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Serum TIMP-1, TIMP-2, and MMP-1 in patients with systemic sclerosis, primary Raynaud's phenomenon, and in normal controls
  1. S A Young-Mina,
  2. C Beetonb,
  3. R Laughtona,
  4. T Plumptonb,
  5. S Bartramc,
  6. G Murphyd,
  7. C Blacke,
  8. T E Cawstona
  1. aDepartment of Rheumatology, University of Newcastle-upon-Tyne, UK, bSchool of Clinical Medicine, University of Cambridge, UK, cDepartment of Rheumatology, Newcastle-upon-Tyne NHS Hospitals Trust, UK, dUniversity of East Anglia, UK, eDepartment of Rheumatology, Royal Free Hospital, London, UK
  1. Dr S A Young-Min, Rheumatology, School of Clinical and Medical Sciences, The Medical School, Catherine Cookson Building, University of Newcastle-upon-Tyne NE2 4HH, UKSteven.youngMin{at}


BACKGROUND Excess tissue matrix accumulates in systemic sclerosis (SSc), accounting for both visceral and dermal fibrosis. It is suggested that decreased serum levels of matrix metalloproteinases (MMPs) or increased levels of tissue inhibitors of matrix metalloproteinases (TIMPs) may account for this matrix accumulation.

OBJECTIVE To measure serum levels of tissue inhibitors of metalloproteinases, TIMP-1, TIMP-2, and collagenase-1 (MMP-1), in patients with diffuse cutaneous systemic sclerosis (dcSSc), limited cutaneous systemic sclerosis (lcSSc), primary Raynaud's phenomenon (RP), and in normal controls.

METHODS Serum samples from patients with dcSSc (n=83), lcSSc (n=87), RP (n=80), and normal controls (n=98) were analysed using enzyme linked immunosorbent 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 post-test was then applied between groups.

RESULTS TIMP-1 levels were significantly raised in dcSSc and lcSSc groups compared 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 lcSSc group. Serum TIMP-2 and MMP-1 levels in dcSSc and lcSSc did not 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), anticentromere antibody, or anti-RNA polymerase). No significant differences in serum TIMP-1, TIMP-2, or MMP-1 levels were shown in the RP group compared with normal controls.

CONCLUSIONS Raised TIMP-1 levels in the SSc groups support the hypothesis that matrix accumulation occurs in SSc at least in part owing to decreased degradation. 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 levels in the SSc groups was not found. This suggests that tissue matrix accumulation is due to increased inhibitors rather than to decreased MMPs.

  • systemic sclerosis
  • Raynaud's phenomenon
  • tissue inhibitors of matrix metalloproteinases
  • collagenase

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