Matrix metalloproteinase-7 (MMP7) is an enzyme that breaks down the extracellular matrix (ECM). The ECM is a network of proteins and molecules providing structural support to cells and tissues. Like other MMPs, MMP7 contains zinc and calcium and functions as an endopeptidase. While secreted by cells to remodel the ECM, its activity must be carefully controlled.
MMP7’s Healthy Role
MMP7 contributes to the body’s normal, healthy processes, particularly in tissue remodeling and repair. It is involved in the continuous breakdown and rebuilding of the ECM, which maintains tissue integrity and function.
In wound healing, MMP7 helps clear out damaged matrix components after an injury. It assists in degrading capillary walls to prepare for new blood vessel growth. MMP7 also influences the reorganization of new tissue matrix in the later stages of wound repair. Additionally, MMP7 can regulate the activity of defensins in the intestinal lining, important for immune responses.
MMP7’s Role in Disease
While MMP7 has beneficial functions, its dysregulation contributes to various disease processes. This enzyme’s ability to degrade ECM proteins and influence cell signaling can promote the progression of several conditions.
MMP7’s role in cancer progression affects tumor growth, invasion, and metastasis. It breaks down extracellular matrix components, such as proteoglycans, fibronectin, elastin, and casein. This degradation creates pathways for cancer cells to invade new areas. MMP7 can also cleave cell surface proteins, like E-cadherin, which reduces cell-to-cell adhesion and increases cancer cell spread.
The enzyme further promotes tumor progression by influencing cell survival and growth. MMP7 can cleave Fas ligand, removing it from the surface of tumor cells and preventing it from triggering cell death pathways. This mechanism helps cancer cells evade programmed cell death and may contribute to their resistance to chemotherapy. Additionally, MMP7 can activate growth factor signaling by increasing the availability of factors such as transforming growth factor-beta, fibroblast growth factor-2, and vascular endothelial growth factor (VEGF)-A, which stimulate tumor growth and angiogenesis.
Beyond cancer, MMP7 is implicated in inflammatory diseases and fibrosis. In inflammatory bowel disease (IBD), for example, MMP7 may contribute to aggravated disease severity and disruption of the intestinal lining. Its presence can establish gradients that coordinate the recruitment and activation of immune cells, such as neutrophils, at sites of inflammation.
In fibrosis, characterized by excessive collagen-rich extracellular matrix deposition, MMP7 contributes to its development. It can contribute to fibrosis in various organs, including the lungs, liver, and kidneys. For instance, in rheumatoid arthritis-associated interstitial lung disease (RA-ILD), elevated MMP7 levels are observed, contributing to subpleural lung inflammation and fibrosis. MMP7’s involvement in fibrosis includes:
Promoting inflammation.
Degrading the ECM.
Influencing abnormal matrix repair.
Facilitating epithelial-mesenchymal transition, a process where epithelial cells transform into cells that contribute to fibrosis.
Targeting MMP7 for Health
Given its involvement in various diseases, modulating MMP7 activity is an active area of research for potential therapeutic strategies. The concept revolves around developing MMP7 inhibitors that can block its harmful actions without disrupting its healthy functions.
MMP7 inhibitors aim to reduce the enzyme’s ability to break down the extracellular matrix and interfere with its pro-tumor or pro-fibrotic signaling pathways. These inhibitors could potentially slow tumor growth, invasion, and metastasis by preventing cancer cells from degrading surrounding tissues and evading immune responses. In fibrotic conditions, inhibiting MMP7 could reduce excessive collagen deposition and inflammation, thereby mitigating tissue scarring.
Developing specific and effective MMP7 inhibitors presents challenges. Early generations of broad-spectrum MMP inhibitors, which targeted many MMPs, showed limited success in clinical trials due to a lack of selectivity and significant side effects, such as musculoskeletal issues. Current research focuses on designing more selective inhibitors that precisely target MMP7 to minimize off-target effects and improve therapeutic outcomes. This involves understanding the unique structural features of MMP7 to create compounds that bind specifically to its active site.