Expression of matrix metalloproteinases in patients with Wegener's granulomatosis (original) (raw)

Abstract

Background: Enhanced activity of matrix metalloproteinases (MMPs) has been reported to have a pathogenic role in several diseases such as cancer and cardiovascular disorders, and seems also to play a part in certain autoimmune diseases.

Objective: To examine whether enhanced MMP activity may also have a role in the pathogenesis of Wegener's granulomatosis (WG).

Methods: In a study group of 15 patients with WG and 15 controls, plasma levels and gene expression were measured in freshly isolated peripheral blood mononuclear cells (PBMCs) of several MMPs and their endogenous inhibitors (that is, tissue inhibitors of metalloproteinases (TIMPs)) by enzyme immunoassays and RNase protection assay, respectively.

Results: Whereas patients with WG in remission had enhanced gene expression of several MMPs and TIMPs in PBMCs, those with active disease had a selective up regulation of MMP-2 and MMP-8 compared with healthy controls, and a down regulation of TIMP-1 and TIMP-3 compared with other patients with WG. Moreover, plasma levels of TIMP-1 and MMP-8 correlated significantly with C reactive protein levels, further supporting an association between activation of the MMP/TIMP system and disease activity in WG. Finally, these changes in MMP/TIMP expression in WG were accompanied by increased total MMP activity in PBMC supernatants, particularly in those with active disease, suggesting a matrix degrading net effect.

Conclusion: These findings suggest that disturbed MMP and TIMP activity has a role in the pathogenesis of WG.

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Figure 1.

Figure 1

Gene expression (RPA) of MMPs in relation to the control gene rpL32 in PBMCs from patients with WG classified as being in remission (n = 8) (A) or as having active disease (n = 7) (B) according to the BVAS, serum levels of CRP, and ESR (see table 1) and 15 healthy controls. Data are given as mean (SEM). *p<0.01 and **p<0.001 versus healthy controls.

Figure 2.

Figure 2

Gene expression (RPA) of TIMPs in relation to the control gene rpL32 in PBMCs from 15 patients with WG classified as having active disease (n = 7) or being in remission (n = 8) according to the BVAS, serum levels of CRP, and ESR (see table 1) and 15 healthy controls. Data are given as mean (SEM). *p<0.01 and **p<0.001 versus active disease and healthy controls.

Figure 3.

Figure 3

Plasma levels of MMP-2 (A), MMP-3 (B), MMP-8 (C), and TIMP-1 (D) in 15 patients with WG and 15 healthy controls. Horizontal lines represent median values.

Figure 4.

Figure 4

Plasma levels of MMP-3 (A), MMP-8 (B), and TIMP-1 (C) in 15 patients with WG classified as having active disease (n = 7) or being in remission (n = 8) according to the BVAS, serum levels of CRP, and ESR (see table 1). Data are given as mean (SEM). *p<0.01 and **p<0.005 versus patients in remission.

Figure 5.

Figure 5

Correlation between plasma levels of CRP and MMP-8 (A) and TIMP-1 (B) in 15 patients with WG.

Figure 6.

Figure 6

MMP activity in PBMC supernatants from patients with WG and healthy controls. (A) Total MMP activity in nine patients with WG and eight healthy controls using a fluorogenic peptide substrate (see "Patients and methods"). (B) Gelatinolytic (MMP-9) activity in PBMC supernatants after incubation for 18 hours in two representative patients with WG and two healthy controls. Gelatinolytic activity was seen as lytic bands and the majority of these were identified as pro-MMP-9 and active MMP-9. Note: pro-MMP-9 was only detected in the WG group. RFU, relative fluorescence units.

Selected References

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