Invasive potential of human rheumatoid tenosynovial cells is in part MT1-MMP dependent.
Jain A., Miller M-C., Troeberg L., Itoh Y., Brennan F., Nanchahal J.
PURPOSE: In rheumatoid arthritis, tenosynovial invasion of tendon is associated with an increased rate of tendon rupture and a worse clinical prognosis compared to noninvasive disease. Tendon is composed predominantly of type I collagen, which can be efficiently degraded by collagenolytic matrix metalloproteinases (MMPs), one of which, MT1-MMP, is membrane bound and inhibited by tissue inhibitor of metalloproteinase-2, but not by TIMP-1. The role of MT1-MMP in tendon disease is unknown. In this report, we investigate the potential role of MT1-MMP in invasion of tenosynovium into tendon. METHODS: Matched synovial specimens were obtained from different regions of the wrist in 36 rheumatoid patients having extensor tenosynovectomy in most instances. The tenosynovium that was removed was surrounding tendons (termed encapsulating) invading tendons (termed invasive), and wrist joint synovium. Samples of tenosynovium were tested for MT1-MMP using Western blotting, and the MT1-MMP activity was quantified using commercial assays. Next, a 3-dimensional collagen assay was created, using freshly isolated tenosynovium. Transwell collagen invasion assays were then performed, using isolated tenosynovial cells to determine MT1-MMP's effect on tendon invasion. RESULTS: The MT1-MMP was present in 9 of 10 joint samples, 4 of 6 encapsulating tenosynovial samples, and 5 of 5 invasive tenosynovial samples. Activity assays demonstrated that mean levels of active MT1-MMP produced by joint samples was 6.1 +/- 4.1 ng/mL; by encapsulating tenosynovium was 3.9 +/- 4.2 ng/mL, and by invasive tenosynovium was 6.2 +/- 1.1 ng/mL. The 3-dimensional gel assays demonstrated that cell invasion was reduced by the addition of TIMP-2 and GM-6001(a broad spectrum matrix metalloproteinase inhibitor) but not by TIMP-1. The addition of TIMP-2 to invasion assays reduced the mean number of cells that invaded the collagen membrane from 11 +/- 5 cells/field to 7 +/- 3 cells/field in treated samples (p = .04). CONCLUSIONS: Our results demonstrate that MT1-MMP is present in rheumatoid tenosynovium and that MT1-MMP facilitates tenosynovial cell invasion into a type I collagen matrix, suggesting that MT1-MMP plays a crucial role in tendon invasion. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.