Serum TIMP-1, TIMP-2, and MMP-1 in patients with systemic sclerosis, primary Raynaud's phenomenon, and in normal controls

Background-Excess tissue matrix accumulates in systemic sclerosis (SSc), ac counting for both visceral and dermal fibrosis. It is suggested that decrea sed serum levels of matrix metalloproteinases (MMPs) or increased levels of tissue inhibitors of matrix metalloproteinases (TIMPs) may account for thi s matrix accumulation. Objective-To measure serum levels of tissue inhibitors of metalloproteinase s, TIMP-1, TIMP-2, and collagenase-1 (MMP-1), in patients with diffuse cuta neous systemic sclerosis (dcSSc), limited cutaneous systemic sclerosis (1cS Sc), primary Raynaud's phenomenon (RP), and in normal controls. Methods-Serum samples from patients with dcSSc (n=83), 1cSSc (n=87), RP (n= 80), and normal controls (n=98) were analysed using enzyme linked immunosor bent assays (ELISAs) for total TIMP-1, TIMP-2, and MMP-1. Results from each assay were analysed by the Kruskal-Wallis test. Dunn's multiple comparison posttest was then applied between groups. Results-TIMP-1 levels were significantly raised in dcSSc and 1cSSc groups c ompared with the RP group and normal controls (p <0.01 to p <0.001). In the dcSSc group, TIMP-1 levels were significantly higher in early disease (<2 years) than in late stage disease (>4 years) (p <0.05). This was not found for the 1cSSc group. Serum TIMP-2 and MMP-1 levels in dcSSc and 1cSSc did n ot differ significantly from those in normal controls. Increased levels of TIMPs were not convincingly associated with organ disease. No assay result correlated with autoantibody status (anti-topoisomerase 1 (anti-Scl-70), an ticentromere antibody, or anti-RNA polymerase). No significant differences in serum TIMP-1, TIMP-2, or MMP-1 levels were shown in the RP group compare d with normal controls. Conclusions-Raised TIMP-1 levels in the SSc groups support the hypothesis t hat matrix accumulation occurs in SSc at least in part owing to decreased d egradation. Moreover, the variation in TIMP-1 levels between the early and late disease stages of dcSSc seems to reflect the early progressive course of dermal fibrosis seen clinically. The expected reduction in serum MMP-1 l evels in the SSc groups was not found. This suggests that tissue matrix acc umulation is due to increased inhibitors rather than to decreased MMPs.