Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/76537
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Type: Journal article
Title: The immunoreceptor tyrosine-based activation motif (ITAM)-related factors are increased in synovial tissue and vasculature of rheumatoid arthritic joints
Author: Crotti, T.
Dharmapatni, A.
Alias, E.
Zannettino, A.
Smith, M.
Haynes, D.
Citation: Arthritis Research & Therapy, 2012; 14(6):1-13
Publisher: BioMed Central Ltd.
Issue Date: 2012
ISSN: 1478-6354
1478-6362
Statement of
Responsibility: 
Tania N Crotti, Anak ASSK Dharmapatni, Ekram Alias, Andrew CW Zannettino, Malcolm D Smith and David R Haynes
Abstract: Introduction: The immunoreceptor tyrosine-based activation motif (ITAM) pathway provides osteoclast co-stimulatory signals and regulates proliferation, survival and differentiation of effector immune cells. In the osteoclast, the receptors Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and Osteoclast Associated Receptor (OSCAR) and their respective adaptor proteins, DAP12 and FcRγ mediate ITAM signals and induce calcium signaling and the crucial transcription factor, NFATc1. In rheumatoid arthritis (RA), OSCAR expression by monocytes is inversely correlated with disease activity. Additionally, serum levels of OSCAR are reduced in RA patients versus healthy controls suggesting that expression and secretion or cleavage of soluble (s) OSCAR is immune modulated. Recent data suggest that endothelial cells may also be a source of OSCAR. Methods: ITAM receptors, their adaptor proteins, and NFATc1 and cathepsin K were detected in human synovial tissues by immunohistochemistry. Synovial tissues from patients with active RA were compared with tissue from patients in remission, osteoarthritis (OA) patients and healthy individuals. OSCAR was measured by immunoassay in synovial fluids recovered from active RA and OA patients. Endothelial cells were cultured with or without 5 ng/mL TNF-α or IL-1β over 72 hours. Temporal expression of OSCAR mRNA was assessed by qRT PCR and OSCAR protein in the supernatant was measured by ELISA. Results: Significantly higher (P < 0.05) NFATc1-positive inflammatory cell aggregates were found in active RA tissues than in healthy synovial tissue. Similarly, the percentage of OSCAR, FcRγ, DAP12 and TREM2 positive cells was significantly higher in active RA tissues compared to the healthy synovial tissue. Notably, OSCAR was strongly expressed in the microvasculature of the active RA tissues (9/9), inactive RA (8/9) weakly in OA (4/9) but only in the lumen of healthy synovial tissue (0/8). OSCAR levels were detected in synovial fluids from both RA (47 to 152 ng/mL) and OA (112 to 145 ng/mL) patients. Moreover, OSCAR mRNA expression and soluble OSCAR release was stimulated by TNF-α and IL1-β in cultured endothelial cells. Conclusions: Increased levels of ITAM related factors were present in synovial tissue from active RA joints compared to OA and healthy joints. OSCAR was strongly expressed by the vasculature of active RA patients and membrane bound and soluble OSCAR was stimulated by inflammatory mediators in endothelial cells in vitro.
Keywords: Joints; Synovial Membrane; Cells, Cultured; Endothelial Cells; Humans; Arthritis, Rheumatoid; Tumor Necrosis Factor-alpha; Adaptor Proteins, Signal Transducing; Membrane Glycoproteins; Membrane Proteins; Receptors, Cell Surface; Receptors, Immunologic; Receptors, Fc; Antirheumatic Agents; Microscopy, Confocal; Immunohistochemistry; Reverse Transcriptase Polymerase Chain Reaction; Gene Expression; Adult; Aged; Aged, 80 and over; Middle Aged; Female; Male; NFATC Transcription Factors; Osteoprotegerin; Interleukin-1beta
Description: Extent: 13p.
Rights: © 2012 Crotti et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
RMID: 0020125199
DOI: 10.1186/ar4088
Appears in Collections:Pathology publications

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