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.
OBJECTIVE
To assess whether different forms of arthritis and disease activity could be distinguished by peripheral blood expression profiles of bone-regulatory factors including tumor necrosis factor (TNF)-superfamily [TNF-related apoptosis-inducing ligand (TRAIL), the Fas ligand (FasL), and the ligand for herpesvirus entry mediator (LIGHT)] and bone morphogenetic protein (BMP)-family members (BMP-2, BMP-4, BMP-6) as well as osteoblast differentiation gene Runx2.


METHODS
Blood cells from healthy controls (n = 25) and patients at different disease stages with rheumatoid arthritis (RA; n = 49), osteoarthritis (OA; n = 17), or spondyloarthritis, including ankylosing spondylitis (AS; n = 27) or psoriatic arthritis (PsA; n = 23), were processed for quantitative polymerase chain reaction. Gene expression was assessed in comparison with control samples, correlated with clinical data of different forms of arthritis, and analyzed for discriminative efficacy between groups by receiver-operation characteristic (ROC) curves. Results were confirmed on diagnostic RA (n = 5) and AS (n = 8) samples.


RESULTS
BMP-4, BMP-6, and Runx2 expressions were significantly decreased in patients with RA and OA versus controls. Patients with RA also had decreased FasL and LIGHT expression, while patients with AS had increased Runx2 expression. Negative correlation with disease activity was found for BMP-4, FasL, and Runx2 in RA and for Runx2 in PsA, while positive correlation was found for BMP-4 in PsA. Gene expression was higher in the therapy-resistant form of AS (for BMP-4, LIGHT, and Runx2) and in methotrexate-treated patients in RA (for BMP-2 and LIGHT). ROC curve analysis confirmed discrimination between groups, particularly decreased LIGHT and Runx2 for RA and increased Runx2 for AS.


CONCLUSIONS
Our study identified BMP and Runx2 as possible biomarkers of bone metabolism in several forms of arthritis, while lower FasL and LIGHT were associated with RA. Correlation between gene expression and disease activity may be clinically useful in assessing therapeutic effectiveness and disease monitoring.
Grcevic
Danka
D
Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia. dgrcevic@mef.hr
Jajic
Zrinka
Z
Kovacic
Natasa
N
Lukic
Ivan Kresimir
IK
Velagic
Vedran
V
Grubisic
Frane
F
Ivcevic
Sanja
S
Marusic
Ana
A
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001168:Arthritis / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology; D015415:Biomarkers / Q000032:analysis; D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000276:immunology; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics* / Q000276:immunology; D005260:Female; D015870:Gene Expression; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D048069:Tumor Necrosis Factors / Q000235:genetics* / Q000276:immunology
D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D012333:RNA, Messenger; C493709:RUNX2 protein, human; D048069:Tumor Necrosis Factors