Hyaluronic Acid: What It Is and How It Works

Hyaluronic acid is one of the key molecules of connective tissue: it fills the joint fluid, retains water in the skin, and creates the "framework" of the intercellular space. It is injected into joints, used in cosmetology, and in recent years increasingly sold in capsules for oral use. The editorial team explains what this substance is and how it works.

What hyaluronic acid is

Hyaluronic acid (hyaluronan, sodium hyaluronate in its salt form) is a linear polysaccharide from the glycosaminoglycan group. Its molecule consists of repeating disaccharide units: D-glucuronic acid and N-acetyl-D-glucosamine. There can be thousands of such units in the chain, so the molecular weight reaches several million daltons.

Unlike other glycosaminoglycans — chondroitin sulfate or keratan sulfate — hyaluronic acid is not sulfated and not attached to a protein core. It is synthesized by hyaluronan synthase enzymes directly on the cell membrane, and it is "pushed out" into the intercellular space.

The main physical property of hyaluronan is its ability to bind a huge amount of water. In solution, the molecule forms a loose coil that occupies a large volume and creates a viscous, elastic gel. This is precisely what provides cushioning and lubrication in tissues.

The body of an adult contains about 15 g of hyaluronic acid, and it is constantly renewed: according to a review by Fraser and colleagues (1997), approximately one-third of the total pool is turned over daily. It is broken down by hyaluronidase enzymes and free radicals, and the fragments are processed mainly in the lymph nodes and liver.

Where it works in the body

The most hyaluronic acid is contained in the skin — about half of the total reserve. Here it retains moisture in the dermis, maintains elasticity, and participates in wound healing. With age, its synthesis in the skin decreases, which is one of the factors in the appearance of dryness and wrinkles.

In the joints, hyaluronan is the main component of synovial fluid, giving it viscosity. It works as a lubricant during slow movements and as a shock absorber under impact loads. In cartilage, hyaluronic acid forms a "backbone" to which aggrecan molecules attach, forming giant aggregates that retain water.

In addition to its mechanical role, hyaluronan is a signaling molecule. It binds to CD44, RHAMM, and other receptors on the cell surface and affects their migration, division, and inflammatory reactions. These functions are described in detail in reviews by Toole (2004) and Stern and colleagues (2006).

In osteoarthritis, the concentration and molecular weight of hyaluronan in the synovial fluid decrease, and the fluid becomes less viscous. It is this fact that became the basis for intra-articular injections of hyaluronic acid preparations — so-called viscosupplementation.

Molecular weight: why it matters

One of the most interesting features of hyaluronan is the dependence of its biological effects on chain length. High-molecular-weight forms (over a million daltons), characteristic of healthy tissues, predominantly have an anti-inflammatory and "protective" effect, preserving the integrity of the matrix.

Low-molecular-weight fragments, which form when tissues are damaged and inflamed, on the contrary, can act as an alarm signal and stimulate inflammatory responses. Stern and colleagues (2006) described this system as "information-rich": the size of the fragment is a kind of message to the cells.

For supplements, this has practical significance: manufacturers indicate the molecular weight of the raw material, and different studies used products with different weights. Therefore, the results of one preparation cannot be automatically transferred to another.

At the same time, it is important not to overestimate this difference for supplements: after oral use, hyaluronan is largely broken down in the intestine, so it is no longer the same molecules that were in the capsule that reach the tissues.

What happens with oral use

For a long time it was believed that the large polar hyaluronan molecule cannot be absorbed from the intestine. A study by Balogh and colleagues (2008) with labeled high-molecular-weight hyaluronic acid showed that, after oral administration in rats and dogs, the radioactive label appeared in the blood and accumulated in connective tissues, in particular in the joints and skin.

Later work, in particular by Kimura and colleagues (2016), showed that a significant part of hyaluronan is broken down by the intestinal microbiota into oligosaccharides that can be absorbed. It is hypothesized that the fragments act as signaling molecules — through receptors in the intestine and the immune system — rather than simply "delivering" hyaluronic acid to the joint.

Thus, the mechanism of action of oral hyaluronan has still not been definitively clarified. Most likely, it is indirect: through an effect on local inflammatory processes and stimulation of its own synthesis in tissues, rather than through direct replenishment of reserves.

Clinically, oral hyaluronic acid has been studied mainly in two directions: for pain in the knee joints (osteoarthritis) and for skin hydration. The results are moderately positive but based on a small number of studies, often funded by manufacturers. More on the evidence base in a separate article.

Methods of use and the limits of knowledge

Hyaluronic acid is used in medicine and consumer products in several forms, and they differ significantly in evidence and risks:

• Intra-articular injections— a medical procedure for osteoarthritis; performed only by a doctor.
• Dermal fillers— cosmetic injections with cross-linked hyaluronic acid.
• Eye drops— for dry eye syndrome.
• Creams and serums— surface hydration of the skin.
• Dietary supplements— capsules, tablets, liquids for oral use.

Even regarding joint injections, professional guidelines are not unanimous: the recommendations of OARSI (2019) and the American College of Rheumatology (2020) assess viscosupplementation cautiously due to the heterogeneity of study results. For oral supplements, the evidence base is even more modest.

A common feature of all forms is good tolerability: hyaluronic acid is a natural component of the body, and oral supplements rarely caused adverse events in studies. However, "naturalness" does not exempt one from attention to product quality and individual restrictions.

Open questions remain about the optimal molecular weight for supplements, the duration of use, and the effect in young healthy people and athletes without joint diseases.

Editorial conclusions

Hyaluronic acid is a natural polysaccharide, critically important for joint lubrication, cartilage structure, and skin hydration.

Its biological effects depend on molecular weight, and oral use probably acts indirectly — through fragments and signaling pathways, rather than through direct replenishment of reserves in tissues.

Clinical data on supplements are moderately positive but limited in scope, so expectations should be realistic.

We also recommend reading our articles "Benefits of Hyaluronic Acid for Athletes: The Evidence Base," "How to Take Hyaluronic Acid: Dosage, Timing, Duration," and "Hyaluronic Acid Side Effects."

References

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2. Toole BP. Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer. 2004;4(7):528–539.
3. Stern R, Asari AA, Sugahara KN. Hyaluronan fragments: an information-rich system. Eur J Cell Biol. 2006;85(8):699–715.
4. Balogh L, Polyak A, Mathe D, et al. Absorption, uptake and tissue affinity of high-molecular-weight hyaluronan after oral administration in rats and dogs. J Agric Food Chem. 2008;56(22):10582–10593.
5. Kimura M, Maeshima T, Kubota T, et al. Absorption of orally administered hyaluronan. J Med Food. 2016;19(12):1172–1179.
6. Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage. 2019;27(11):1578–1589.
7. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Rheumatol. 2020;72(2):220–233.