Retroviral gene transfer of an antisense construct against membrane type 1 matrix metalloproteinase reduces the invasiveness of rheumatoid arthritis synovial fibroblasts

Abstract

Conclusion. The data demonstrate that an antisense RNA expression construct against MT1-MMP can be generated and expressed in RASFs for at least 60 days. Inhibition of MT1-MMP significantly reduces the cartilage degradation by RASFs.Membrane-type matrix metalloproteinases (MTMMPs) are cell membrane-anchored MMPs that have been associated with both normal tissue remodeling and various diseases. Six different MT-MMPs have thus far been described, of which membrane type 1 MMP (MT1-MMP) has been studied most intensively. MT1-MMP (also called MMP-14) has a specific structural organization that is characterized by a hydrophobic transmembrane domain and a short cytoplasmic tail. It also contains a recognition site for furin-like proprotein convertases, which, by furin-dependent cleavage, activate MT1-MMP intracellularly (1). MT1-MMP digests interstitial collagens as well as other extracellular matrix components, including fibronectin, laminin, aggrecan,

High concentrations of hydrogen sulphide elevate the expression of a series of pro-inflammatory genes in fibroblast-like synoviocytes derived from rheumatoid and osteoarthritis patients

“…However, the specific contribution of MMP-14 to direct, fibroblast-mediated destruction of articular extracellular matrix is incompletely understood. It is interesting to note that inhibition of MMP-14 production in RA-FLS was accompanied by a significant decline in their invasiveness in the Severe Combined Immunodeficiency (SCID) mouse model [35].…”

Membrane-Type I Matrix Metalloproteinase-Dependent Regulation of Rheumatoid Arthritis Synoviocyte Function

“…Further, the possibility that the MT1-MMP dominant-negative construct exerts more complex effects on cell function by sequestering signaling molecules that normally bind to the MT1-MMP cytosolic tail has not yet been evaluated (55). In a similar fashion, an earlier report documented the ability of a MT1-MMP antisense construct to partially inhibit RA synoviocyte cartilage invasion in a SCID mouse-xenograft model (56). In this case, MT1-MMP activity was not inhibited completely, and the specificity of the antisense construct for MT1-MMP alone was not established.…”

Innate Mechanisms of Synovitis – Fibrin Deposits Contribute to Invasion

“…Of this family, MT1-MMP (also MMP-14), which is over-expressed in rheumatoid synovial fibroblasts, is thought to confer to these cells some of their invasive potential (Yamanaka et al, 2000). In this regard, experiments carried out in the SCID mouse co-implantation model have shown the participation of MMP-1 and MT1-MMP in the degradation of cartilage by rheumatoid synovial fibroblasts (Rutkauskaite et al, 2004;Rutkauskaite et al, 2005). Based on this evidence, the pathway of MMPs has been for a while a promising area of research for therapeutics, not only in rheumatoid arthritis but also in metastatic tumours.…”