Nature's Corner Newsletter

A: Hyaluronic acid

Hyaluronic acid (also called hyaluronan or hyaluronate) is a glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is one of the chief components of the extracellular matrix, contributes significantly to cell proliferation and migration, and may also be involved in the progression of some malignant tumors.

Hyaluronic acid has been nicknamed by the press as the "key to the fountain of youth" because it has been noted that at least some people who ingest a lot of it in their diets tend to live to ripe old ages. ABC News had a show on a village in Japan and hyaluronic acid entitled, "The Village of Long Life: Could Hyaluronic Acid Be an Anti-Aging Remedy?". (It should be noted that the people in the ABC news show were thought to get high amounts of HA from starchy root vegetables their natural diets. They were not taking supplements.)

While a number of studies have linked abnormal levels of HA to either connective tissue disorders (CTDs) or conditions common in CTDs, such as premature aging, there are also a number of studies on Pubmed noting associations of high levels of HA to some forms of cancer. With HA as with other substances in the human body, such as estrogen and cholesterol, there are most likely optimal levels, and disease often occurs when these levels become out of range in either direction. Low estrogen levels have been linked to bone loss, while high estrogen levels have been associated with breast cancer. High cholesterol levels have been linked to heart attacks and stroke, while low levels have been linked to bleeding problems and depression. HA has been studied less than either cholesterol or estrogen, but the prudent path would be to assume that the body has optimal levels of HA, as it does for cholesterol, estrogen and many other substances.

In multiple sclerosis, a version of the hyaluronic acid builds up around lesions.

Larry Sherman, a scientist at the Oregon Health and Sciences University, believes that the presence of hyaluronic acid somehow interrupts the repair process when the coating of nerve cells (myelin) is damaged.

Sherman and other scientists are researching how to eliminate the molecules of hyaluronic acid from the areas of MS disease activity to encourage nerve cells to repair themselves.

There is a paradox of sorts when dealing with injections versus oral supplements. Many people would much rather take an oral supplement than have an injection administered. However, the efficacy of injections has been proven to a greater extent than oral supplements.

Part of the reason hyaluronic acid is so effective is that it has a very large molecular weight, which reflects its ability to hold water, and thus its great moisturizing power. When HA is injected, the absorption of the heavy HA molecules is easily taken care of – which is not necessarily the case when oral HA supplements are taken.

Many scientists agree that the stomach has a hard time absorbing the heavy HA molecules. One source from the University of Connecticut Medical School explained, “Hyaluronic acid itself is not absorbed but possibly some of its derivatives are when taken orally and therefore its use at this point is limited to an injectable form.”

Meanwhile, several commercial sites that boast chemically enhanced HA molecules for oral supplementation, which have a lower molecular weight, and thus will have an easier time being absorbed.

The paradox is that these oral supplements may be safer than injections, and the HA will have an easier time being absorbed – but – if you lose the molecular weight, you lose much of the efficacy so unique to HA. After reviewing the potential side effect of injections with a doctor, many people may come to the conclusion that injections offer the greatest potential solution.

Studies show improvement in for most participants after only 2 to 4 months of oral supplementation, and some patients are able to decrease their dose after the desired results are achieved.

There have been no serious side effects associated with HA, although some people find that their skin is irritated at the injection site, and there have been rare reports of oral supplements causing rashes and skin irritation as well.

A controlled study reported that males taking 600 mg per day of hyaluronic acid for four weeks had higher blood levels of the enzyme alkaline phosphatase (liver). The significance of this finding is unclear, although elevated liver levels are associated with liver damage, such as cirrhosis.

As such, it is always prudent to consult your doctor before you decide to take HA or any other type of supplement to make sure it is an appropriate treatment for your particular health condition.

Hyaluronic Acid and Connective Tissue Disorders

The list below contains links to a sample of the studies where subjects with connective tissue disorders have been shown to have hyaluronic acid (HA) abnormalities:

Ehlers-Danlos syndrome

Marfan syndrome

Osteogenesis imperfecta

Stickler syndrome

Not surprisingly, these disorders all have a lot of overlapping features, and many of these overlapping features, when studied individually, are also linked to hyaluronic acid abnormalities. In every study for connective tissue disorders that examined hyaluronic acid, the levels were always abnormal in patients with connective tissue disorders.

In human and animal studies, hyaluronic acid abnormalities occur in:

Heart valves with MVP
TMJ
Joint instability
Osteoarthritis
Detached retinas
Muscle contractures
Rachitic skeletal features (pectus excavatum, pectus carinatum, scoliosis, bowed limbs, hypermobility, etc.)
Glaucoma
Keratoconus
Poor scar formation (fetuses do not scar because of the high content of HA in amniotic fluid)
Acrogeria (prematurely wrinkled skin)
Fibromyalgia
Premature aging syndromes* (which share many features with connective tissue disorders, especially Ehlers-Danlos)

Hyaluronic acid, or commercial preparations containing hyaluronic acid, are in use, or being studied to be used, to prevent, treat or aid in the surgical repair for many the types of problems people with connective tissue disorders tend to have such as:

Fractures
Hernias
Glaucoma
Keratoconus
Detached retinas
Osteoarthritis (HA injections are the new breakthrough treatment for this condition)
Muscle contractures
TMJ
Prevents scarring
Vocal cord insufficiency
Wrinkled skin
Cartilage damage
Wound healing
Ligament Healing

The list below contains a partial list of common features of several connective tissue disorders. Both the syndromes and the individual features of the syndrome (even when the individual features are studied in the general population, not just in people with genetic disorders), all have links to hyaluronic acid abnormalities.

Syndrome with hyaluronic acid abnormalities	*Features linked to both* the syndrome and hyaluronic acid abnormalities**
Ehlers-Danlos syndrome	mitral valve prolapse, prematurely wrinkled skin, pectus excavatum, pectus carinatum, scoliosis, bowed limbs, hypermobility, keratoconus, hernias, poor wound healing, joint instability, TMJ, contractures, osteoarthritis, fractures
Osteogenesis imperfecta	mitral valve prolapse, pectus excavatum, pectus carinatum, scoliosis, keratoconus, fractures, bowed limbs, hernias
Stickler syndrome	mitral valve prolapse, keratoconus, pectus excavatum, pectus carinatum, scoliosis, osteoarthritis, hypermobility, bowed limbs
Marfan syndrome	mitral valve prolapse, scoliosis, pectus excavatum, pectus carinatum, osteoarthritis, keratoconus, hypermobility, bowed limbs, hernias, detached retinas, glaucoma

Since the ABC special on hyaluronic acid called it the "Fountain of Youth", it is interesting that one of the defining characteristics of premature aging syndromes, such as Progeria, is hyaluronic acid abnormalities.

Hyaluronic Acid and Environmental Factors

There are many factors known to influence hyaluronic acid levels. Genes are likely to be a factor, but there are many environmental factors that are known to have an impact, including zinc and magnesium availability. Not surprisingly, magnesium and zinc deficiencies are known to be associated with many of the same symptoms associated with hyaluronic acid abnormalities, such as mitral valve prolapse and poor wound healing, respectively. Perhaps this is because the zinc or magnesium deficiency contributes to the hyaluronic acid abnormality, which in turn causes the symptom.

There are a multitude of studies on Medline regarding hyaluronic acid and a wide variety of environmental factors. Here is a sample of some of the interesting ones that relate to connective tissue disorders:

Hyaluronic acid becomes abnormally elevated in the skin of swine who have zinc deficiencies. Magnesium is needed for hyaluronic acid synthesis. Perhaps a lack of magnesium is one of the factors in some connective tissue disorders. Magnesium supplementation is an established treatment for many of the symptoms of connective tissue disorders, such as fibromyalgia, mitral valve prolapse and contractures.

Ascorbic acid can degrade hyaluronic acid. Estrogen treatment increases activity of hyaluronic acid. Estrogen is known to increase utilization of nutrients like magnesium and zinc - nutrients that are known to affect hyaluronic acid levels. Cigarette smoke is known to degrade hyaluronic acid.

In a study of rats, hyaluronic acid turnover and metabolism were affected by age, dietary composition, and caloric intake. If what rats ate affected their hyaluronic acid levels, then this may be a good clue that diet may well affect hyaluronic levels in humans, too. In another study on rats, hyaluronic acid deposition in rat cerebellum is affected by thyroid deficiency, thyroxine treatment and undernutrition. In a study of humans, hyaluronic acid levels were altered by physical activity and food ingestion.

In a study on rats, skin hyaluronic acid concentration was higher than normal in energy deficiency, but below normal levels in prolonged protein deficiency. In rats suffering from prolonged malnutrition, the collagen concentrations are reduced. (Reduced collagen concentrations are also found in some of the connective tissue disorders such as osteogenesis imperfecta, as are a plethora of other conditions also associated with hyaluronic acid abnormalities. Not surprisingly, zinc deficits are known to affect hyaluronic acid levels. In a study on rats, among other symptoms, a deficiency in zinc resulted in impaired collagen synthesis.)

Strep and staph bacteria emit an enzyme called hyaluronidase. Hyaluronidase is an enzyme which breaks down hyaluronic acid, thus allowing an entry point for the bacteria to enter the body. This may be why people may become hypermobile or develop heart aliments like mitral valve prolapse after illnesses such as rheumatic fever--because the hyaluronic acid in their connective tissue has been degraded by the bacteria that causes their illness.

If animals that are genetically similar to humans such as rats can have reduced collagen levels and hyaluronic acid abnormalities from changes in their diets, then it would be logical to consider diet as a causative factor in people with the hyaluronic acid abnormalities.

Functions

Until the late 1970s, hyaluronan was described as a "goo" molecule, a ubiquitous carbohydrate polymer that is part of the extracellular matrix. For example, hyaluronan is a major component of the synovial fluid and was found to increase the viscosity of the fluid. Along with lubricin, it is one of the fluid's main lubricating components.

While it is abundant in extracellular matrices, hyaluronan also contributes to tissue hydrodynamics, movement and proliferation of cells, and participates in a number of cell surface receptor interactions, notably those including its primary receptor, CD44. Upregulation of CD44 itself is widely accepted as a marker of cell activation in lymphocytes. Hyaluronan's contribution to tumor growth may be due to its interaction with CD44. CD44 participates in cell adhesion interactions required by tumor cells.

Although hyaluronan binds to CD44, there are evidence to support that hyaluronan degradation products transduce their inflammatory signal through Toll-like receptor 2 (TLR2), TLR4 or both TLR2 and TLR4 in macrophages and dendritic cells. TLR and hyaluronan play a role in innate immunity.

Structure

The chemical structure of hyaluronan was determined in the 1950s in the laboratory of Karl Meyer. Hyaluronan is a polymer of disaccharides themselves composed of D-glucuronic acid and D-N-acetylglucosamine, linked together via alternating beta-1,4 and beta-1,3 glycosidic bonds. Polymers of hyaluronan can range in size from 10² to 10⁴ kDa in vivo.

Hyaluronan is energetically stable in part because of the stereochemistry of its component disaccharides. Bulky groups on each sugar molecule are in sterically favored positions while the smaller hydrogens assume the less favorable axial positions.

Synthesis

Hyaluronan is synthesized by a class of integral membrane proteins called hyaluronan synthases, of which vertebrates have three types: HAS1, HAS2, and HAS3. These enzymes lengthen hyaluronan by repeatedly adding glucuronic acid and N-acetylglucosamine to the nascent polysaccharide.

Degradation

Hyaluronan is degraded by a family of enzymes called hyaluronidases. In humans, there are at least seven types of hyaluronidase-like enzymes, several of which are tumor suppressors. The degradation products of hyaluronan, the oligosaccharides and very low molecular weight hyaluronan, exhibit pro-angiogenic properties. In addition, recent studies showed that hyaluronan fragments, not native high molecular mass of hyaluronan, can induce inflammatory responses in macrophages and dendritic cells in tissue injury and in skin transplant rejection.

Medical applications

Hyaluronan is naturally found in many tissues of the body such as skin, cartilage, and the vitreous humor. It is therefore well suited to biomedical applications targeting these tissues. The first hyaluronan biomedical product, Healon, was developed in the 1970s and 1980s and is approved for use in eye surgery (i.e. corneal transplantation, cataract surgery, glaucoma surgery and surgery to repair retinal detachment). Other biomedical companies also produce brands of hyaluronan for ophthalmic surgery.

Hyaluronan is also used to treat osteoarthritis of the knee. Such treatments are administered as a course of injections into the knee joint and are believed to supplement the viscosity of the joint fluid thereby lubricating the joint, cushioning the joint and producing an analgesic effect. It has also been suggested that hyaluronan has positive biochemical effects on cartilage cells. However, some placebo controlled studies have cast doubt on the efficacy of hyaluronan injections and hyaluronan is recommended primarily as a last alternative to surgery.

Due to its high biocompatibility and its common presence in the extracellular matrix of tissues, hyaluronan is gaining popularity as a biomaterial scaffold in tissue engineering research.

In some cancers, hyaluronan levels correlate well with malignancy and poor prognosis. Hyaluronan is thus often used as a tumor marker for prostate and breast cancer. It may also be used to monitor the progression of the disease.

Hyaluronan may also be used postoperatively to induce tissue healing, notably after cataract surgery. Current models of wound healing propose that larger polymers of hyaluronic acid appear in the early stages of healing to physically make room for white blood cells, which mediate the immune response.

Cosmetic application

In 2003 the FDA has approved hyaluronan injections for filling soft tissue defects such as facial wrinkles. Restylane is a common trade name for the product. Hyaluronan injections temporarily smooth wrinkles by adding volume under the skin, with effects typically lasting for six months.

Many companies have begun selling hyaluronic acid (as well as chondroitin sulfate and glucosamine) as a vastly overpriced, nutritional supplement that is supposed to have curative properties against arthritis, cancer, and other ailments. The idea is that the supplements will help your body replace worn out cartilage. The problems with this supposition are: first, our digestive tracts are very good at breaking large molecules down into their subunits, and tend to absorb only the subunits preferentially; second, hyaline cartilage is an avascular tissue, that is, it doesn't get its nutrients directly from the bloodstream; and third, a functional extracellular matrix must be synthesized by the cells to have the right properties, and cartilage cells prefer to use unmodified sugars - like glucose and galactose - to synthesize its own precursors.

Etymology

Hyaluronic acid is derived from hyalos (Greek for vitreous) and uronic acid because it was first isolated from the vitreous humor and possesses a high uronic acid content.

The term hyaluronate refers to the conjugate base of hyaluronic acid. Because the molecule typically exists in vivo in its polyanionic form, it is most commonly referred to as hyaluronan.

Use caution when using any form of hyaluronic acid, especially if allergic to any sources (beef, chicken, horse, swine, etc....) used in the manufacturing process and/or if a person suffers from a connective tissue disorder.