Polymorphisms have been identified in the Xq28 locus as risk loci for rheumatoid arthritis (RA). Here, we investigated the association between three polymorphisms in the Xq28 region containing ...TMEM187 and IRAK1 (rs13397, rs1059703, and rs1059702) in two unstudied populations: Tunisian and French. The rs13397 G and rs1059703 T major alleles were significantly increased in RA patients (n=408) compared with age-matched controls (n=471) in both Tunisian and French women. These results were confirmed by a meta-analysis replication study including two independent Greek and Korean cohorts. The rs1059702 C major allele was significantly associated with RA, only with French women. In the French population, the GTC haplotype displayed a protective effect against RA, while the ATC, GCC, and GTT haplotypes conferred significant risk for RA. No association for these haplotypes was found in the Tunisian population. Our results replicated for the first time the association of the three Xq28 polymorphisms with RA risk in Tunisian and French populations and suggested that RA susceptibility is associated with TMEM187-IRAK1 polymorphisms in women. Our data further support the involvement of X chromosome in RA susceptibility and evidence ethnicities differences that might be explained by differences in the frequencies of SE HLA-DRB1 alleles between both populations.
Epigenetic abnormalities are part of the pathogenetic alterations involved in the development of rheumatic disorders. In this context, the main musculoskeletal cell lineages, which are generated from ...the pool of mesenchymal stromal cells (MSCs), and the immune cells that participate in rheumatic diseases are deregulated. In this Review, we focus on microRNA (miRNA)-mediated regulatory pathways that control cell proliferation, drive the production of proinflammatory mediators and modulate bone remodelling. The main studies that identify miRNAs as regulators of immune cell fate, MSC differentiation and immunomodulatory properties - parameters that are altered in rheumatoid arthritis (RA) and osteoarthritis (OA) - are also discussed, with emphasis on the importance of miRNAs in the regulation of cellular machinery, extracellular matrix remodelling and cytokine release. A deeper understanding of the involvement of miRNAs in rheumatic diseases is needed before these regulatory pathways can be explored as therapeutic approaches for patients with RA or OA.
RNA interference (RNAi) is a powerful endogenous process initiated by short double-stranded RNAs, which results in sequence-specific posttranscriptional gene silencing. The possibility of blocking ...the expression of any protein carries huge expectations for potential therapeutic applications in a wide range of diseases. For clinical development, however, the use of RNAi-based therapeutics has to overcome major obstacles, mainly targeted delivery and safety issues.
In this short review, we provide an overview of specifications for RNAi-based gene therapy in rheumatoid arthritis (RA) and discuss recent progresses in the development of efficient silencing, focusing on expression of short hairpin RNAs.
Combining advances in RNAi methodology with gene therapy technology opens avenues for rapid applications to RA.
Rationale:
Monocytes play critical roles in the pathogenesis of arthritis by contributing to the inflammatory response and bone erosion. Among genes involved in regulating monocyte functions, ...miR-146a negatively regulates the inflammatory response and osteoclast differentiation of monocytes. It is also the only miRNA reported to differentially regulate the cytokine response of the two classical Ly6C
high
and non-classical Ly6C
low
monocyte subsets upon bacterial challenge. Although miR-146a is overexpressed in many tissues of arthritic patients, its specific role in monocyte subsets under arthritic conditions remains to be explored.
Methods:
We analyzed the monocyte subsets during collagen-induced arthritis (CIA) development by flow cytometry. We quantified the expression of miR-146a in classical and non-classical monocytes sorted from healthy and CIA mice, as well as patients with rheumatoid arthritis (RA). We monitored arthritis features in miR-146a
-/-
mice and assessed
in vivo
the therapeutic potential of miR-146a mimics delivery to Ly6C
high
monocytes. We performed transcriptomic and pathway enrichment analyses on both monocyte subsets sorted from wild type and miR-146a
-/-
mice.
Results:
We showed that the expression of miR-146a is reduced in the Ly6C
high
subset of CIA mice and in the analogous monocyte subset (CD14
+
CD16
-
) in humans with RA as compared with healthy controls. The ablation of miR-146a in mice worsened arthritis severity, increased osteoclast differentiation
in vitro
and bone erosion
in vivo
.
In vivo
delivery of miR-146a to Ly6C
high
monocytes, and not to Ly6C
low
monocytes, rescues bone erosion in miR-146a
-/-
arthritic mice and reduces osteoclast differentiation and pathogenic bone erosion in CIA joints of miR-146a
+/+
mice, with no effect on inflammation. Silencing of the non-canonical NF-κB family member RelB in miR-146a
-/-
Ly6C
high
monocytes uncovers a role for miR-146a as a key regulator of the differentiation of Ly6C
high
, and not Ly6C
low
, monocytes into osteoclasts under arthritic conditions.
Conclusion:
Our results show that classical monocytes play a critical role in arthritis bone erosion. They demonstrate the theranostics potential of manipulating miR-146a expression in Ly6C
high
monocytes to prevent joint destruction while sparing inflammation in arthritis.
IL-10 is a potent anti-inflammatory cytokine that has received growing attention for its therapeutic potential. We examined the efficiency of adenoviral-mediated gene transfer of IL-10 on the ...incidence and severity of murine collagen-induced arthritis (CIA). Male DBA1 mice immunized with collagen II were treated by systemic administration of 10(9) plaque-forming units of replication-defective adenoviral vector expressing viral IL-10 (vIL-10) on day 30, when clinical symptoms of arthritis start. The transgene was shown to inhibit the onset of CIA, to decrease severity, and profoundly suppress the overall joint histopathology of the experimental arthritis. Significant IL-10 concentrations were obtained in the serum of injected animals for 7 days. Inhibition of arthritis was enhanced by administration of increasing doses of adenovirus-vIL-10. In addition, the local immunosuppressive effect of gene-delivered vIL-10 could be neutralized by a monoclonal anti-vIL-10 Ab. The CIA symptoms in the group treated with the same construct expressing inactive vIL-10 (vIL-10 mut) were similar to those in untreated animals. Our data indicate that a single systemic administration of an adenoviral vector encoding vIL-10 may be a good candidate to suppress arthritis.
Juvenile idiopathic arthritis (JIA) is a heterogeneous and multifactorial group of chronic arthritis with an onset before the age of 16 years. The pathogenesis of this disease is poorly understood, ...which makes the distinction among subtypes unclear, delays diagnosis and optimal therapeutic management. MicroRNAs (miRNAs) are small non-coding RNAs that play a critical role in the regulation of immune responses. Their expression is tightly controlled to ensure cellular homeostasis and function of innate and adaptive immune cells. Abnormal expression of miRNAs has been associated with the development of many inflammatory and autoimmune diseases. In this review, we gather results published on miRNAs expression profiles in JIA patients with the aim to identify miRNAs that can be used as diagnostic biomarkers and provide information on disease activity and progression. We also focus on miRNAs deregulated in different forms of JIA to shed light on common pathways potentially involved in disease pathophysiology.
•Juvenile idiopathic arthritis is clinically heterogeneous and remains poorly understood•MiRNAs regulate gene expression and are involved in the pathogenesis of rheumatic diseases•MiRNAs aberrantly expressed in body fluids of JIA patients are promising biomarkers for diagnosis and prognosis•MiRNAs might help to identify molecular mechanisms involved in the pathogenesis of the different types of JIA.
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting joints and causing progressive damage and disability. Macrophages are of critical importance in the initiation and ...perpetuation of synovitis in RA, they can function as antigen presenting cells leading to T-cell dependent B-cell activation, assume a variety of inflammatory cell states with the production of destructive cytokines, but also contribute to tissue homeostasis/repair. The recent development of high-throughput technologies, including bulk and single cells RNA-sequencing, has broadened our understanding of synovial cell diversity, and opened novel perspectives to the discovery of new potential therapeutic targets in RA. In this review, we will focus on the relationship between the synovial macrophage infiltration and clinical disease severity and response to treatment. We will then provide a state-of-the-art picture of the biological roles of synovial macrophages and distinct macrophage subsets described in RA. Finally, we will review the effects of approved conventional and biologic drugs on the synovial macrophage component and highlight the therapeutic potential of future strategies to re-program macrophage phenotypes in RA.
•Synovial macrophages have been shown to be linked to RA severity and response to treatment.•High-throughput technologies have widened our understanding of synovial cell state diversity to an unprecedent level.•A stratified medicine approach must be considered to better define disease subtypes and improve treatment response in RA.•Macrophage-targeting strategies represent a promising avenue in the precision management of RA.
Biotherapies have revolutionized the treatment of RA. However, much work is needed to understand all the mechanisms of these biotherapies, and alternatives are needed to circumvent adverse effects ...and the high cost of these long-lasting treatments. In this article we outline some of the approaches we have used to target monocytes/macrophages as major components of inflammation and bone homeostasis. We also discuss how anti-TNF-α antibodies target monocytes/macrophages in the complex mechanisms contributing to inhibition of inflammation.
•microRNAs control the proliferation and activation of innate immune cells and their expression is disrupted in autoinflammatory disorders.•The study of the role of miRNAs in autoinflammatory ...disorders is only recently emerging and remains scarce.•Most of the miRNAs identified to be abnormally expressed in inflammasomopathies are targeting genes involved in their activated pathways.
microRNAs (miRNAs) are small non-coding RNA sequences that negatively regulate the expression of protein-encoding genes at the post-transcriptional level. They play a role in the regulation of inflammatory responses by controlling the proliferation and activation of immune cells and their expression is disrupted in several immune-mediated inflammatory disorders. Among these, autoinflammatory diseases (AID) are a group of rare hereditary disorders caused by abnormal activation of the innate immune system and characterized by recurrent fevers. Major groups of AID are inflammasomopathies, which are associated with hereditary defects in the activation of inflammasomes, cytosolic multiprotein signaling complexes regulating IL-1 family cytokine maturation and pyroptosis. The study of the role of miRNAs in AID is only recently emerging and remains scarce in inflammasomopathies. In this review, we describe the AID and inflammasomopathies, and the current knowledge on the role of miRNAs in disease processes.
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