Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that exhibit collagenolytic activity as well as proteolytic activity against other extracellular matrix (ECM) components (aggrecan, gelatin, fibronectin, vitronectin, etc.). These enzymes are primarily responsible for the physiological (i.e. embryogenesis, organogenesis, wound healing, etc.) and pathological turnover of connective tissues. As such, MMP inhibitors could prove a useful therapeutic target for diseases where connective tissue degradation and tissue re-modelling are prominent features. In fact, numerous MMP inhibitors have been studied for their therapeutic potential in several disease contexts. However, they have all failed in clinical trials due to severe adverse effects caused by the test compounds’ broad-spectrum MMP inhibition. Identifying and evaluating MMP inhibitors that can specifically target MMPs implicated in disease progression could improve therapeutics options for osteoarthritis, rheumatoid arthritis, cancer, and fibrotic diseases.
Below are summaries of the involvement of MMPs in these diseases. For more information on the different types of MMPs, their substrates, and physiological roles, please continue reading here.
Osteoarthritis (OA) is a degenerative disease characterized by the degradation of articular cartilage, typically associated with mechanical injury to joints. MMPs are key in the cartilage destruction seen in OA patients (1,2). MMP-1 (collagenase), MMP-2 (gelatinase), MMP-9 (gelatinase), and MMP-13 (collagenase) are expressed at higher levels in OA patient synovial fluid (SF) than in healthy controls (2, 3). However, there is a difference in the expression profile of these MMPs. MMP-2 and MMP-9 overexpression is observed primarily in the more advanced stages of OA (2), while MMP-13 (Collagenase-3) levels are highest in the initial phase/onset of OA patients (2), and in animal models. Surgically-induced OA models using transgenic mice further support the role of MMP-13 in OA progression as MMP-13 overexpressing mice spontaneously develop an OA-like phenotype (4) while MMP-13 inhibitors reduced OA progression in the transgenic mice (5).
Overexpression of MMP-13 by chondrocytes in articular cartilage is also associated with the onset of OA, especially in OA caused by a joint injury. Rodent models of OA have shown that cyclic tensile stress can upregulate MMP-13 expression through the Runx-2/Cbfa1 pathway (6). Furthermore, when a joint becomes damaged or experiences excessive mechanical stress, chondrocytes and synoviocytes release pro-inflammatory cytokines like IL-1β, TNF-α, and TGF-β that promote MMP expression (6). Compounds that specifically inhibit MMP-13 expression or activity could be valuable treatment options for patients in the early stages of OA.
Rheumatoid arthritis (RA) is an autoimmune disease where aberrant immune response to collagen and excessive inflammation lead to joint destruction and immobility. In RA patients, the synovial tissue surrounding joints is chronically inflamed, resulting in a thickening of the synovium, pannus formation, and eventually total loss of the joint function. Numerous MMPs have been observed in RA patient synovial tissue: MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10, MMP-12, MMP-13, and MT1-MMP (7). The pro-inflammatory cytokine milieu (specifically IL-1, IL-17, and TNFα) released in RA patient synovial tissue stimulates MMP-13 and MT1-MMP expression from synovial fibroblasts, especially at the pannus and cartilage interface (7, 8). Rodent RA models, including the Collagen-Induced Arthritis (CIA) Model, indicate a prominent role of MMP-13 in arthritis progression because the arthritis can be ameliorated by administrating MMP-13 specific inhibitors (9). Similarly, MT1-MMP inhibitor administration inhibited cartilage destruction in the mouse CIA model (7). These results suggest that MMP-13 and MT1-MMP contribute to degradation of cartilage in RA. Furthermore, MMP-9 and MMP-2 have been shown to promote RA synovial fibroblast survival, invasion into joints, and cartilage destruction (10). Given the upregulation of collagenase and gelatinase activity in RA, MMPs are an obvious choice for therapeutic intervention.
However, the role of MMPs in RA pathogenesis is further complicated by the ability of MMPs to modulate inflammatory signaling through proteolytic processing of cytokines and chemokines. Several MMPs, including MMP-1, MMP-2, MMP-3, MMP-9, and MMP-12, are capable of activating IL-1β and TNF-α (both upregulated in RA SF, [11]) (12). MMP-12 expression is also associated with macrophage infiltration of the joint and pro-inflammatory signaling (7), further supporting the role of MMPs in perpetuating inflammatory reactions . Clearly, the roles of MMPs in RA pathogenesis are varied and complex. More research is needed to determine the therapeutic potential of specific MMP and collagenase (MMP-1 and MMP-13) inhibitors in treating RA. The Collagen Antibody-Induced Arthritis (CAIA) model and the CIA model offer reproducible, reliable, and well characterized animal models for studying MMPs in the context of autoimmune arthritis.
MMP expression in cancer patients is markedly higher than in healthy controls, although the MMP expression pattern differs among cancer types (13, 14). MMPs in the tumor microenvironment are primarily released by nonmalignant stromal cells (i.e. fibroblasts) rather than malignant cells themselves (13,15). The released MMPs degrade the ECM in the tumor microenvironment and promote/direct angiogenesis, ultimately stimulating tumor growth (13). Additionally, MMPs mediate tissue remodeling in distant sites through signaling of exosome, a type of extracellular vesicle, that establish a pre-metastatic niche (16). More specifically, MMP-13 and MT1-MMP were identified in exosomes (17). Additionally, MMP-14 has been shown to promote activation of exosome derived MMP-2 and promote type I collagen remodeling (16).
On the other hand, MMPs have shown tumor suppressive effects in studies with transgenic mice (18). For instance, MMP-8 knockout mice have been shown to be more prone to skin cancer, connective tissue cancers, and melanoma than normal mice (19). Interestingly, MMP-3, MMP-9, MMP-11, and MMP-19 have been shown to either promote or suppress tumor growth depending on the cancer type (18).
These opposing functions of MMPs in tumor pathology are suggestive of the intricate network of biochemical pathways that are regulated by MMP activity. While MMPs are an attractive therapeutic target for malignant cancers and arthritis, the complexities of MMP activity and regulation has confounded therapeutics efforts. Future research that can parse the context-specific roles of MMPs in various cancer types could lead to new treatment options that, when used in combination with immune checkpoint inhibitors, may improve patient prognosis.
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