Discovering MMPs and their role in skin aging

From the age of 25, the first signs of aging begin to appear on the surface of the skin. Fine lines come into sight and, over time, wrinkles, loss of hydration and elasticity are perceived in the skin. The unavoidable process of aging has always been attributed to exogenous factors such as exposure to ultraviolet (UV) radiation, pollution, and chemicals. Nowadays, it is well known that skin aging is influenced by a combination of exogenous and endogenous factors such as genetics and cellular metabolism. Among all the endogenous factors involved, there is a family of enzymes mostly unknown despite their important role during skin aging (1,2).

MMPs contribute to skin wrinkling, a characteristic of premature skin aging


The matrix metalloproteinase enzymes (MMPs) appeared for the first time in studies concerning the process of metamorphosis in frogs. As tadpoles were able to reabsorb their tails, scientists supposed the existence of enzymes that could degrade collagen. Ever since matrix metalloproteinases (MMPs) have been widely studied for their ability to degrade most components of the extracellular matrix (ECM). The ECM is a complex network of collagen, basement membrane, and elastin fibers secreted by keratinocytes and fibroblasts, located in the dermis, where its primary function is to provide structural integrity and a “youthful” appearance to the skin (3,4).

Collagen appearance before (a) and after (b) exposure to MMPs.

(Fligiel, S. et al., 2002)


There is a large variety of proteolytic targets for MMPs. These include cell surface molecules, pericellular proteins, and proteins present in the ECM. The degradation of these molecules allows MMPs to play an important role in biological functions in both healthy and pathological conditions. Under normal physiological conditions, MMPs are involved in many different processes such as embryonic growth, tissue morphogenesis, skeletal growth, remodeling, and wound healing. Moreover, impaired regulation of MMPs by tissue inhibitors of metalloproteinases (TIMPs) causes pathological conditions such as chronic wounds, tumor invasion, fibrosis, and dermal aging (4–6).


It is assumed that around 80% of skin aging is caused by UV exposure, which induces MMPs expression in human skin cells (MMP-1, MMP-2, and MMP-9) in both epidermis and dermis. Although the exact mechanism responsible for MMPs expression in response to acute UV radiation is not fully understood, it is widely accepted that UV exposure causes the generation of reactive oxygen species (ROS) such as superoxide anion and hydrogen peroxide. ROS stimulates the increased expression of MMPs by skin cells and, therefore, the degradation of collagen and elastin fibers in the extracellular matrix. Evidence of this process is the inevitable formation of fine lines and wrinkles as clinical manifestations of skin aging when there are alterations in collagen and elastin fiber in the ECM (7–9).


UV radiation and the accumulation of damage over time promote protease (MMPs) production, leading to a loss of ECM structure and organization. (Rodriguez, S. et al., 2017)



Because MMPs expression is directly related to oxidative stress and ROS production in cells, natural products with antioxidant activity appear to be our best option to fight MMPs action in our skin. These natural products include polyphenols and carotenoids with antioxidant, anti-inflammatory, photoprotective, or anticarcinogenic properties. Example of specific MMPs inhibitor is the extract from Polypodium leucotomos, which is rich in polyphenols that directly inhibit the activity and expression of MMPs; another important natural compound is the carotenoid lutein that reduces proliferation of mutated keratinocytes and inhibition of MMP expression in ultraviolet radiation-exposed fibroblasts; and xanthohumol, a flavonoid, which directly inhibits MMPs and promotes collagen synthesis in dermal fibroblasts (10).

Now that you know that MMPs are directly involved in skin aging. Are you properly taking care of your skin? Remember that protecting yourself from UV exposure and eating healthy food high in antioxidants will reduce the generation of reactive oxygen species and consequently, the degradation of collagen by MMPs.


References

1. Tu, Y. & Quan, T. Oxidative Stress and Human Skin Connective. 1–12 (2016). doi:10.3390/cosmetics3030028

2. Apte, S. S. & Parks, W. C. Metalloproteinases : A parade of functions in matrix biology and an outlook for the future. Matrix Biol. 4446, 1–6 (2015).

3. Nguyen, T. T., Mobashery, S. & Chang, M. Roles of Matrix Metalloproteinases in Cutaneous Wound Healing. in Wound Healing- New insights into ancient challenges (2016).

4. Ravanti, L. & Kähäri, V. Matrix metalloproteinases in wound repair ( Review ). Int. J. Mol. Med. 6, 391–407 (2000).

5. Caley, M. P., Martins, V. L. C. & Toole, E. A. O. Metalloproteinases and Wound Healing. 4, 225–234 (2015).

6. Rodrigues, M., Kosaric, N., Bonham, C. A. & Gurtner, G. C. Wound Healing : A cellular perspective. Physiol. ’Rev 99, 665–706 (2019).

7. Freitas-Rodríguez, S., Folgueras, A. R. & López-Otín, C. The role of matrix metalloproteinases in aging : Tissue remodeling and. BBA - Mol. Cell Res. 1864, 2015–2025 (2017).

8. Pittayapruek, P., Meephansan, J., Prapapan, O. & Komine, M. Role of Matrix Metalloproteinases in Photoaging and Photocarcinogenesis. (2016). doi:10.3390/ijms17060868

9. Freitas-rodríguez, S., Folgueras, A. R. & López-otín, C. BBA - Molecular Cell Research The role of matrix metalloproteinases in aging : Tissue remodeling and. BBA - Mol. Cell Res. 1864, 2015–2025 (2017).

10. Philips, N., Auler, S., Hugo, R. & Gonzalez, S. Beneficial Regulation of Matrix Metalloproteinases for Skin Health. 2011, (2011).

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