High levels of osteoprotegerin and soluble receptor activator of nuclear factor kappa B ligand in serum of rheumatoid arthritis patients and their normalization after anti-tumor necrosis factor alpha treatment.
OBJECTIVE
To test the hypotheses that 1) proinflammatory cytokines affect osteoprotegerin (OPG) and soluble receptor activator of nuclear factor kappa B ligand (sRANKL) production and therefore the OPG and sRANKL levels differ in rheumatoid arthritis (RA) patients in comparison with healthy individuals; and 2) anti-tumor necrosis factor alpha (anti-TNF alpha) therapy influences OPG and sRANKL levels.


METHODS
Sera were obtained from healthy individuals or RA patients receiving the combination of infliximab and methotrexate. Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) were isolated from RA patients. Fibroblast-like synoviocytes (FLS) were isolated from synovial tissue obtained at total knee replacement in RA patients. Supernatants from cells stimulated with cytokines were collected after culture in vitro. Concentrations of OPG and sRANKL were determined by enzyme-linked immunosorbent assays.


RESULTS
A strong positive correlation between OPG concentration and age was observed in healthy individuals but not in RA patients. The OPG and sRANKL levels were higher in RA patients than in healthy controls. Cultured FLS spontaneously secreted much higher amounts of OPG than PBMCs or SFMCs. Proinflammatory cytokines enhanced OPG production. Anti-TNF alpha treatment resulted in the normalization of serum OPG and sRANKL levels in RA patients without influencing the OPG:sRANKL ratio.


CONCLUSIONS
Although higher serum levels of OPG and sRANKL are present in RA patients than in healthy individuals, the ratio of OPG:sRANKL is similar. There is an age-dependent increase of OPG but not sRANKL levels in healthy subjects. Anti-TNF alpha treatment results in the normalization of elevated levels of OPG and sRANKL in RA patients.
Department of Pathophysiology and Immunology, Institute of Rheumatology, Warsaw, Poland. zpatiir@warman.com.pl
Maria
M
Ziolkowska
Mariola
M
Kurowska
Anna
A
Radzikowska
Grazyna
G
Luszczykiewicz
Piotr
P
Wiland
Wojciech
W
Dziewczopolski
Anna
A
Filipowicz-Sosnowska
Jacek
J
Pazdur
Jacek
J
Szechinski
Jacek
J
Kowalczewski
Maria
M
Rell-Bakalarska
Wlodzimierz
W
Maslinski
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000188:drug therapy*; D004797:Enzyme-Linked Immunosorbent Assay; D006023:Glycoproteins / Q000097:blood*; D006801:Humans; D000069285:Infliximab; D008727:Methotrexate / Q000008:administration & dosage / Q000627:therapeutic use; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear / Q000097:blood*; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D013582:Synovial Fluid / Q000166:cytology; D053319:Tumor Necrosis Factor Decoy Receptors
D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D006023:Glycoproteins; D009363:Neoplasm Proteins; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; C506030:TNFRSF11B protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D000069285:Infliximab; D008727:Methotrexate