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Arthritis Res Ther. 2006; 8(2): R43.
Published online Feb 3, 2006. doi:  10.1186/ar1900
PMCID: PMC1526602
CXCL12 is displayed by rheumatoid endothelial cells through its basic amino-terminal motif on heparan sulfate proteoglycans
Begoña Santiago,1 Françoise Baleux,2 Guillermo Palao,1 Irene Gutiérrez-Cañas,1 Juan C Ramírez,1 Fernando Arenzana-Seisdedos,3 and José L Pabloscorresponding author1
1Servicio de Reumatología y Unidad de Investigación, Hospital 12 de Octubre, Avda. de Córdoba s/n, 28041 Madrid, Spain
2Organic Chemistry Unit, Pasteur Institute, 28 Rue Dr. Roux, 75724 Paris CEDEX, France
3Viral Immunology Unit, Pasteur Institute, 28 Rue Dr. Roux, 75724 Paris CEDEX, France
corresponding authorCorresponding author.
Begoña Santiago: reuma/at/h12o.es; Françoise Baleux: baleux/at/pasteur.fr; Guillermo Palao: gpbnas/at/yahoo.es; Irene Gutiérrez-Cañas: irene/at/cifrasystem.com; Juan C Ramírez: jcramirez/at/h12o.es; Fernando Arenzana-Seisdedos: farenzan/at/pasteur.fr; José L Pablos: jlpablos/at/h12o.es
Received September 7, 2005; Revisions requested October 20, 2005; Revised January 9, 2006; Accepted January 17, 2006.
Abstract
The chemokine CXCL12 (also known as stromal cell-derived factor, SDF-1) is constitutively expressed by stromal resident cells and is involved in the homeostatic and inflammatory traffic of leukocytes. Binding of CXCL12 to glycosaminoglycans on endothelial cells (ECs) is supposed to be relevant to the regulation of leukocyte diapedesis and neoangiogenesis during inflammatory responses. To improve our understanding of the relevance of this process to rheumatoid arthritis (RA), we have studied the mechanisms of presentation of exogenous CXCL12 by cultured RA ECs. RA synovial tissues had higher levels of CXCL12 on the endothelium than osteoarthritis (OA) tissues; in both, CXCL12 colocalized to heparan sulfate proteoglycans (HSPGs) and high endothelial venules. In cultured RA ECs, exogenous CXCL12α was able to bind in a CXCR4-independent manner to surface HSPGs. Desulfation of RA EC HSPGs by pretreatment with sodium chlorate, or by replacing in a synthetic CXCL12α the residues Lys24 and Lys27 by Ser (CXCL12α-K2427S), decreased or abrogated the ability of the chemokine to bind to RA ECs. Ex vivo, synovial ECs from patients with either OA or RA displayed a higher CXCL12-binding capacity than human umbilical vein ECs (HUVECs), and in HUVECs the binding of CXCL12 was increased on exposure to tumor necrosis factor-α or lymphotoxin-α1β2. Our findings indicate that CXCL12 binds to HSPGs on ECs of RA synovium. The phenomenon relates to the interaction of HSPGs with a CXCL12 domain with net positive surface charge located in the first β strand, which encompasses a canonical BXBB HSPG-binding motif. Furthermore, we show that the attachment of CXCL12 to HSPGs is upregulated by inflammatory cytokines. Both the upregulation of a constitutive chemokine during chronic inflammation and the HSPG-dependent immobilization of CXCL12 in EC surfaces are potential sites for therapeutic intervention.
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