Peripheral Blood Expression Profiles of Bone Morphogenetic Proteins, Tumor Necrosis Factor-superfamily Molecules, and Transcription Factor Runx2 Could Be Used as Markers of the Form of Arthritis, Disease Activity, and Therapeutic Responsiveness

Grčević, Danka; Jajić, Zrinka; Kovačić, Nataša; Lukić, Ivan; Velagić, Vedran; Grubišić, Frane; Ivčević, Sanja; Marušić, Ana

doi:10.3899/jrheum.090167

Cited by 59 publications

(62 citation statements)

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“…Haroon et al used whole genome expression arrays to identify a response to anti-TNF treatment. 143 A subset of 1428 genes was differentially expressed in response to treatment and downregulation of 4 inflammation-associated genes, including LIGHT, whose downregulation has also been associated with RA suggesting this gene maybe generally associated with inflammatory processes, 144 was confirmed. Only recently however have large-scale whole genome expression profiling studies on the complete PBMC population been undertaken in AS or SpA by ourselves 145 and David Yu's group at UCLA.…”

Section: Circulating Cell Studiesmentioning

confidence: 89%

The genomics and genetics of ankylosing spondylitis

Kenna¹,

Davidson²,

Thomas³

2011

AGG

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Abstract:The spondyloarthropathies are a group of arthritides which specifically target the spine and pelvis with ankylosing spondylitis (AS) being the most prevalent and debilitating of these conditions. Unique to AS is the progression to excessive uncontrolled bone formation following an initial inflammatory phase that can result in joint fusion and significant disability. Spondyloarthritis is estimated to affect 1%-2% of the population, twice as many as rheumatoid arthritis and thus constitutes a significant health problem. Currently AS pathogenesis is very poorly understood but recent large-scale genetics and gene expression profiling studies have identified some of the underlying mechanisms and pathways contributing to the disease. Genome-wide association studies have identified a number of candidate genes associated with AS sharing the same pathways which are now being targeted for therapeutic intervention. However, although such approaches can identify genes contributing to the disease process and are very informative as to disease aetiopathogenesis, they cannot profile the actual changes in gene/cell activity at any point in the disease process or possibly more importantly at specific sites. Such information is generated using expression profiling. A number of expression profiling studies have been undertaken in AS, looking at both circulating cells and tissues from affected joints. Although some common genes/pathways have been identified, overall the results to date have been somewhat disappointing due to differences in experimental design and tissue source as well as the low power of the studies. More recent better powered studies have shown some potential in developing gene expression profiling as a diagnostic tool in AS. True future success will rely on larger genetic and genomic studies and the combination of these datasets in eQTL studies requiring significant collaborative efforts. Such larger-scale approaches will also generate sufficient power to target specific disease stages and sites.

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Section: Circulating Cell Studiesmentioning

confidence: 89%

The genomics and genetics of ankylosing spondylitis

Kenna¹,

Davidson²,

Thomas³

2011

AGG

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“…As a major cell type responsible for bone reabsorption, OCs are formed in the mononuclear macrophage system and directly involved in the bone reformation (Eeles et al, 2015). Cellular research suggested that tartrate resistant acid phosphatase (TRAP) staining showed a positive response only after the differentiation and maturation of OC (Grcevic et al, 2010;Won et al, 2012). Other studies in AS-related hyperplasia also demonstrated the existence of large amounts of TRAP-positive mono-or poly-nuclear cells adhesive in the synovial tissue near the disease site, whereas no TRAP signal could be detected in cells near normal synovial tissues.…”

Section: Discussionmentioning

confidence: 99%

Expression of TNF-α, VEGF, and MMP-3 mRNAs in synovial tissues and their roles in fibroblast-mediated osteogenesis in ankylosing spondylitis

Liu¹,

He²,

Tan³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to explore the mRNA levels of tumor necrosis factor-α (TNF-α), vessel endothelial growth factor (VEGF), and matrix metalloproteinase-3 (MMP-3) in synovial tissues in ankylosing spondylitis (AS), and to analyze the functions of these proteins in the differentiation of AS synovial tissue fibroblasts into osteoblasts (OB) and osteoclasts. Synovial tissue samples from 22 AS patients and 22 normal individuals were collected. In situ hybridization was utilized to detect TNF-α, VEGF, and MMP-3 transcripts. After counting numbers of positive cells, Spearman analysis was used to determine the correlation between transcriptional levels of the three mRNAs and the AS disease activity index (BASDAI) and the C-response protein (CRP) levels. With the addition of TNF-α, VEGF, or both factors into cultured normal synovial fibroblasts, osteocalcin (bone gla protein, BGP) secretion levels were compared. We found that expression of TNF-α, VEGF, and MMP-3 was identified exclusively in the disease group. mRNA levels were significantly positively (2015) correlated with BASDAI (r = 0.42, 0.38, and 0.47, respectively; P < 0.05) and CRP (r = 0.44, 0.34, and 0.47 respectively; P < 0.05) scores. The secretion level of BGP in normal synovial fibroblasts increased progressively with increasing concentrations of VEGF or TNF-α (P < 0.01 compared to levels before treatment). Furthermore, co-incubation using both VEGF and TNF-α significantly elevated BGP levels compared to the single addition of VEGF or TNF-α (P < 0.01). These results suggest TNF-α, VEGF, and MMP-3 might directly participate in the differentiation of fibroblasts into OBs.

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“…In two recent studies it was demonstrated that anti-TNF alpha treatment leads to significant alteration of gene expression and protein profiles, supporting the use of systematic gene expression and proteomic analysis to shed new light on pathogenic pathways with importance in the chronic inflammation of AS (Haroon et al, 2010;Grcevic et al, 2010). Anti-TNF therapy induced a rapid change in the expression profile within 2 weeks in AS patients with down-regulation of lymphotoxins exhibiting inducible expression and competing with herpes simplex virus glycoprotein D for herpesvirus entry mediator, a receptor expressed by T lymphocytes (LIGHT), interferon receptor 1 (IFNAR1), interleukin 17 receptor (IL17R) and erythropoietin receptor (EPOR) genes.…”

Section: Gene Expression Changes After Anti-tnfα Therapymentioning

confidence: 99%

“…Although these results are interesting more studies are needed for validation. Another study using peripheral blood expression profiles based on PBMCs cells assessed several bone-regulatory factors as potential discriminators of different forms of arthritis, disease activity and therapy responsiveness (Grcevic et al, 2010). ROC curve analysis suggested higher expression of Runx2 was a potential molecular marker for AS.…”

Section: Gene Expression Changes After Anti-tnfα Therapymentioning

confidence: 99%