Hyaluronic Acid

Other common names

Hyaluronan, Hyaluronate

What is The History of Hyaluronic Acid?

Hyaluronic acid has gone from obscurity to skin hero in only a short number of years. In 1934, Karl Meyer and John Palmer discovered a new glycosaminoglycan (GAG) when examining the glue-like substance in the eyes of cows. They named it ‘hyaluronic acid’. Over the decades, scientists found this substance in other organs (joints, skin, rooster comb, human umbilical cord, etc.) and other tissues (connective, epithelial, and nervous). Not only is Hyaluronic acid (HA) found in all mammal tissues but can also be produced via microbial fermentation (using Streptococcus zooepidemicus, Escherichia coli, Bacillus subtilis).

There are many glycosaminoglycans in the human body. They are complex polyanionic polysaccharides located on the surface of all cells and in the cellular matrix. Hyaluronic acid is the simplest of theses glycosaminoglycans and it plays an essential role in the body’s regulatory activities with respect to epidermal proliferation and for its ability to retain water. 

Despite the simplicity of its composition, it has been found to have a great number of biological functions. It not only functions as a biological glue that participates in lubricating joints or holding together gel-like connective tissues, but it also functions as a micro-environmental signal that co-regulates cell behaviour during embryonic development and morphogenesis, wound healing, repair, and regeneration.

The quantity of hyaluronic acid in the skin gradually decreases due to ageing. This ageing is accelerated by UV damage, smoking, poor diet and nutritional deficiencies, and environmental pollutions. For example, a person in their 70’s has only a quarter of the amount of hyaluronic acid in their skin compared to a 19-year-old person.

Because the turnover for the skin is said to be about 28 days, functionality and preservation of our skin through oral ingestion of hyaluronic acid, will require long-term continuous intake to replenish supplies and activate skin regeneration receptors and genes.

RECOGNISED TARGETS AND MECHANISM OF ACTION

Hyaluronic acid (HA) is a body component that is present in every connective tissue and organ, such as skin, synovial fluid, blood vessels, serum, the brain, cartilage, heart valves, and the umbilical cord. In particular, the skin has the largest quantity of hyaluronic acid in the body, containing 50% of total body levels.

SKIN ACTIVITY

• Interacts with receptors, enzymes, and many other biomolecules.
• Contributes to cell proliferation, migration, and morphogenesis.
• Binds to three main classes of cell surface receptors: CD44 (a membrane glycoprotein), receptor for hyaluronate-mediated motility (RHAMM), and Intercellular Adhesion Molecule 1 (ICAM-1), which all perform different functions.
• Inhibits signal transduction through CD44 and RHAMM hyaluronic acid receptors.
• Augments the production of nitric oxide (NO) in a CD44-dependent mechanism.
• Binds: lymphatic vessel endothelial hyaluronan receptor (LYVE-1), and hyaluronic acid receptor for endocytosis (HARE) - also known as Stabilin-2.
• Maintains cellular viscoelasticity and enhances lubricating potential.
• Restores rheological properties and metabolism of fibroblasts.
• Scavenges ROS/RNS and exerts antioxidative effects.
• Reduces production of MMPs (MMP-1, MMP-3, and MMP-13).
• Reduces production and activity of IL-1β, and other pro-inflammatory mediators.
• Inhibits synthesis of PGE2 and bradykinin.
• Mitigates synovial hypertrophy and increases the number of synovial fibroblast-like cells, while decreasing macrophages, lymphocytes, mast cells and adipocytes.
• Enhances synthesis of chondrocytes and proteoglycan.
• Interacts with hyaluronic acid receptors on or around the free nerve endings, producing analgesic activity.

JOINT ACTIVITY

• Inhibits the expression of u-PA, PAI-1, u-PAR, and MMPs in chondral, meniscal, and synovial cultures of early osteoarthritis.
• Decreases cytokines, leptin, and Bradykinin in synovial fluid and serum of osteoarthritis patients.
• Ameliorates IL-1β-induced gene expression of matrix degrading enzyme (MMP1, MMP13, ADAMTS5), inflammatory mediators (IL6, PTGS2) by human osteoarthritis chondrocytes and synovial fibroblasts.
• Inhibits phosphorylation of cell signalling molecules (JNK, p38, and NF-κB).
• Inhibits expression of ADAMTS4 (aggrecanase-1) in human osteoarthritis chondrocytes.
• Inhibits PPAR-γ mRNA expression and exerts anti-chondroptosis to prevent cartilage degeneration.
• Suppresses IL-1β-induced-transcriptional activity of type α2(VI) collagen.
• Exerts anti-Fas-induced apoptosis in human chondrocytes through interaction with CD44 and CD54 (ICAM1).
• Influences multiple receptors, proteins and signalling pathways.
• Increases RANKL expression in bone marrow stromal cells through CD44 receptor to improve bone metabolism.
• Inhibits expression of u-PA, PAI-1, u-PAR, and MMPs in synovial fibroblasts of osteoarthritic joints.
• Reduces nitric oxide, superoxide, hydroxyl radicals, and PGE2 to reduce cell damage.
• Protects mitochondria from oxidative stress, and chondrocytes from apoptosis.
• Increases cAMP in synovial fluid to enhance repair and protection.
• Inhibits osteoclast differentiation via Toll-like receptor 4.

WOUND HEALING ACTIVITY

• Assists regulation of keratinocyte proliferation in response to extracellular stimuli and to maintain local hyaluronic acid homeostasis.
• Plays an important biological role in skin and mucosal wound healing by influencing inflammation, granulation, and re-epithelialisation.
• Regulates thrombin-induced formation of fibrin clots, which decreases the lag time before clotting and increases the rate of clot formation.
• Stimulates mesenchymal cell migration.
• Stimulates HAS-2 enzyme synthesis expression.
• Regulates water balance, osmotic pressure and ion flow and functions as a sieve, excluding certain molecules, enhancing the extracellular domain of cell surfaces and stabilising skin structures by electrostatic interactions.

ANTI-CANCER ACTIVITY

• Serves a general function in receptor tyrosine kinase (RTK) activation.
• The use of hyaluronic acid alone or in combination with established agents (doxorubicin, taxol, vincristine, methotrexate, imatinib, gemcitabine, cisplatin, 5-fluorouracel) seems to be a promising new avenue for anticancer therapeutics.

 

* These statements have not been evaluated by the FDA or TGA. This product is not intended to diagnose, treat, cure or prevent any disease.

Front Vet Sci. 2019; 6: 192. Published online 2019 Jun 25. doi: 10.3389/fvets.2019.00192 Hyaluronic Acid: Molecular Mechanisms and Therapeutic Trajectory. Ramesh C. Gupta, Rajiv Lall, Ajay Srivastava, and Anita Sinha

Clin Cosmet Investing Dermatol. 2017; 10: 267–273. Published online 2017 Jul 18. doi: 10.2147/CCID.S141845 Oral hyaluronan relieves wrinkles: a double-blinded, placebo-controlled study over a 12-week period. Mariko Oe, Seigo Sakai, Hideto Yoshida, Nao Okado, Haruna Kaneda, Yasunobu Masuda, and Osamu Urushibata

Experimental and Therapeutic Medicine. Published online: July 12, 2010 (Pages: 817-827) Evaluation of the effects of a supplementary diet containing chicken comb extract on symptoms and cartilage metabolism in patients with knee osteoarthritis. Authors: Isao Nagaoka, Kunihiro Nabeshima, Saya Murakami, Tetsuro Yamamoto, Keita Watanabe, Akihito Tomonaga, Hideyo Yamaguchi

Hyaluronic Acid, a Promising Skin Rejuvenating Biomedicine: A Review of Recent Updates and Pre-clinical and Clinical Investigations on Cosmetic and Nutricosmetic Effects September 2018 International Journal of Biological Macromolecules 120(Pt B) DOI:10.1016/j.ijbiomac.2018.09.188 Projects: Biomaterials for Drug Delivery Pharmaceutical Viability of Biomaterials

Dermatoendocrinol. 2012 Jul 1; 4(3): 253–258. doi: 10.4161/derm.21923. Hyaluronic acid: A key molecule in skin aging. Eleni Papakonstantinou,  Michael Roth, and George Karakiulakis