Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Increased Circulating Osteoclast Precursors and Lesional Osteoclast-Like Multinucleated Giant Cells in the Lung of Patients with Wegener's Granulomatosis.
Park1, Jin Kyun, Askin2, Frederic, Rosen3, Antony, Levine1, Stuart M.
Tissue-infiltrating multinucleated giant cells (MNGCs) surrounding areas of geographic necrosis are the pathologic hallmarks of Wegener's granulomatosis (WG). However, the origin, phenotype, and function of these cells in WG remain undefined.
MNGC phenotype was examined by immunohistochemistry in serial paraffin sections of WG lung tissue (N=12) using antibodies recognizing the osteoclast (OC)-lineage markers CD68, cathepsin K and tartrate-resistant-acid-phophatase (TRAP). To examine whether WG patients had an increased propensity toward MNGC formation over healthy control subjects, peripheral blood mononuclear cells (PBMC) obtained from 11 patients (5 with limited and 6 with systemic disease) and 7 healthy controls were cultured in 96- well plates in the presence of RANKL and M-CSF to induce MNGC formation. After 9 days in culture, MNGC morphology and TRAP expression were examined. OC-like giant cells were defined as TRAP (+) cells containing 3 or more nuclei. Mean MNGC values were compared between groups using the Mann-Whitney U test or Student's t-test where appropriate. P-values of < 0.05 were considered statistically significant.
WG lung tissue granulomata contained numerous MNGCs. All tissue-infiltrating MNGCs expressed CD68, indicative of monocytic lineage, and exhibited robust TRAP and cathepsin K staining, a phenotype thought to be unique to bone-resident osteoclasts. After co-incubation with the osteoclastogenic cytokines RANKL and M-CSF, patients with WG formed significantly more MNGCs at Day 9 than healthy controls (109 +/- 112 MNGC/well vs. 18 +/- 16 MNGC/well, p=0.03). Patients with systemic disease produced significantly more MNGC than both controls (167 +/- 114 MNGC/well vs. 18 +/- 16 MNGC/well, p=0.01) and those with a limited disease phenotype (167 +/- 114 MNGC/well vs. 39 +/- 62 MNGC/well, p=0.03). No significant difference in MNGC formation was noted between patients with limited WG and controls (p=0.87).
We demonstrate for the first time that MNGCs in Wegener's granulomata in the lung have osteoclast-like features. We further show that WG patients have a higher propensity to from OC-like MNGC from the peripheral blood than do healthy controls, a feature that might be more pronounced in patients with a systemic disease phenotype. Inhibition of the pathways leading to the enhanced formation and migration of these cells to target tissues in WG might provide a novel therapeutic opportunity in this disease.
To cite this abstract, please use the following information:
Park, Jin Kyun, Askin, Frederic, Rosen, Antony, Levine, Stuart M.; Increased Circulating Osteoclast Precursors and Lesional Osteoclast-Like Multinucleated Giant Cells in the Lung of Patients with Wegener's Granulomatosis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :677