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Collagen and elastin are major components of the extracellular matrix (ECM), generating the structural strength and elasticity of a vast array of tissues such as skin, lungs, and blood vessels. Their resilience to proteolytic degradation is significant for tissue function. However, some enzymes known as matrix metalloproteinases (MMPs) have evolved to remodel these tough proteins, playing vital roles in both physiological processes and diseases.
Structure and Function of Collagen and Elastin
Collagen is the most abundant ECM protein, having a triple-helical structure composed of three polypeptide chains. This provides tensile strength to tissues and renders collagen essential for structural support. Elastin, on the other hand, provides elasticity to tissues, allowing them to resume shape after stretching or contraction. This is particularly important in dynamic tissues like the lungs and arteries.
Matrix Metalloproteinases: Regulatory Proteins in ECM Remodeling
The MMPs represent a family of zinc-requiring endopeptidases involved in the cleavage of multiple ECM constituents like collagen and elastin. In spite of maintaining the integrity of tissues by ECM strength under healthy conditions, tissue repair, angiogenesis, and embryonic growth require controlled MMP proteolysis. In contrast, dysregulation of MMP activity has a role to play in disease, including arthritis, cancer metastasis, and cardiovascular disease.
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Degradation of Collagen by MMPs
The triple-helix structure of collagen protects it against the action of most proteases. Certain MMPs, like interstitial collagenases MMP-1, MMP-8, and MMP-13, have the unique ability to cleave native collagen. These enzymes target particular sites in the collagen triple helix, uncoiling it so that further degradation is facilitated.
The hemopexin-like (HPX) domain in these MMPs plays a critical role in collagenolysis. Structural studies have shown that the HPX domain engages the collagen triple helix and positions the catalytic domain to effectively cleave peptide bonds. In addition to providing substrate specificity, this also optimizes the efficiency of the enzyme in remodeling the ECM.
Elastin Degradation by MMPs
The extended and elastic configuration of elastin is responsible for the elastic tissue’s function. MMPs such as MMP-2, MMP-9, and MMP-12 degrade elastin in a process called elastolysis. Elastin degradation is regulated because elastolysis is abnormal when too much of it leads to conditions like emphysema and aneurysms.
For MMP-12, or macrophage elastase, elastin breakdown requires specific regions known as exosites on the catalytic domain. These exosites bind to elastin, orienting the substrate so that it can be cleaved effectively. Exosite mutations have been shown to decrease elastolytic activity, proving their function in substrate recognition and processing.
Regulation of MMP Activity
The activity of MMPs is stringently regulated at various levels, including gene expression, zymogen activation, and inhibition by endogenous tissue inhibitors of metalloproteinases (TIMPs). Regulation is designed to keep ECM deposition and degradation in balance. Loss of equilibrium, often presented as overexpression of MMPs, may cause pathological remodeling of the tissues and disease progression.
Implications in Disease and Therapeutic Potential
Pathological MMP activity has also been implicated. For instance, excessive degradation of collagen by MMPs leads to cartilage breakdown in osteoarthritis, while enhanced degradation of elastin is characteristic of disease conditions like COPD and aortic aneurysm.
Elucidating the individual interaction of MMPs with substrates opens up new avenues for therapy. Catalytic site inhibitors may have been explored but the problem still exists with the requirement for specificity to avoid off-target effects. Research into the unique domains and substrate-specific exosites has promise for the design of more specific inhibitors that may have effects on MMP activity but without affecting their usual biological functions.
Foods to prevent collagen degradation by MMPs
Certain foods contain naturally occurring substances that help to prevent excessive MMP activity, which protects against tissue breakdown and inflammation. Polyphenolic foods like green tea, berries, grapes, and dark chocolate contain antioxidants like EGCG and resveratrol, which suppress MMP expression. Omega-3 fatty acids in fatty fish, flaxseeds, and walnuts suppress MMP activation. Vitamin C-rich foods like citrus fruits, bell peppers, and kiwis help in the synthesis of collagen while suppressing MMPs. Turmeric’s curcumin, sulforaphane from cruciferous vegetables, tomato’s and watermelon’s lycopene once again regulate MMP activity. Garlic, onions, soy foods like tofu, and yogurt- and fermented food-borne probiotics all suppress MMP. Pomegranate, also ellagic acid-containing, also inhibits tissue degradation. Incorporating these foods into a balanced diet may reduce the risk for diseases related to uncontrolled MMP activity, such as arthritis, cardiovascular disease, and cancer formation.
Conclusion
The intricate interplay between MMPs and ECM molecules like collagen and elastin is at the heart of tissue homeostasis. While necessary remodeling processes are facilitated by MMPs, their dysregulation underlies many pathological states. Research into the structural and functional characteristics of MMP-substrate interactions remains promising for the development of targeted therapies to control ECM remodeling in disease.
