Hyaluronic Acid: The Body's Water-Holding Molecule

Table of Contents

1. 1. What Hyaluronic Acid Is
2. 2. How the Body Makes and Breaks Down Hyaluronic Acid
3. 3. Where Hyaluronic Acid Is Found in the Body
4. 4. Molecular Size and Why It Matters
5. 5. Is Hyaluronic Acid an Antioxidant?
6. 6. Discovery and History
7. 7. Forms Used in Medicine and Cosmetics
8. 8. Food Sources and the Body’s Own Production
9. 9. Benefits
10. Key Research Papers
11. Connections

1. What Hyaluronic Acid Is

Hyaluronic acid belongs to a family of long sugar chains called glycosaminoglycans. Its chain is a single repeating pair of sugars, a disaccharide, joined end to end: D-glucuronic acid linked to N-acetyl-D-glucosamine, then the next pair, and the next, with no side branches (Stern 2006; Fallacara 2018).

The second sugar in that pair is a close relative of glucosamine, the amino sugar every cell makes from glucose. When hyaluronic acid is broken down inside cells, glucuronic acid and a glucosamine derivative are released back into the cell for other uses (Stern 2004). That is why hyaluronic acid sits on this site next to glucosamine, among the amino-acid derivatives: the nitrogen in its amino sugar comes, through the hexosamine pathway, from the amino acid glutamine.

Hyaluronic acid is the odd one out among its relatives. The other glycosaminoglycans, such as chondroitin sulfate and heparin, carry sulfate groups, are assembled in the cell’s Golgi apparatus and are attached to a protein core. Hyaluronic acid has no sulfate, is not attached to a protein, and is made at the inner face of the cell’s outer membrane (Fraser 1997; Fallacara 2018).

Its best-known property is how it behaves in water. Even at concentrations below 1 milligram per millilitre, the long chains tangle into a network, which gives hyaluronic acid solutions their unusual thick, slippery and springy flow (Laurent 1996). That network holds water in tissues and lets joint fluid both lubricate and absorb shock.

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2. How the Body Makes and Breaks Down Hyaluronic Acid

Making it: three hyaluronan synthases

Mammals have three enzymes that build hyaluronic acid, called hyaluronan synthases HAS1, HAS2 and HAS3 (Itano 1999; Triggs-Raine 2015). Each one sits in the cell membrane and adds the two activated sugars, UDP-glucuronic acid and UDP-N-acetylglucosamine, one after the other to a growing chain (Itano 1999). Both activated sugars are made from glucose inside the cell.

The three enzymes are not interchangeable. In laboratory tests HAS3 made shorter chains than HAS1 and HAS2, and in cultured cells HAS2 made extremely large hyaluronic acid, averaging more than 2 million daltons (Itano 1999). HAS2 is essential: mouse embryos with no working HAS2 die with heart defects, and one person with HAS2 deficiency had heart disease. Too much HAS2 activity is behind the deep skin folds of shar-pei dogs and is found in the naked mole rat (Triggs-Raine 2015).

Breaking it down: hyaluronidases

Hyaluronic acid is broken down by enzymes called hyaluronidases. Three are named in humans, HYAL1, HYAL2 and HYAL3 (Triggs-Raine 2015). In the pathway described by Stern, the chain is caught by a cell-surface receptor called CD44, cut by HYAL2 and HYAL1 into smaller and smaller pieces, and finished inside the cell’s lysosomes by two more enzymes that free the individual sugars (Stern 2004). People born without working HYAL1, a rare condition called mucopolysaccharidosis IX reported in four people, have joint disease as the main feature (Triggs-Raine 2015). Reactive oxygen species are the second route of breakdown, alongside the enzymes (Fallacara 2018).

A fast turnover

Stern’s review states that “there are 15 g of hyaluronan in the 70-kg individual, of which 5 g are cycled daily” (Stern 2004), and Fallacara repeats both figures (Fallacara 2018). Fraser and colleagues describe a tissue half-life ranging from less than a day to several days. Hyaluronic acid is broken down where it is made, or carried by lymph to the lymph nodes, which degrade much of it; what reaches the blood is cleared within minutes, mainly by the liver (Fraser 1997). One review estimates half-lives of about a day in skin and up to 70 days in the vitreous of the eye, citing earlier work (Fallacara 2018).

The balance between making and breaking matters in disease. In knee synovium from people with osteoarthritis and rheumatoid arthritis, the messages for HAS1 and HAS2 were lower, and for HYAL2 higher, than in healthy donors. The authors offer this as one possible reason the joint fluid in these diseases holds less hyaluronic acid, in smaller chains (Yoshida 2004).

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3. Where Hyaluronic Acid Is Found in the Body

Hyaluronic acid is found in every vertebrate tissue and body fluid, and in some bacteria; it is especially abundant in loose connective tissue (Fraser 1997). Four places stand out:

• Skin. “Approximately 50% of the total HA resides in the skin,” according to a 2018 review (Fallacara 2018). The measured figure comes from rats, where more than half of the body’s hyaluronic acid was in the skin, about a quarter in the skeleton and supporting tissues, and less than a tenth in muscle (Reed 1988).
• Joints. Hyaluronic acid is a major component of synovial tissue and fluid (Laurent 1996), at about 3 to 4 milligrams per millilitre of synovial fluid (Fallacara 2018). It is what makes healthy joint fluid thick and slippery.
• The eye. The vitreous, the clear gel filling the eyeball, holds about 0.1 milligram per millilitre (Fallacara 2018). It was in the vitreous that hyaluronic acid was first found.
• The umbilical cord. The jelly of the cord is rich in it, which made umbilical cords one of the early sources for extraction (Fallacara 2018).

Whether the skin loses hyaluronic acid with age is less settled than often stated. When Meyer and Stern measured skin taken at autopsy across all ages, they found no significant change in the concentration or the chain size of hyaluronic acid with age. What changed was how tightly it was held in the tissue: the tightly bound fraction rose from 7% in fetal skin to 23% in the skin of the oldest people (Meyer 1994). Later reviews describe a decline of skin hyaluronic acid with age (Papakonstantinou 2012). Both findings are reported on Hyaluronic Acid for Skin.

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4. Molecular Size and Why It Matters

Hyaluronic acid is not one fixed molecule but a chain of any length, and its length changes what it does. In the body the chains can be enormous: Stern and colleagues give a top figure of 2 × 10⁴ kilodaltons, about 20 million daltons (Stern 2006), and rat skin hyaluronic acid, corrected for breakdown during extraction, was estimated at several million daltons (Reed 1988). Sources differ on the very top figure, but all agree the native molecule runs into the millions of daltons.

Stern’s group describes hyaluronic acid as an “information-rich system” because size acts as a signal (Stern 2006; Stern 2004):

• Large chains fill space, hold water, slow the growth of new blood vessels and calm the immune system.
• Small fragments, produced when tissue is injured or inflamed, do the opposite: they are inflammatory, stimulate the immune system and promote new blood vessels, acting as an internal “danger signal”.
• Very small pieces, such as tetrasaccharides of four sugars, were reported to protect cells from programmed cell death.

Reviews of wound biology describe the same split, with high-molecular-weight hyaluronic acid anti-inflammatory and low-molecular-weight hyaluronic acid pro-inflammatory (Litwiniuk 2016). This is why products are described by their molecular weight, why trials compare “low” and “high” molecular weight forms, and why a broken-down chain in an inflamed joint is not simply a smaller version of a healthy one.

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5. Is Hyaluronic Acid an Antioxidant?

Only in a limited, laboratory sense. In test tubes hyaluronic acid reacts with the hydroxyl radical, and high-molecular-weight hyaluronic acid protected cultured cells from hydroxyl-radical damage better than smaller chains (Presti 1994). Low-molecular-weight preparations scavenged several radicals in the test tube and, given by mouth to immunosuppressed mice, raised the activity of antioxidant enzymes (Ke 2011). The two studies disagree about which size works better.

In inflamed joints, reactive oxygen species break hyaluronic acid down, so it acts more as a target that is used up than as an antioxidant that is recycled (Soltés 2006). The 2018 review states that an antioxidant role “has only been hypothesized, as it is not sufficiently supported by experimental data” (Fallacara 2018). No human trial was found that measured hyaluronic acid as an antioxidant, which is why it is not grouped with vitamin C, vitamin E, glutathione and the other classic antioxidants. The full account is on Hyaluronic Acid as an Antioxidant.

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6. Discovery and History

In 1934 Karl Meyer and John W. Palmer, published “The polysaccharide of the vitreous humor” in the Journal of Biological Chemistry (Meyer 1934). According to the 2018 review by Fallacara and colleagues, they isolated it from the vitreous of cow eyes, found that it contained an amino sugar and a uronic acid, and named it from “hyaloid” (vitreous) and “uronic acid” (Fallacara 2018).

The same review traces the story both earlier and later (Fallacara 2018):

• 1880: Portes described a substance in the vitreous that he called “hyalomucine”.
• 1934: Meyer and Palmer isolate and name hyaluronic acid from the vitreous.
• 1930s to 1950s: it is also isolated from human umbilical cord, rooster comb and streptococcal bacteria.
• 1979: Balazs produces the first pharmaceutical-grade hyaluronic acid, from rooster combs and umbilical cords.

Balazs went on to describe hyaluronic acid solutions as viscoelastic devices for eye surgery, used to protect delicate tissue and hold space during cataract, vitreoretinal, glaucoma and corneal transplant operations (Balazs 2008). From there it spread into joint injections, eye drops, wound dressings, cosmetic fillers and skin creams.

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7. Forms Used in Medicine and Cosmetics

Hyaluronic acid for medical and cosmetic use was first extracted from rooster combs and umbilical cords and is now also made by bacterial fermentation (Fallacara 2018). The products differ mainly in chain size and in whether the chains are chemically cross-linked, which makes them last longer in the body. The main forms studied are:

• Joint injections (viscosupplementation), injected into the knee or other joints with osteoarthritis; some products are cross-linked (Rutjes 2012). The evidence is on Hyaluronic Acid for Joints.
• Dermal fillers, usually cross-linked gels injected into the skin of the face.
• Creams, lotions and serums, in low- and high-molecular-weight versions.
• Oral capsules and drinks, studied in trials of skin and knee comfort.
• Eye drops, as sodium hyaluronate artificial tears for dry eye.
• Surgical viscoelastic gels used during eye operations (Balazs 2008).
• Wound dressings and topical agents for chronic ulcers.

The research on each, including the safety findings and the disputed question of whether swallowed hyaluronic acid reaches the skin and joints intact, is covered in the four Benefits articles below.

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8. Food Sources and the Body’s Own Production

Hyaluronic acid occurs in animal connective tissues. Rooster comb and other animal tissues are the traditional sources from which it has been extracted (Fallacara 2018), and the same tissues end up in slow-cooked foods made from bones, skin and joints.

One laboratory study looked at a chicken-and-vegetable bone broth. It found a fraction of the broth containing both hyaluronic acid and chondroitin sulfate; in rats with bone loss after removal of the ovaries, the whole broth and that fraction raised bone mineral density, and the fraction slowed the formation of bone-resorbing cells in culture (Seki 2024). That is an animal and cell study about bone. It did not measure how much hyaluronic acid the broth contains or whether eating it raises hyaluronic acid in human skin or joints, and no verified figures for the hyaluronic acid content of foods were found.

The larger source is the body itself, which makes its own hyaluronic acid every day from glucose-derived sugars (Itano 1999; Stern 2004). Vitamin C is often mentioned alongside it in skin products, but vitamin C’s documented role is in building collagen, the protein that hyaluronic acid surrounds in the skin, not in building hyaluronic acid.

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9. Benefits

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Key Research Papers

1. Meyer K, Palmer JW. The polysaccharide of the vitreous humor. J Biol Chem. 1934;107(3):629-634. DOI: 10.1016/S0021-9258(18)75338-6
2. Fraser JR, Laurent TC, Laurent UB. Hyaluronan: its nature, distribution, functions and turnover. J Intern Med. 1997;242(1):27-33. PubMed PMID: 9260563
3. Laurent TC, Laurent UB, Fraser JR. The structure and function of hyaluronan: An overview. Immunol Cell Biol. 1996;74(2):A1-7. PubMed PMID: 8724014
4. Stern R. Hyaluronan catabolism: a new metabolic pathway. Eur J Cell Biol. 2004;83(7):317-25. PubMed PMID: 15503855
5. Stern R, Asari AA, Sugahara KN. Hyaluronan fragments: an information-rich system. Eur J Cell Biol. 2006;85(8):699-715. PubMed PMID: 16822580
6. Reed RK, Lilja K, Laurent TC. Hyaluronan in the rat with special reference to the skin. Acta Physiol Scand. 1988;134(3):405-11. PubMed PMID: 3227957
7. Itano N, Sawai T, Yoshida M, Lenas P, Yamada Y, Imagawa M, Shinomura T, Hamaguchi M, Yoshida Y, Ohnuki Y, Miyauchi S, Spicer AP, McDonald JA, Kimata K. Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties. J Biol Chem. 1999;274(35):25085-92. PubMed PMID: 10455188
8. Triggs-Raine B, Natowicz MR. Biology of hyaluronan: Insights from genetic disorders of hyaluronan metabolism. World J Biol Chem. 2015;6(3):110-20. PubMed PMID: 26322170
9. Fallacara A, Baldini E, Manfredini S, Vertuani S. Hyaluronic Acid in the Third Millennium. Polymers (Basel). 2018;10(7):701. PubMed PMID: 30960626
10. Yoshida M, Sai S, Marumo K, Tanaka T, Itano N, Kimata K, Fujii K. Expression analysis of three isoforms of hyaluronan synthase and hyaluronidase in the synovium of knees in osteoarthritis and rheumatoid arthritis by quantitative real-time reverse transcriptase polymerase chain reaction. Arthritis Res Ther. 2004;6(6):R514-20. PubMed PMID: 15535829
11. Meyer LJ, Stern R. Age-dependent changes of hyaluronan in human skin. J Invest Dermatol. 1994;102(3):385-9. PubMed PMID: 8120424
12. Papakonstantinou E, Roth M, Karakiulakis G. Hyaluronic acid: A key molecule in skin aging. Dermatoendocrinol. 2012;4(3):253-8. PubMed PMID: 23467280
13. Litwiniuk M, Krejner A, Speyrer MS, Gauto AR, Grzela T. Hyaluronic Acid in Inflammation and Tissue Regeneration. Wounds. 2016;28(3):78-88. PubMed PMID: 26978861
14. Presti D, Scott JE. Hyaluronan-mediated protective effect against cell damage caused by enzymatically produced hydroxyl (OH.) radicals is dependent on hyaluronan molecular mass. Cell Biochem Funct. 1994;12(4):281-8. PubMed PMID: 7834818
15. Ke C, Sun L, Qiao D, Wang D, Zeng X. Antioxidant acitivity of low molecular weight hyaluronic acid. Food Chem Toxicol. 2011;49(10):2670-5. PubMed PMID: 21787831
16. Soltés L, Mendichi R, Kogan G, Schiller J, Stankovska M, Arnhold J. Degradative action of reactive oxygen species on hyaluronan. Biomacromolecules. 2006;7(3):659-68. PubMed PMID: 16529395
17. Balazs EA. Hyaluronan as an ophthalmic viscoelastic device. Curr Pharm Biotechnol. 2008;9(4):236-8. PubMed PMID: 18691081
18. Rutjes AW, Jüni P, da Costa BR, Trelle S, Nüesch E, Reichenbach S. Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Ann Intern Med. 2012;157(3):180-91. PubMed PMID: 22868835
19. Seki Y, Ohkuma RC, Miyakawa Y, Karakida T, Yamamoto R, Yamakoshi Y. Hyaluronan and chondroitin sulfate in chicken-vegetable bone broth delay osteoporosis progression. J Food Sci. 2024;89(3):1791-1803. PubMed PMID: 38317402

PubMed Topic Searches

1. PubMed: Hyaluronan synthases
2. PubMed: Hyaluronan turnover and breakdown
3. PubMed: Hyaluronan size and inflammation
4. PubMed: Hyaluronan and skin aging

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Connections

• Hyaluronic Acid Benefits: What the Research Shows
• Hyaluronic Acid for Skin
• Hyaluronic Acid for Joints
• Hyaluronic Acid for Eyes and Wound Healing
• Hyaluronic Acid as an Antioxidant
• Amino Acid Derivatives
• Glucosamine
• Collagen
• Redox Cofactors and the Body’s Own Antioxidants
• Vitamin C and Collagen Synthesis
• Tremella for Skin and Hydration
• Silicon
• Osteoarthritis
• Dry Eye Disease
• Bone Broth

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