on the different roles in synovial inflammation and bone remodeling,” Cellular Signalling, vol. 25, no. 10, pp. 2069–2078, 2013. View at: Publisher Site | Google Scholar
  32. S.-R. Kwon, M.-J. Lim, and C.-H. Suh, “Dickkopf-1 level is lower in patients with ankylosing spondylitis than in healthy people and is not influenced by anti-tumor necrosis factor therapy,” Rheumatology International, vol. 32, no. 8, pp. 2523–2527, 2012. View at: Publisher Site | Google Scholar
  33. G. R. Heiland, H. Appel, D. Poddubnyy et al., “High level of functional dickkopf-1 predicts protection from syndesmophyte formation in patients with ankylosing spondylitis,” Annals of the Rheumatic Diseases, vol. 71, no. 4, pp. 572–574, 2012. View at: Publisher Site | Google Scholar
  34. D. Daoussis, S. N. C. Liossis, E. E. Solomou et al., “Evidence that Dkk-1 is dysfunctional in ankylosing spondylitis,” Arthritis & Rheumatology, vol. 62, no. 1, pp. 150–158, 2010. View at: Publisher Site | Google Scholar
  35. C. Molnar, A. Scherer, X. Baraliakos et al., “TNF blockers inhibit spinal radiographic progression in ankylosing spondylitis by reducing disease activity: results from the Swiss clinical quality management cohort,” Annals of the Rheumatic Diseases, vol. 77, no. 1, pp. 63–69, 2017. View at: Publisher Site | Google Scholar
  36. A. Deodhar, “TNF inhibitors and structural damage in ankylosing spondylitis,” Nature Reviews Rheumatology, vol. 14, no. 1, pp. 5-6, 2018. View at: Publisher Site | Google Scholar
  37. D. Diarra, M. Stolina, K. Polzer et al., “Dickkopf-1 is a master regulator of joint remodeling,” Nature Medicine, vol. 13, no. 2, pp. 156–163, 2007. View at: Publisher Site | Google Scholar
  38. Z. Hu, M. Xu, Q. Li et al., “Adalimumab significantly reduces inflammation and serum DKK-1 level but increases fatty deposition in lumbar spine in active ankylosing spondylitis,” International Journal of Rheumatic Diseases, vol. 15, no. 4, pp. 358–365, 2012. View at: Publisher Site | Google Scholar
  39. S. Uderhardt, D. Diarra, J. Katzenbeisser et al., “Blockade of Dickkopf (DKK)-1 induces fusion of sacroiliac joints,” Annals of the Rheumatic Diseases, vol. 69, no. 3, pp. 592–597, 2010. View at: Publisher Site | Google Scholar
  40. N. Kim, H.-Y. Sun, M.-Y. Youn, and J.-Y. Yoo, “IL-1β-specific recruitment of GCN5 histone acetyltransferase induces the release of PAF1 from chromatin for the de-repression of inflammatory response genes,” Nucleic Acids Research, vol. 41, no. 8, pp. 4495–4506, 2013. View at: Publisher Site | Google Scholar
  41. T. Roger, J. Lugrin, D. Le Roy et al., “Histone deacetylase inhibitors impair innate immune responses to Toll-like receptor agonists and to infection,” Blood, vol. 117, no. 4, pp. 1205–1217, 2011. View at: Publisher Site | Google Scholar
  42. M.-H. Moon, J.-K. Jeong, Y.-J. Lee, J.-W. Seol, C. J. Jackson, and S.-Y. Park, “SIRT1, a class III histone deacetylase, regulates TNF-α-induced inflammation in human chondrocytes,” Osteoarthritis and Cartilage, vol. 21, no. 3, pp. 470–480, 2013. View at: Publisher Site | Google Scholar
  43. L. Chen, M. H. Al-Mossawi, A. Ridley et al., “miR-10b-5p is a novel Th17 regulator present in Th17 cells from ankylosing spondylitis,” Annals of the Rheumatic Diseases, vol. 76, no. 3, pp. 620–625, 2017. View at: Publisher Site | Google Scholar
  44. T. Nakasa, H. Shibuya, Y. Nagata, T. Niimoto, and M. Ochi, “The inhibitory effect of microRNA-146a expression on bone destruction in collagen-induced arthritis,” Arthritis & Rheumatology, vol. 63, no. 6, pp. 1582–1590, 2011. View at: Publisher Site | Google Scholar
  45. X. Ma, F. Wu, L. Xin et al., “Differential plasma microRNAs expression in juvenile idiopathic arthritis,” in Modern Rheumatology, vol. 26, pp. 224–232, 2016. View at: Google Scholar
  46. G. Sánchez-Duffhues, C. Hiepen, P. Knaus, and P. ten Dijke, “Bone morphogenetic protein signaling in bone homeostasis,” Bone, vol. 80, pp. 43–59, 2015. View at: Publisher Site | Google Scholar
  47. R. Baum and E. M. Gravallese, “Bone as a target organ in rheumatic disease: impact on osteoclasts and osteoblasts,” Clinical Reviews in Allergy & Immunology, vol. 51, pp. 1–15, 2016. View at: Google Scholar
  48. C. Hou, M. Zhu, M. Sun, and Y. Lin, “MicroRNA let-7i induced autophagy to protect T cell from apoptosis by targeting IGF1R,” Biochemical and Biophysical Research Communications, vol. 453, no. 4, pp. 728–734, 2014. View at: Publisher Site | Google Scholar
  49. D. J. Banks, M. Barnajian, F. J. Maldonado-Arocho, A. M. Sanchez, and K. A. Bradley, “Anthrax toxin receptor 2 mediates Bacillus anthracis killing of macrophages following spore challenge,” Cellular Microbiology, vol. 7, no. 8, pp. 1173–1185, 2005. View at: Publisher Site | Google Scholar
  50. K. Soderstrom, E. Stein, P. Colmenero et al., “Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 107, no. 29, pp. 13028–13033, 2010. View at: Publisher Site | Google Scholar
  51. M. Kurowska-Stolarska, S. Alivernini, L. E. Ballantine et al., “MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 108, no. 27, pp. 11193–11198, 2011. View at: Publisher Site | Google Scholar
  52. K. M. Pauley, M. Satoh, A. L. Chan, M. R. Bubb, W. H. Reeves, and E. K. L. Chan, “Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients,” Arthritis Research & Therapy, vol. 10, no. 4, article no. R101, 2008. View at: Publisher Site | Google Scholar
  53. E. Sonkoly, M. Ståhle, and A. Pivarcsi, “MicroRNAs: novel regulators in skin inflammation,” Clinical and Experimental Dermatology, vol. 33, no. 3, pp. 312–315, 2008. View at: Publisher Site | Google Scholar
  54. E. Zilahi, T. Tarr, G. Papp, Z. Griger, S. Sipka, and M. Zeher, “Increased microRNA-146a/b, TRAF6 gene and decreased IRAK1 gene expressions in the peripheral mononuclear cells of patients with Sjögren's syndrome,” Immunology Letters, vol. 141, no. 2, pp. 165–168, 2012. View at: Publisher Site | Google Scholar
  55. J. Lu, B. C.-H. Kwan, F. M.-M. Lai et al., “Glomerular and tubulointerstitial miR-638, miR-198 and miR-146a expression in lupus nephritis,” Nephrology, vol. 17, no. 4, pp. 346–351, 2012. View at: Publisher Site | Google Scholar
  56. J. H. Wang, K. S. Shih, Y. W. Wu, A. W. Wang, and C. R. Yang, “Histone deacetylase inhibitors increase microRNA-146a expression and enhance negative regulation of interleukin-1β signaling in osteoarthritis fibroblast-like synoviocytes,” Osteoarthritis and Cartilage, vol. 21, no. 12, pp. 1987–1996, 2013. View at: Publisher Site | Google Scholar
  57. J. A. Didonato, F. Mercurio, and M. Karin, “NF-κB and the link between inflammation and cancer,” Immunological Reviews, vol. 246, no. 1, pp. 379–400, 2012. View at: Publisher Site | Google Scholar
  58. X. Li, W. Chai, G. Zhang et al., “Down-regulation of lncRNA-AK001085 and its Influences on the diagnosis of ankylosing spondylitis,” Medical Science Monitor, vol. 23, pp. 11–16, 2017. View at: Publisher Site | Google Scholar

Copyright © 2019 Chong Chen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

Article of the Year Award: Outstanding research contributions of 2020, as selected by our Chief Editors. Read the winning articles.