SCIENTIFIC ARTICLE Invasive Potential of Human Rheumatoid Tenosynovial Cells Is in Part MT1-MMP Dependent Abhilash Jain, PhD, Mary-Clare Miller, MD, Linda Troeberg, PhD, Yoshifumi Itoh, PhD, Fionula Brennan, PhD, Jagdeep Nanchahal, PhD 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 tenosy- novial 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 inhib- itor) 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. (J Hand Surg 2009;34A:1282–1290. © 2009 Published by Elsevier Inc. on behalf of the American Society for Surgery of the Hand.) Type of study/level of evidence Prognostic IV. Key words Invasion, MT1-MMP, rheumatoid, tendon. From the Kennedy Institute of Rheumatology Division, Imperial College London, London, UK. Received for publication January 22, 2009; accepted in revised form April 9, 2009. A.J. and J.N. received support from an Arthritis Research Campaign Clinical Research Fellowship, M.C.M. received support from the Royal College of Surgeons of England Surgical Research Fellowship and Core Grant Support from the Kennedy Institute of Rheumatology, and L.T. received support from Wellcome Trust. We are grateful for support from the NIHR Biomedical Research Centre funding scheme. Corresponding author: Abhilash Jain, PhD, 11 Greenhalgh Walk, Hampstead Garden Suburb, Lon- don, N2 0DJ, UK; e-mail: Ajainuk@aol.com. 0363-5023/09/34A07-0017$36.00/0 doi:10.1016/j.jhsa.2009.04.015 1282  ©  Published by Elsevier, Inc. on behalf of the ASSH.