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Raloxifene reduces urokinase-type plasminogen activator-dependent proliferation of synoviocytes from patients with rheumatoid arthritis.
Arthritis Res Ther. 2005; 7(6):R1244-53.AR

Abstract

Extracellular fibrinolysis, controlled by the membrane-bound fibrinolytic system, is involved in cartilage damage and rheumatoid arthritis (RA) synovitis. Estrogen status and metabolism seem to be impaired in RA, and synoviocytes show receptors for estrogens. Our aims in this study were to evaluate in healthy and RA synoviocytes the effects of Raloxifene (RAL), a selective estrogen receptor modulator (SERM), on: proliferation; the components of the fibrinolytic system; and chemoinvasion. The effects of RAL were studied in vitro on synoviocytes from four RA patients and four controls. Proliferation was evaluated as cell number increase, and synoviocytes were treated with 0.5 microM and 1 microM RAL with and without urokinase-plasminogen activator (u-PA) and anti-u-PA/anti-u-PA receptor (u-PAR) antibodies. Fibrinolytic system components (u-PA, u-PAR and plasminogen activator inhibitor (PAI)-1) were assayed by ELISA with cells treated with 0.5 microM and 1 microM RAL for 48 h. u-PA activity was evaluated by zymography and a direct fibrinolytic assay. U-PAR/cell and its saturation were studied by radioiodination of u-PA and a u-PA binding assay. Chemoinvasion was measured using the Boyden chamber invasion assay. u-PA induced proliferation of RA synoviocytes was blocked by RAL (p < 0.05) and antagonized by antibodies alone. The inhibitory effect of RAL was not additive with u-PA/u-PAR antagonism. RA synoviocytes treated with RAL showed, compared to basal, higher levels of PAI-1 (10.75 +/- 0.26 versus 5.5 +/- 0.1 microg/10(6) cells, respectively; p < 0.01), lower levels of u-PA (1.04 +/- 0.05 versus 3.1 +/- 0.4 ng/10(6) cells, respectively; p < 0.001), and lower levels of u-PAR (11.28 +/- 0.22 versus 23.6 +/- 0.1 ng/10(6) cells, respectively; p < 0.001). RAL also significantly inhibited u-PA-induced migration. Similar effects were also shown, at least partially, in controls. RAL exerts anti-proliferative and anti-invasive effects on synoviocytes, mainly modulating u-PAR and, to a lesser extent, u-PA and PAI-1 levels, and inhibiting cell migration and proliferation.

Links

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Authors+Show Affiliations

Guiducci S
Division of Rheumatology, Department of Internal Medicine, University of Florence, Florence, Italy. serena16@libero.it
Del Rosso A
No affiliation info available
Cinelli M
No affiliation info available
Perfetto F
No affiliation info available
Livi R
No affiliation info available
Rossi A
No affiliation info available
Gabrielli A
No affiliation info available
Giacomelli R
No affiliation info available
Iori N
No affiliation info available
Fibbi G
No affiliation info available
Del Rosso M
No affiliation info available
Cerinic MM
No affiliation info available

MeSH

Arthritis, RheumatoidCell MovementCell ProliferationCells, CulturedDose-Response Relationship, DrugFemaleHumansKnee JointMalePlasminogen Activator Inhibitor 1Raloxifene HydrochlorideReceptors, Cell SurfaceReceptors, Urokinase Plasminogen ActivatorSelective Estrogen Receptor ModulatorsSynovial MembraneUrokinase-Type Plasminogen Activator

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16277677

Citation

Guiducci, S, et al. "Raloxifene Reduces Urokinase-type Plasminogen Activator-dependent Proliferation of Synoviocytes From Patients With Rheumatoid Arthritis." Arthritis Research & Therapy, vol. 7, no. 6, 2005, pp. R1244-53.
Guiducci S, Del Rosso A, Cinelli M, et al. Raloxifene reduces urokinase-type plasminogen activator-dependent proliferation of synoviocytes from patients with rheumatoid arthritis. Arthritis Res Ther. 2005;7(6):R1244-53.
Guiducci, S., Del Rosso, A., Cinelli, M., Perfetto, F., Livi, R., Rossi, A., Gabrielli, A., Giacomelli, R., Iori, N., Fibbi, G., Del Rosso, M., & Cerinic, M. M. (2005). Raloxifene reduces urokinase-type plasminogen activator-dependent proliferation of synoviocytes from patients with rheumatoid arthritis. Arthritis Research & Therapy, 7(6), R1244-53.
Guiducci S, et al. Raloxifene Reduces Urokinase-type Plasminogen Activator-dependent Proliferation of Synoviocytes From Patients With Rheumatoid Arthritis. Arthritis Res Ther. 2005;7(6):R1244-53. PubMed PMID: 16277677.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Raloxifene reduces urokinase-type plasminogen activator-dependent proliferation of synoviocytes from patients with rheumatoid arthritis. AU - Guiducci,S, AU - Del Rosso,A, AU - Cinelli,M, AU - Perfetto,F, AU - Livi,R, AU - Rossi,A, AU - Gabrielli,A, AU - Giacomelli,R, AU - Iori,N, AU - Fibbi,G, AU - Del Rosso,M, AU - Cerinic,M Matucci, Y1 - 2005/09/08/ PY - 2004/09/10/received PY - 2005/07/28/revised PY - 2005/08/10/accepted PY - 2005/11/10/pubmed PY - 2006/1/13/medline PY - 2005/11/10/entrez SP - R1244 EP - 53 JF - Arthritis research & therapy JO - Arthritis Res Ther VL - 7 IS - 6 N2 - Extracellular fibrinolysis, controlled by the membrane-bound fibrinolytic system, is involved in cartilage damage and rheumatoid arthritis (RA) synovitis. Estrogen status and metabolism seem to be impaired in RA, and synoviocytes show receptors for estrogens. Our aims in this study were to evaluate in healthy and RA synoviocytes the effects of Raloxifene (RAL), a selective estrogen receptor modulator (SERM), on: proliferation; the components of the fibrinolytic system; and chemoinvasion. The effects of RAL were studied in vitro on synoviocytes from four RA patients and four controls. Proliferation was evaluated as cell number increase, and synoviocytes were treated with 0.5 microM and 1 microM RAL with and without urokinase-plasminogen activator (u-PA) and anti-u-PA/anti-u-PA receptor (u-PAR) antibodies. Fibrinolytic system components (u-PA, u-PAR and plasminogen activator inhibitor (PAI)-1) were assayed by ELISA with cells treated with 0.5 microM and 1 microM RAL for 48 h. u-PA activity was evaluated by zymography and a direct fibrinolytic assay. U-PAR/cell and its saturation were studied by radioiodination of u-PA and a u-PA binding assay. Chemoinvasion was measured using the Boyden chamber invasion assay. u-PA induced proliferation of RA synoviocytes was blocked by RAL (p < 0.05) and antagonized by antibodies alone. The inhibitory effect of RAL was not additive with u-PA/u-PAR antagonism. RA synoviocytes treated with RAL showed, compared to basal, higher levels of PAI-1 (10.75 +/- 0.26 versus 5.5 +/- 0.1 microg/10(6) cells, respectively; p < 0.01), lower levels of u-PA (1.04 +/- 0.05 versus 3.1 +/- 0.4 ng/10(6) cells, respectively; p < 0.001), and lower levels of u-PAR (11.28 +/- 0.22 versus 23.6 +/- 0.1 ng/10(6) cells, respectively; p < 0.001). RAL also significantly inhibited u-PA-induced migration. Similar effects were also shown, at least partially, in controls. RAL exerts anti-proliferative and anti-invasive effects on synoviocytes, mainly modulating u-PAR and, to a lesser extent, u-PA and PAI-1 levels, and inhibiting cell migration and proliferation. SN - 1478-6362 UR - https://www.unboundmedicine.com/medline/citation/16277677/Raloxifene_reduces_urokinase_type_plasminogen_activator_dependent_proliferation_of_synoviocytes_from_patients_with_rheumatoid_arthritis_ DB - PRIME DP - Unbound Medicine ER -