Collagen or Hyaluronic acid: what's the difference

Collagen and hyaluronic acid are often advertised together — “for joints and skin”. Both substances really are key components of connective tissue, but in chemistry, function and behaviour in the digestive tract they differ radically. Our editorial team explains what exactly sets them apart and what this means for the supplement user.

Protein versus polysaccharide: the chemical difference

Collagen is a protein, the most abundant in the human body. Its molecule consists of three polypeptide chains twisted into a triple helix. Its amino acid composition is unusual: roughly every third amino acid is glycine, and there is also a lot of proline and hydroxyproline, which are scarce in other proteins.

More than two dozen types of collagen are known. Type I predominates in skin, bones and tendons, type II in articular cartilage, type III in vessels and loose connective tissue. Supplements most often use hydrolysed collagen (collagen peptides) from bovine, porcine or fish raw material, as well as undenatured type II collagen.

Hyaluronic acid (hyaluronan) is an entirely different compound. It is not a protein but a long linear polysaccharide, built from repeating disaccharide units of glucuronic acid and N-acetylglucosamine. The molecular mass of natural hyaluronan can reach millions of daltons.

The main physicochemical property of hyaluronic acid is its ability to bind and retain a large amount of water, forming viscous gels. This is precisely why it is called a natural tissue “moisturiser”. For supplements, hyaluronan obtained by bacterial fermentation or from rooster combs, of various molecular mass, is used.

So collagen is a structural protein with a strong fibrous structure, while hyaluronic acid is a gel-forming polysaccharide that fills the space between fibres and cells.

Roles in the body: framework and “moisturiser”

Collagen fibres form the mechanical framework of connective tissue. They provide tensile strength to tendons and ligaments, elasticity of the skin, and the structure of the bone matrix and cartilage. Without full-value collagen, tissues become fragile — this is clearly seen in the example of scurvy, when a deficiency of vitamin C impairs collagen maturation.

Hyaluronic acid performs other tasks. In synovial fluid it provides the viscosity and lubrication of joint surfaces; in cartilage it is part of large aggregates with aggrecan that retain water and cushion loads. In the skin, hyaluronan maintains the hydration of the dermis.

The turnover of these substances also differs. Collagen in tendons and bones is renewed slowly, whereas hyaluronan has a very rapid turnover: according to review papers, a significant part of the body's hyaluronic acid is broken down and synthesised anew every day.

Metaphorically, collagen can be compared to rebar and hyaluronic acid to a gel that fills the space and holds water. Both components are needed, but they do not replace one another.

What happens to the supplement after swallowing

Collagen taken orally, like any protein, is digested into amino acids and short peptides. Some di- and tripeptides, in particular those containing hydroxyproline (for example, prolyl-hydroxyproline), appear in the blood after intake of a hydrolysate. The hypothesis is that such peptides may serve as a signal for fibroblasts and chondrocytes, and also supply “raw material” for the synthesis of the body's own collagen.

It is important to understand: collagen from a supplement is not “built into” the skin or cartilage in finished form. The body breaks it into parts and uses them at its own discretion. So the effect depends on overall protein nutrition, vitamin C and the mechanical load on the tissues.

Hyaluronic acid taken orally also does not reach the joint as a whole large molecule. It is partly broken down by gut bacteria into smaller fragments that can be absorbed. The mechanism of a possible effect of the oral form is explained by indirect effects, but it has been studied less thoroughly than for collagen.

The situation with injectable hyaluronic acid is fundamentally different: intra-articular injections (viscosupplementation) and dermal fillers are medical procedures, and they cannot be equated with capsules.

The evidence base: joints, skin, tendons

For collagen peptides there is a series of randomised trials. In the 24-week study by Clark and colleagues (2008) in athletes with activity-related joint pain, taking a collagen hydrolysate was accompanied by a reduction in pain compared with placebo. Proksch and colleagues (2014) reported an improvement in skin elasticity in women after taking specific collagen peptides.

For sports medicine the work by Shaw and colleagues (2017) is of interest: gelatin enriched with vitamin C an hour before a short bout of exercise raised a marker of collagen synthesis in the blood. This supports the idea of taking collagen before rehabilitation exercises for tendons, although clinical outcomes still need confirmation.

For oral hyaluronic acid there are fewer data, and the studies are mostly small and often sponsored by manufacturers. There are randomised works, for example by Oe and colleagues (2017), where hyaluronan intake was linked to a reduction in wrinkles, as well as small studies in knee pain.

As for the injectable form in osteoarthritis, the guidelines diverge: OARSI (2019) gives limited support for intra-articular hyaluronan, while the American College of Rheumatology (2019) conditionally recommends against it in knee osteoarthritis.

Safety and product quality

Both supplements have a favourable safety profile. Collagen is a dietary protein, so side effects are usually limited to a feeling of heaviness in the stomach or an unpleasant aftertaste. People allergic to fish should avoid marine collagen, and those who follow religious or ethical restrictions should pay attention to the animal source.

It is worth remembering that collagen is an incomplete protein: it contains virtually no tryptophan and little leucine. So collagen peptides do not replace whey or other complete protein for muscle growth.

Oral hyaluronic acid is usually well tolerated. Injectable forms, however, have their own procedure-related risks: pain, swelling, rarely infections, and in the case of fillers vascular complications, so they are performed only by qualified doctors.

As for quality, it is worth paying attention to the stated source, the type of collagen, the dosage in grams for collagen and the molecular mass for hyaluronan, as well as the presence of independent laboratory control.

Editorial conclusions

Collagen and hyaluronic acid are different classes of substance: a protein that gives tissues strength, and a polysaccharide that retains water and provides lubrication.

In the digestive tract both are broken down, so it is impossible to “deliver” them to a joint or the skin unchanged; the possible effects are linked to bioactive fragments and signals for the body's own synthesis.

The evidence base for collagen peptides is broader than for oral hyaluronic acid, but in both cases the effects are moderate.

For the practical choice, read our article “Collagen vs Hyaluronic acid: what to choose and for whom”, as well as pieces on vitamin C for connective tissue and on tendon rehabilitation.

References

1. Fraser JRE, Laurent TC, Laurent UBG. Hyaluronan: its nature, distribution, functions and turnover. J Intern Med. 1997;242(1):27–33.
2. Clark KL, Sebastianelli W, Flechsenhar KR, et al. 24-Week study on the use of collagen hydrolysate as a dietary supplement in athletes with activity-related joint pain. Curr Med Res Opin. 2008;24(5):1485–1496.
3. Proksch E, Segger D, Degwert J, et al. Oral supplementation of specific collagen peptides has beneficial effects on human skin physiology: a double-blind, placebo-controlled study. Skin Pharmacol Physiol. 2014;27(1):47–55.
4. Shaw G, Lee-Barthel A, Ross ML, et al. Vitamin C-enriched gelatin supplementation before intermittent activity augments collagen synthesis. Am J Clin Nutr. 2017;105(1):136–143.
5. Oe M, et al. Oral hyaluronan relieves wrinkles: a double-blinded, placebo-controlled study over a 12-week period. Clin Cosmet Investig Dermatol. 2017;10:267–273.
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 Care Res. 2020;72(2):149–162.