The immunoreceptor tyrosine-based activation motif (ITAM) -related factors are increased in synovial tissue and vasculature of rheumatoid arthritic joints

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 As...

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Published in:Arthritis research & therapy 2012-11, Vol.14 (6), p.R245-R245
Main Authors: Crotti, Tania N, Dharmapatni, Anak A S S K, Alias, Ekram, Zannettino, Andrew C W, Smith, Malcolm D, Haynes, David R
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Adult
Aged
Aged, 80 and over
Antirheumatic Agents - therapeutic use
Arthritis, Rheumatoid - drug therapy
Arthritis, Rheumatoid - genetics
Arthritis, Rheumatoid - metabolism
Care and treatment
Cathepsins
Cell proliferation
Cells, Cultured
Complications and side effects
Development and progression
Endothelial Cells - drug effects
Endothelial Cells - metabolism
Endothelium
Female
Gene Expression - drug effects
Genetic aspects
Humans
Immunohistochemistry
Interleukin-1beta - pharmacology
Joints - blood supply
Joints - metabolism
Male
Membrane Glycoproteins - genetics
Membrane Glycoproteins - metabolism
Membrane Proteins - genetics
Membrane Proteins - metabolism
Microscopy, Confocal
Middle Aged
NFATC Transcription Factors - genetics
NFATC Transcription Factors - metabolism
Osteoarthritis
Osteoblasts
Osteoprotegerin - genetics
Osteoprotegerin - metabolism
Phenols
Physiological aspects
Proteins
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
Receptors, Fc - genetics
Receptors, Fc - metabolism
Receptors, Immunologic - genetics
Receptors, Immunologic - metabolism
Reverse Transcriptase Polymerase Chain Reaction
Rheumatoid factor
RNA
Synovial Membrane - blood supply
Synovial Membrane - metabolism
Tumor Necrosis Factor-alpha - pharmacology
Tyrosine
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Summary: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. 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. 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. 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.
ISSN:1478-6354
1478-6362
DOI:10.1186/ar4088