Matrix Metalloproteinase 3 (MMP-3), also known as Stromelysin-1, is an enzyme belonging to a larger family of zinc-dependent enzymes called matrix metalloproteinases. These enzymes specialize in breaking down proteins that form the extracellular matrix (ECM), the structural network providing support to cells. The primary function of MMP-3 is to act as a molecular tool, disassembling components of this matrix. This ability to remodel the cellular environment is part of a complex system that allows tissues to grow, repair, and maintain their structure. MMP-3 is produced by various cell types, and its activity is tightly regulated within the body.
The Biological Roles of MMP-3
In its normal physiological capacity, MMP-3 is a participant in the constant turnover and remodeling of the extracellular matrix. It has a broad range of targets, enabling it to degrade various ECM proteins, including proteoglycans, fibronectin, laminin, and several types of collagen such as types III, IV, and IX. This wide substrate specificity makes it a versatile tool for tissue restructuring.
The functions of MMP-3 are apparent during processes that require significant tissue alteration. For instance, during embryonic development, MMP-3 helps shape developing organs by clearing paths for cell migration. In wound healing, it is expressed to help form and later resolve granulation tissue, the new connective tissue that forms on a wound’s surface.
Beyond its direct degradation of matrix components, MMP-3 has a regulatory role within its enzyme family. It can activate other MMPs, known as pro-MMPs, including MMP-1, MMP-9, and MMP-13. This activation initiates a cascade of enzymatic activity, amplifying the breakdown of the ECM where needed. It can also release other bioactive molecules, such as growth factors, which are embedded in the matrix, thereby influencing cellular behavior in a controlled manner.
MMP-3’s Involvement in Disease
While the controlled activity of MMP-3 is beneficial, its dysregulation, particularly overexpression, is implicated in the progression of several diseases. When its activity becomes excessive, it can drive tissue destruction. This is seen in inflammatory joint diseases like rheumatoid arthritis and osteoarthritis, where MMP-3 is a contributor to cartilage degradation, causing joint pain and inflammation.
In rheumatoid arthritis, inflammatory cytokines stimulate synovial cells to produce large amounts of MMP-3, which degrades the cartilage matrix and contributes to joint erosion. MMP-3 levels are particularly high in the pannus, an abnormal tissue layer that forms over the joint surface. In osteoarthritis, MMP-3 is upregulated in response to joint injury or mechanical stress, where it contributes to the slow degradation of cartilage.
The role of MMP-3 extends to the progression of cancer. Its ability to degrade the extracellular matrix is used by tumor cells to facilitate invasion into surrounding tissues, a step for metastasis. MMP-3 also promotes angiogenesis, the formation of new blood vessels that supply tumors with nutrients, by releasing pro-angiogenic factors from the matrix. Studies indicate MMP-3 is involved in promoting tumor growth in various cancers, including prostate and oral squamous cell carcinoma.
In the cardiovascular system, MMP-3 activity is linked to conditions such as atherosclerosis. The enzyme can degrade components of the fibrous cap that covers atherosclerotic plaques, contributing to plaque instability. A rupture of this cap can lead to the formation of a blood clot, potentially causing a heart attack or stroke. MMP-3 has also been implicated in the development of aortic aneurysms, where its activity weakens the wall of the aorta, causing it to bulge and potentially rupture.
Clinical Significance of MMP-3
Given its involvement in tissue destruction, MMP-3 serves as both a biomarker and a therapeutic target. The levels of MMP-3 can be measured in bodily fluids, most commonly blood serum and the synovial fluid of joints, to help manage conditions like rheumatoid arthritis (RA).
In patients with RA, serum MMP-3 levels often correlate with disease activity, the degree of joint inflammation, and the rate of joint destruction. This makes it a useful biomarker for monitoring the progression of the disease and assessing how well a treatment is working. A decrease in serum MMP-3 levels following therapy often indicates a positive response. Both the total amount of MMP-3 and its activated form are studied, with the active form being a more direct indicator of ongoing tissue degradation.
The role of MMP-3 in disease has led to efforts to develop drugs that can inhibit its activity. The strategy of using MMP inhibitors aims to halt or slow pathological tissue destruction in diseases like arthritis and cancer. However, developing effective and safe MMP inhibitors has been challenging.
A primary difficulty is achieving specificity. The MMP family includes over 25 members, many of which perform necessary physiological functions, and broad-spectrum inhibitors can cause side effects by disrupting these normal processes, such as proper wound healing. Early clinical trials with non-specific MMP inhibitors were largely unsuccessful due to low efficacy and side effects like musculoskeletal pain. Current research is focused on developing highly selective inhibitors that target only MMP-3 or a small subset of disease-relevant MMPs.