Selective Inhibition of Membrane Type 1 Matrix Metalloproteinase Abrogates Progression of Experimental Inflammatory Arthritis: Synergy With Tumor Necrosis Factor Blockade.

Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by progressive infiltration of the joints by leukocytes, production of mediators of inflammation, and the eventual destruction of joints, including the cartilage and bone 1. The introduction of tumor necrosis factor (TNF) inhibitors has greatly improved the management of RA. However, there remains a need to develop more effective and longer‐lasting treatments for RA because a proportion of patients fail to respond to TNF inhibitors or their responsiveness is lost over time 2, 3. Approaches combining a TNF inhibitor and other approved biologic agents that target different immunomodulatory pathways, such as CTLA‐4 and interleukin‐1 (IL‐1), have shown no added efficacy but an increased risk of serious infections has been reported 4, 5, suggesting that it is important to identify a new combination partner that improves response to anti‐TNF therapy without increasing the risk of side effects. During the progression of RA, the synovium becomes hyperplastic and locally invasive (commonly known as pannus), penetrating the surface of the cartilage and degrading its extracellular matrix 6. The cartilage extracellular matrix is primarily composed of fibrillar type II collagen and proteoglycan aggrecan, the degradation of which by pannus is associated with increased activity of proteolytic enzymes, including matrix metalloproteinases (MMPs) and aggrecanases 7. Early aggrecanase‐mediated loss of aggrecan from cartilage can be reversed, but after the induction of MMP‐mediated breakdown of collagen, cartilage damage becomes irreversible and leads to joint dysfunction 8. Thus, collagen degradation by MMPs is thought to be a critical step in the progression of joint damage. The RA synovium consists of 2 major resident cell types, macrophage‐like synoviocytes and fibroblast‐like synoviocytes (FLS), along with recruited inflammatory cells, such as T cells, macrophages, B cells, dendritic cells, and mast cells 9. Among these cells, FLS and macrophages are the major sources of MMPs. FLS activated through cellular interactions and soluble factors produce MMP‐1, MMP‐2, MMP‐13, and membrane type 1 MMP (MT1‐MMP; also known as MMP‐14), which can degrade type II collagen. Macrophages also produce MMP‐1, MMP‐2, and MT1‐MMP 7, 10. However, the precise functions of these MMPs in cartilage degradation remain elusive. The failure of broad‐spectrum MMP inhibitors in clinical trials of cancer and RA 11 emphasizes the importance of targeting specific enzymes. Among these collagenolytic MMPs, MT1‐MMP is a type I transmembrane proteinase that is expressed on the cell surface and the only collagenase that directly promotes cellular invasion into 3‐dimensional collagen matrices 12. Our previous work showed that MT1‐MMP is highly expressed in FLS and macrophages at the cartilage–pannus junction in the joints of patients with RA and promotes the invasion of RA FLS into cartilage in vitro 13. Similar results were obtained by Sabeh et al 14, who demonstrated that silencing MT1‐MMP, but not MMP‐1, MMP‐2, or MMP‐13, inhibited cartilage invasion by RA synoviocytes 14. The findings of these studies suggest that MT1‐MMP is a key enzyme in cartilage invasion by pannus in RA. We used the collagen‐induced arthritis (CIA) mouse model in the present study to determine whether MT1‐MMP is a potential therapeutic target for joint damage in RA. We demonstrated that selective inhibition of MT1‐MMP protects joints from cartilage damage and disease progression and enhances the response to anti‐TNF treatment in established CIA.