Joint-specific regulation of homeobox D10 expression in rheumatoid arthritis fibroblast-like synoviocytes.

Rheumatoid arthritis (RA) is a systemic immune-mediated disease characterized by joint inflammation and destruction. The disease typically affects small joints in the hands and feet, later progressing to involve larger joints such as the knees, shoulders, and hips. While the reasons for these joint-specific differences are unclear, distinct epigenetic patterns associated with joint location have been reported.

Systems-biology analysis of rheumatoid arthritis fibroblast-like synoviocytes implicates cell line-specific transcription factor function.

Rheumatoid arthritis (RA) is an immune-mediated disease affecting diarthrodial joints that remains an unmet medical need despite improved therapy. This limitation likely reflects the diversity of pathogenic pathways in RA, with individual patients demonstrating variable responses to targeted therapies. Better understanding of RA pathogenesis would be aided by a more complete characterization of the disease.

Caspase-8 Variant G Regulates Rheumatoid Arthritis Fibroblast-Like Synoviocyte Aggressive Behavior.

Objective: Fibroblast-like synoviocytes (FLS) play a pivotal role in rheumatoid arthritis (RA) by contributing to synovial inflammation and progressive joint damage. An imprinted epigenetic state is associated with the FLS aggressive phenotype. We identified CASP8 (encoding for caspase-8) as a differentially marked gene and evaluated its pathogenic role in RA FLSs.

Therapeutic Effects of Tryptanthrin and Tryptanthrin-6-Oxime in Models of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease involving joint and bone damage that is mediated in part by proteases and cytokines produced by synovial macrophages and fibroblast-like synoviocytes (FLS). Although current biological therapeutic strategies for RA have been effective in many cases, new classes of therapeutics are needed. We investigated anti-inflammatory properties of the natural alkaloid tryptanthrin (TRYP) and its synthetic derivative tryptanthrin-6-oxime (TRYP-Ox).

Joint Location-Specific JAK-STAT Signaling in Rheumatoid Arthritis Fibroblast-like Synoviocytes.

Objective: Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) derived from hip and knee have distinctive DNA methylation and transcriptome patterns in interleukin (IL)-6 signaling and Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathways. To determine the functional effects of these joint-specific signatures, we evaluated how RA hip and knee FLS differ in their response to IL-6.

Methods: Hip or knee RA FLS were obtained after arthroplasty.

PTPN14 phosphatase and YAP promote TGFβ signalling in rheumatoid synoviocytes.

Objective: We aimed to understand the role of the tyrosine phosphatase PTPN14-which in cancer cells modulates the Hippo pathway by retaining YAP in the cytosol-in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA).

Methods: Gene/protein expression levels were measured by quantitative PCR and/or Western blotting. Gene knockdown in RA FLS was achieved using antisense oligonucleotides.

Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes.

Epigenetics contributes to the pathogenesis of immune-mediated diseases like rheumatoid arthritis (RA). Here we show the first comprehensive epigenomic characterization of RA fibroblast-like synoviocytes (FLS), including histone modifications (H3K27ac, H3K4me1, H3K4me3, H3K36me3, H3K27me3, and H3K9me3), open chromatin, RNA expression and whole-genome DNA methylation. To address complex multidimensional relationship and reveal epigenetic regulation of RA, we perform integrative analyses using a novel unbiased method to identify genomic regions with similar profiles.

Regulation and function of apoptosis signal-regulating kinase 1 in rheumatoid arthritis.

Despite improved therapy, rheumatoid arthritis (RA) remains an unmet medical need. Previous efforts to validate therapeutic targets in the mitogen-activated protein kinase (MAPK) family have had minimal success. Therefore, we evaluated the potential for targeting an upstream MAPK, namely apoptosis signal-regulating kinase 1 (ASK1), as an alternative approach.

Epigenetics of inflammatory arthritis.

Purpose Of Review: Aberrant epigenetic changes in DNA methylation, histone marks, and noncoding RNA expression regulate the pathogenesis of many rheumatic diseases. The present article will review the recent advances in the epigenetic profile of inflammatory arthritis and discuss diagnostic biomarkers and potential therapeutic targets.

Recent Findings: Methylation signatures of fibroblast-like synoviocytes not only distinguish rheumatoid arthritis (RA) and osteoarthritis (OA), but also early RA from late RA or juvenile idiopathic arthritis.

Regulation of the Cell Cycle and Inflammatory Arthritis by the Transcription Cofactor Gene.

Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) display unique aggressive behavior, invading the articular cartilage and promoting inflammation. Using an integrative analysis of RA risk alleles, the transcriptome and methylome in RA FLS, we recently identified the limb bud and heart development () gene as a key dysregulated gene in RA and other autoimmune diseases. Although some evidence suggests that LBH could modulate the cell cycle, the precise mechanism is unknown and its impact on inflammation in vivo has not been defined.

LBH Gene Transcription Regulation by the Interplay of an Enhancer Risk Allele and DNA Methylation in Rheumatoid Arthritis.

Objective: To identify nonobvious therapeutic targets for rheumatoid arthritis (RA), we performed an integrative analysis incorporating multiple "omics" data and the Encyclopedia of DNA Elements (ENCODE) database for potential regulatory regions. This analysis identified the limb bud and heart development (LBH) gene, which has risk alleles associated with RA/celiac disease and lupus, and can regulate cell proliferation in RA. We identified a novel LBH transcription enhancer with an RA risk allele (rs906868 G [Ref]/T) 6 kb upstream of the LBH gene with a differentially methylated locus.

Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes.

Stratifying patients on the basis of molecular signatures could facilitate development of therapeutics that target pathways specific to a particular disease or tissue location. Previous studies suggest that pathogenesis of rheumatoid arthritis (RA) is similar in all affected joints. Here we show that distinct DNA methylation and transcriptome signatures not only discriminate RA fibroblast-like synoviocytes (FLS) from osteoarthritis FLS, but also distinguish RA FLS isolated from knees and hips.

Abnormal enhancer methylation promotes rheumatoid arthritis fibroblast-like synoviocyte aggressiveness and joint inflammation.

The gene, encoding the tyrosine phosphatase SHP-2, is overexpressed in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) compared with osteoarthritis (OA) FLS and promotes RA FLS invasiveness. Here, we explored the molecular basis for overexpression in RA FLS and the role of SHP-2 in RA pathogenesis. Using computational methods, we identified a putative enhancer in intron 1, which contained a glucocorticoid receptor- binding (GR-binding) motif.

Anti-Inflammatory Effects and Joint Protection in Collagen-Induced Arthritis after Treatment with IQ-1S, a Selective c-Jun N-Terminal Kinase Inhibitor.

c-Jun N-terminal kinases (JNKs) participate in many physiologic and pathologic processes, including inflammatory diseases. We recently synthesized the sodium salt of IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime) and demonstrated that it is a high-affinity JNK inhibitor and inhibits murine delayed-type hypersensitivity. Here we show that IQ-1S is highly specific for JNK and that its neutral form is the most abundant species at physiologic pH.

The Rheumatoid Arthritis Risk Gene LBH Regulates Growth in Fibroblast-like Synoviocytes.

Objective: Fibroblast-like synoviocytes (FLS) are key players in the synovial pathology of rheumatoid arthritis (RA). Currently, there is no treatment that specifically targets these aggressive cells. By combining 3 different "omics" data sets, i.

Differential regulation of anti-inflammatory genes by p38 MAP kinase and MAP kinase kinase 6.

Background: Conventional p38α inhibitors have limited efficacy in rheumatoid arthritis, possibly because p38 blockade suppresses the counter-regulatory mechanisms that limit inflammation. In contrast, targeting the upstream MAP kinase kinases, MKK3 and MKK6, partially maintains p38-mediated anti-inflammatory responses in bone marrow-derived macrophages (BMDM). In this study, we explored the mechanisms that preserve anti-inflammatory gene expression by evaluating differential regulation of IL-10 and p38-dependent anti-inflammatory genes in MKK3-/-, MKK6-/-, and p38 inhibitor-treated wildtype cells.

Phosphoinositide 3-kinase δ regulates migration and invasion of synoviocytes in rheumatoid arthritis.

Cartilage destruction mediated by invasive fibroblast-like synoviocytes (FLS) plays a central role in pathogenesis of rheumatoid arthritis (RA). Increased cell migration and degradation of extracellular matrix are fundamental to these processes. The class I PI3Ks control cell survival, proliferation, and migration, which might be involved in cartilage damage in RA.

Differential roles of MAPK kinases MKK3 and MKK6 in osteoclastogenesis and bone loss.

Bone mass is maintained by osteoclasts that resorb bone and osteoblasts that promote matrix deposition and mineralization. Bone homeostasis is altered in chronic inflammation as well as in post-menopausal loss of estrogen, which favors osteoclast activity that leads to osteoporosis. The MAPK p38α is a key regulator of bone loss and p38 inhibitors preserve bone mass by inhibiting osteoclastogenesis.

Antiinflammatory functions of p38 in mouse models of rheumatoid arthritis: advantages of targeting upstream kinases MKK-3 or MKK-6.

Objective: Inhibitors of p38 demonstrate limited benefit in rheumatoid arthritis (RA), perhaps due to the antiinflammatory functions of p38α. This study was performed to determine if selective deletion of p38α in macrophages affects the severity of arthritis and whether blocking upstream kinases in the p38 pathway, such as MKK-3 or MKK-6, avoids some of the limitations of p38 blockade.

Methods: Wild-type (WT) mice and mice with selective deletion of p38α in macrophages (p38α(ΔLysM) ) were injected with K/BxN sera.

Decreased collagen-induced arthritis severity and adaptive immunity in MKK-6-deficient mice.

Objective: The MAPK kinases MKK-3 and MKK-6 regulate p38 MAPK activation in inflammatory diseases such as rheumatoid arthritis (RA). Previous studies demonstrated that MKK-3 or MKK-6 deficiency inhibits K/BxN serum-induced arthritis. However, the role of these kinases in adaptive immunity-dependent models of chronic arthritis is not known.

Suppression of collagen-induced arthritis in growth arrest and DNA damage-inducible protein 45β-deficient mice.

Objective: Growth arrest and DNA damage-inducible protein 45β (GADD45β) is involved in stress responses, cell cycle regulation, and oncogenesis. Previous studies demonstrated that GADD45β deficiency exacerbates K/BxN serum-induced arthritis and experimental allergic encephalomyelitis (EAE) in mice, indicating that GADD45β plays a suppressive role in innate and adaptive immune responses. To further understand how GADD45β regulates autoimmunity, we evaluated collagen-induced arthritis in GADD45β-/- mice.

Synoviocyte innate immune responses: TANK-binding kinase-1 as a potential therapeutic target in rheumatoid arthritis.

Objectives: Innate immune responses in the rheumatoid synovium contribute to inflammation and joint destruction in RA. Two IκB kinase (IKK)-related kinases, TNF receptor associated factor (TRAF) family member-associated nuclear factor κ-light-chain enhancer of activated B cells (NF-κB) activator (TANK)-binding kinase 1 (TBK1) and IKKε, potentially regulate synovitis by activating IFN response genes. These kinases induce the expression of inflammatory mediators such as C-X-C motif ligand 10 (CXCL10)/IFN-γ-induced protein 10 kDa (IP-10) in fibroblast-like synoviocytes (FLS).

Gadd45beta deficiency in rheumatoid arthritis: enhanced synovitis through JNK signaling.

Objective: JNK-mediated cell signaling plays a critical role in matrix metalloproteinase (MMP) expression and joint destruction in rheumatoid arthritis (RA). Gadd45beta, which is an NF-kappaB-regulated gene, was recently identified as an endogenous negative regulator of the JNK pathway, since it could block the upstream kinase MKK-7. This study was carried out to evaluate whether low Gadd45beta expression in RA enhances JNK activation and overproduction of MMPs in RA, and whether Gadd45beta deficiency increases arthritis severity in passive K/BxN murine arthritis.

Role of MAPK kinase 6 in arthritis: distinct mechanism of action in inflammation and cytokine expression.

Development of p38alpha inhibitors for rheumatoid arthritis has been hindered by toxicity and limited efficacy. Therefore, we evaluated whether MKK6, an upstream kinase that regulates multiple p38 isoforms, might be an alternative therapeutic target in inflammatory arthritis. Wild-type (WT), MKK6(-/-), and MKK3(-/-) mice were administered K/BxN serum to induce arthritis.

Synoviocyte innate immune responses: I. Differential regulation of interferon responses and the JNK pathway by MAPK kinases.

JNK is a key regulator of matrix metalloproteinase production in rheumatoid arthritis. It is regulated by two upstream kinases known as MKK4 and MKK7. Previous studies demonstrated that only MKK7 is required for cytokine-mediated JNK activation and matrix metalloproteinase expression in cultured fibroblast-like synoviocytes (FLS).