The soluble terminal complement complex (SC5b-9) up-regulates osteoprotegerin expression and release by endothelial cells: implications in rheumatoid arthritis.
OBJECTIVE
Complement activation products contribute to a large number of inflammatory diseases, including RA. We have investigated whether osteoprotegerin (OPG) may concur with the soluble terminal complement complex (SC5b-9) to the inflammatory cascade characterizing RA.


METHODS
Levels of SC5b-9 and OPG in the plasma and SF of patients with active RA were determined by ELISA. The presence of SC5b-9 and OPG in RA synovial lesions was analysed by immunohistochemistry. Cultured endothelial cells were used for in vitro leucocyte/endothelial cell adhesion assays. In addition, endothelial cells were exposed to SC5b-9 in order to evaluate the effects on the production of OPG protein, as well as the activation of the OPG promoter.


RESULTS
Patients affected by active RA are characterized by elevated levels of both SC5b-9 and OPG in plasma and/or SF. Of note, we have observed a co-localization of SC5b-9 and OPG in endothelial cells of post-capillary venules of RA synovial lesions. Data on endothelial cell cultures showed that exposure to SC5b-9 induced the up-regulation of OPG expression/release, stimulating the transcriptional activity of the OPG promoter, and synergized with TNF-alpha in up-regulating OPG production.


CONCLUSIONS
Our findings demonstrate that SC5b-9 induces OPG production by endothelial cells and we propose that the SC5b-9-mediated up-regulation of OPG may be an important mechanism whereby complement contributes in promoting and/or enhancing the inflammation in RA.
Corallini
Federica
F
Interdepartmental Center of Molecular Medicine, University of Trieste, Trieste, Italy.
Bossi
Fleur
F
Gonelli
Arianna
A
Tripodo
Claudio
C
Castellino
Gabriella
G
Mollnes
Tom E
TE
Tedesco
Francesco
F
Rizzi
Lucia
L
Trotta
Francesco
F
Zauli
Giorgio
G
Secchiero
Paola
P
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D015938:Complement Membrane Attack Complex / Q000494:pharmacology / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020556:Neutrophil Infiltration / Q000502:physiology; D009504:Neutrophils / Q000502:physiology; D053244:Osteoprotegerin / Q000096:biosynthesis*; D013583:Synovial Membrane / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D015938:Complement Membrane Attack Complex; D053244:Osteoprotegerin; C047610:SC5b-9 protein complex; C506030:TNFRSF11B protein, human