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Rheumatology Advance Access published online on October 24, 2006
Rheumatology, doi:10.1093/rheumatology/kel356
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received June 24, 2006
Accepted September 15, 2006

Original Papers

Rheumatoid synovial endothelial cells produce macrophage colony-stimulating factor leading to osteoclastogenesis in rheumatoid arthritis

K. Nakano 1, Y. Okada 1, K. Saito 1, R. Tanikawa 1, N. Sawamukai 1, Y. Sasaguri 2, T. Kohro 3, Y. Wada 4, T. Kodama 5, and Y. Tanaka 1 *

1 First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
2 Department of Pathology and Cell Biology, University of Occupational and Environmental Health, Kitakyushu, Japan
3 Department of Translational Research for Healthcare and Clinical Science, Graduate School of Medicine, University of Tokyo, Japan
4 The Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
5 Laboratory for Systems Biology and Medicine at RCAST, The University of Tokyo, Japan

* To whom correspondence should be addressed.
Y. Tanaka, E-mail: tanaka{at}med.uoeh-u.ac.jp


  Abstract

Objectives. Periarticular osteoporosis and joint destruction are major complications in rheumatoid arthritis (RA), caused by osteoclast-mediated bone resorption. However, the mechanisms of monocyte/osteoclast maturation and role of RA endothelial cells (RAECs) in the control of osteoclastogenesis remain unclear. The present study was designed to determine the most important factors that influence monocyte accumulation and osteoclast formation among the many factors produced by RAEC.

Methods. We analysed the expression profiles of various genes in human endothelial cells from various organs (RA synovium, umbilical vein, skin, liver sinusoid, renal glomerulus and brain) using oligonucleotide microarrays. Specifically, up-regulated gene in RAECs was assessed by real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and immunostaining of RA synovia. Migration of monocytes was assessed by the chemotactic chamber EZ-TAXIScanTM. Tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cell (MNC) formation was observed by microscopy.

Results. Among many epithelial-expressed factors, macrophage colony-stimulating factor (M-CSF) gene was abundantly expressed specifically in RAECs. Genes of fibroblast growth factor-2, interleukin-6 and osteoprotegerin were also overexpressed in RAECs. Migration of monocytes and osteoclast formation in co-cultures promoted by culture supernatants of RAECs were inhibited by M-CSF neutralizing antibody.

Conclusions. M-CSF produced by RAECs is involved in osteoclastogenesis from monocytes, migration and TRAP-positive MNC formation.

Keywords: Rheumatoid arthritis; Osteoclasts; Pathogenesis; Endothelial cell; Macrophage colony-stimulating factor; Oligonucleotide microarray.
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