The effect of bosentan on matrix metalloproteinase-9 levels in patients with systemic sclerosis-induced pulmonary hypertension.
OBJECTIVE
Systemic sclerosis (SSc) is an autoimmune disease that can potentially involve all tissues and organs of the human body. Based on the extent of the disease and organ involvement, different subsets of patients and organ involvement, different subsets of patients have been identified and several classifications proposed have been identified and several classifications proposed aiming to better stratify affected patients. The occurrence aiming to better stratify affected patients. The occurrence of pulmonary arterial hypertension (PAH), characterized of pulmonary arterial hypertension (PAH), characterized by altered tissue remodelling of the entire vessel wall, is the most severe complication that influences prognosis and survival. The molecular basis underlying the vascular damage is not yet known, but a family of enzymes named matrix metalloproteinases (MMPs), with a proteolytic activity towards several extra-cellular matrix (ECM) components, is likely to be involved. Recently, a dual inhibitor of endothelin-1, bosentan, has been successfully evaluated in clinical trials in PAH patients.


METHODS
The aim of this study is to investigate the expression of MMP-2 and MMP-9 in the serum of different subsets of SSc patients, and in patients treated with bosentan. Thirty-five Caucasian patients with SSc were enrolled in the study, 12 of whom were found to have isolated PAH assessed by Doppler echocardiography. Eight patients fully met the inclusion criteria and were eligible for therapy with bosentan given at the dosage of 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily for 50 weeks(15). The remaining patients (4/12) initiated bosentan therapy for a few weeks and, therefore, were considered at the baseline level only. Serum samples were analysed by gelatine zymography.


RESULTS
The results suggest that MMP-9 but not MMP-2 is differently expressed according to the degree of organ involvement. In particular, MMP-9 serum levels are significantly decreased in PAH with respect to other subsets of SSc patients. Moreover, in bosentan-treated patients, after 12 months of therapy MMP-9 significantly (p < 0.05) increased and correlated with an improved clinical outcome, as measured by the '6-minutes walking' test.


CONCLUSIONS
This is the first time that MMP-9 serum levels are reported to be down-regulated in PAH patients and up-regulated following bosentan treatment. Whether MMP-9 has a pathogenetic role in the vascular damage observed in PAH patients or it is a marker of bosentan effectiveness is not yet known. However, MMP-9 may be an important molecule that needs further investigation in SSc patients to better define its role.
Giannelli
Gianluigi
G
Department of Internal Medicine, Immunology and Infectious Diseases, Section of Internal Medicine, University of Bari Medical School, Bari, Italy. g.giannelli@intmed.uniba.it
Iannone
Florenzo
F
Marinosci
Felice
F
Lapadula
Giovanni
G
Antonaci
Salvatore
S
D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D000077300:Bosentan; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000097:blood; D008875:Middle Aged; D012595:Scleroderma, Systemic / Q000150:complications*; D013449:Sulfonamides / Q000627:therapeutic use*
D000959:Antihypertensive Agents; D013449:Sulfonamides; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000077300:Bosentan