Molecular Madness

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Hyaluronic Acid is the most ubiquitous glycosaminoglycan (GAG) in the skin, an important component of the extracellular matrix, surrounding and supporting cells within the tissue architecture. This sugar polymer consists of repeating disaccharides of D-glucuronic acid and N-acetyl-D-glucosamine, linked together via glycosidic bonds (1). Primarily produced by dermal fibroblasts, and to a lesser extent within the epidermal keratinocyte (2), HA is involved in tissue wound repair, immune surveillance, cell migration, as well as acting as a molecular chaperone for a family of proteins known as hyaldherins (3) (4). HA is most famously known as a humectant, with myriad hydroxyl groups on its chemical structure able to bind to water molecules, keeping the skin hydrated, lubricated, and plump.

As we age, the amount of HA synthesized in our skin starts to decline, leading to a disproportionate portfolio of GAGs secreted, as well as the reduced proliferation of fibroblasts (5). This, of course, is one of the numerous reasons we experience cutaneous aging (6) (7). Naturally, our industry was inclined to find ways to supplement the HA we lose over time, and so cosmetic suppliers provided us with topical HA and promised miracles would occur, touting it as an anti-aging holy grail. The truth, however, is much less exciting than that. Topically applied HA is far too large of a molecule to penetrate an intact Stratum Corneum, though interesting evidence does exist showing cutaneous HA penetration independent of molecular mass (8) (9).

The value that topical HA provides to the skin is really two-fold – water retention, keeping the surface of your skin hydrated and happy, as well as acting as a pseudo-barrier, supporting the repair of a damaged Stratum Corneum due to a variety of external (and internal) aggressors.

Understanding the limitations topical HA has regarding replenishment of the naturally produced HA in the skin, and its decline over time, the “clever” (or not so clever) industry chemists decided to fragment the large HA polymer (HMW-HA) into smaller pieces (LMW-HA), to facilitate better delivery into the skin. This is where the disconnect between scientific evidence and industry/brand marketers begins. To be fair, the molecular language in the literature is rather complex to understand, even for seasoned physicians.

While the various molecular weights share some similarities as it relates to hydration, their biological functions in the skin are radically different. Under normal, physiological conditions, the native HA that is synthesized in your skin is always of high molecular weight (>1,000 kDa), supporting skin homeostasis and the stability of the skin architecture. The ONLY time you will find low molecular weight fragments of HA in the skin is subsequent to injury, and there is good reason for this. Upon injury, the amount of HA synthesis ramps up, as does frantic enzymatic activity (hyaluronidases).

These enzymes are designed to catabolize the large HA polymer into smaller pieces, where they act as a biofeedback mechanism within the damaged tissue, triggering the alarm system of inflammation (10). Upon fragmentation, the low-weight HA interacts with pattern-recognition receptors on cell surfaces, known as TLR-2 & TLR-4, or Toll-like Receptors. This receptor activation is the “on” switch for the built-in alarm system, with subsequent recruitment of pro-inflammatory cytokines, macrophages (11), and defensins (12) to the area of injury. This is the very definition of inflammation.

While HMW-HA is known to attenuate the inflammatory response, LMW-HA is a potent trigger of inflammation and is known to promote fibrotic collagen deposition (13) (14). It is important to remember that when we discuss inflammation in this context, it does not mean the skin will be red, angry, and visibly inflamed. Sub-clinical inflammation underneath the skin can produce seemingly “positive” cosmetic benefits since inflammation-mediated edema can make your skin plump (something these brands and suppliers touting LMW-HA are banking on).

So, while these small-weight HA fragments do penetrate the skin, they are, unfortunately, a potent stimulus for inflammation. When we know definitively that inflammation is anathema to anti-aging, does it make any logical sense that exposing the skin to repeat inflammatory insults can somehow produce an opposite response? The answer is no, and the reams of evidence within the scientific literature support this (15) (16). There is no excuse here, and science will win over-glorified sensationalism any day. In the words of my friend and mentor, world-renowned physician/researcher, Dr. Lance Setterfield, when it comes to the topical use of LMW-HA, it’s about time we “stop defending the indefensible”. I couldn’t agree more.

(1) Weissmann B, Meyer K. The structure of hyalobiuronic acid and of hyaluronic acid from umbilical cord. J Am Chem Soc. 1954;76:1753–7.

(2) Malaisse J, Pendaries V, Hontoir F, De Glas V, Van Vlaender D, Simon M, Lambert de Rouvroit C, Poumay Y, Flamion B. Hyaluronan Does Not Regulate Human Epidermal Keratinocyte Proliferation and Differentiation. J Biol Chem. 2016 Mar 18;291(12):6347-58.

(3) Toole BP. Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer. 2004 Jul;4(7):528-39.

(4) Dowthwaite GP, Edwards JCW, Pitsillides AA. An Essential Role for the Interaction Between Hyaluronan and Hyaluronan Binding Proteins During Joint Development. Journal of Histochemistry & Cytochemistry. 1998;46(5):641-651.

(5) Matuoka K, Hasegawa N, Namba M, Smith GJ, Mitsui Y. A decrease in hyaluronic acid synthesis by aging human fibroblasts leading to heparan sulfate enrichment and growth reduction. Aging (Milano). 1989 Sep;1(1):47-54.

(6)Tzellos TG, Klagas I, Vahtsevanos K, Triaridis S, Printza A, Kyrgidis A, Karakiulakis G, Zouboulis CC, Papakonstantinou E. Extrinsic ageing in the human skin is associated with alterations in the expression of hyaluronic acid and its metabolizing enzymes. Exp Dermatol. 2009 Dec;18(12):1028-35.

(7)Meyer LJ, Stern R. Age-dependent changes of hyaluronan in human skin. J Invest Dermatol.1994 Mar;102(3):385-9.

(8) Essendoubi, Mohammed & Gobinet, Cyril & Reynaud, Romain & Angiboust, Jean-François & Manfait, M & Piot, Olivier. (2015). Human skin penetration of hyaluronic acid of different molecular weights as probed by Raman spectroscopy. Skin Research and Technology. 22.10.1111/srt.12228.

(9) Brown TJ, Alcorn D, Fraser JR. Absorption of hyaluronan applied to the surface of intact skin. J Invest Dermatol. 1999 Nov;113(5):740-6.

(10) Krasiński R, Tchórzewski H. Hialuronian jako czynnik regulujacy proces zapalenia [Hyaluronan-mediated regulation of inflammation]. Postepy Hig Med Dosw (Online). 2007 Nov 19;61:683-9.

(11) Rayahin JE, Buhrman JS, Zhang Y, Koh TJ, Gemeinhart RA. High and low molecular weight hyaluronic acid differentially influence macrophage activation. ACS Biomater Sci Eng. 2015 Jul 13;1(7):481-493.

(12) Gariboldi S, Palazzo M, Zanobbio L, Selleri S, Sommariva M, Sfondrini L, Cavicchini S, Balsari A, Rumio C. Low molecular weight hyaluronic acid increases the self-defense of skin epithelium by induction of beta-defensin 2 via TLR2 and TLR4. J Immunol. 2008 Aug 1;181(3):2103-10.

(13) Petrey AC, de la Motte CA. Hyaluronan, a crucial regulator of inflammation. Front Immunol. 2014 Mar 11;5:101.

(14) Zgheib C, Xu J, Liechty KW. Targeting Inflammatory Cytokines and Extracellular Matrix Composition to Promote Wound Regeneration. Adv Wound Care (New Rochelle). 2014;3(4):344-355.

(15) Ruppert SM, Hawn TR, Arrigoni A, Wight TN, Bollyky PL. Tissue integrity signals communicated by high-molecular weight hyaluronan and the resolution of inflammation. Immunol Res. 2014;58(2-3):186-192.

(16) Papakonstantinou E, Roth M, Karakiulakis G. Hyaluronic acid: A key molecule in skin aging. Dermatoendocrinol. 2012;4(3):253-258.

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