The Multi-Faceted Benefits of Hyaluronic Acid
The Multi-Faceted Benefits of Hyaluronic Acid
By Chris D. Meletis, ND on 31/10/2009
Last month, we introduced a new highly bioavailable form of hyaluronic acid (HA) that provides the most effective delivery system available for this nutrient. This month, we will focus on the many ways that this high molecular weight HA lozenge can contribute to overall health.
HA is ubiquitous throughout the body, the highest amounts being found in the extracellular matrix of soft connective tissues such as synovial fluid (joint lubricant), vitreous fluid in the eyes, and in the skin. It is involved in several key processes, including cell signaling, wound repair and regeneration, morphogenesis, and matrix organization.1 As a fundamental component that helps maintain cellular structure and function, HA acts as a lubricant, an antioxidant, a shock absorber during weight bearing, and a cushion to protect against physical trauma. The fact that HA is so important in so many aspects of health makes it particularly unfortunate that the levels of HA decline with advancing age.
HA supplementation can make up for age-related deficiencies of this nutrient. Research has shown success with HA supplementation in inflammatory processes in areas such as rheumatology, ophthalmology, dermatology, and dentistry, as described below.
HA has been used in osteoarthritis for more than 30 years. Many studies have documented the long-lasting pain-relieving effects of intra-articular supplementation with HA in subjects with knee osteoarthritis, a procedure that was approved by the FDA in 1997.2
Oral supplementation with HA also shows promising results as seen in a recent study. This placebo-controlled trial enrolled 20 male and female subjects aged 40 years and older with knee osteoarthritis (pain for at least 15 days in the previous month and symptoms present for at least 6 months) who were randomized to oral supplementation of HA or placebo.3 At the end of the study period, HA-treated participants experienced a greater decrease in total symptom scores based on a standardized osteoarthritis index, compared with placebo after just 8 weeks (-18.6 vs -15.8). There was also a greater magnitude of pain relief in the HA-treated group compared with placebo (11.1 vs. 2.2) as well as a significant improvement in physical component summary scores (6.1 vs. 3.6). The researchers also observed that the HA group needed half the amount of pain rescue medication (500 mg acetaminophen capsules) compared with the placebo group during the study. In addition, compared with placebo, more HA subjects perceived improvement in joint pain (75 percent vs. 50 percent) and muscle aches (75 percent vs. 38 percent). The researchers concluded that oral HA “was useful to enhance several markers of quality of life in adults with osteoarthritis of the knee.”
The impressive results seen with oral HA supplementation may be particularly advantageous in elderly subjects in whom osteoarthritis-related pain results in a serious limitation of activities of daily living.3 Oral supplementation also has obvious advantages over intra-articular HA by avoiding potential complications at the injection site and discomfort associated with repeated injections.4
Clinical studies have confirmed anti-inflammatory, anabolic, and cartilage-protective actions of HA in reducing pain and improving patient function.5 HA appears to have a stimulatory effect on the metabolism of chondrocytes (cells found in the cartilage) through its interaction with CD44 receptors.6
Researchers have speculated this could lead to permanent improvement of cartilage with oral supplementation, which can elevate plasma HA concentrations over a long time period.3
A growing body of evidence also indicates that mitochondrial dysfunction and DNA damage play a causal role in disorders such as osteoarthritis that are linked to excessive generation of free radicals. Pretreatment of chondrocytes with HA has been shown to enhance their survival by decreasing mitochondrial damage and enhancing DNA repair capacity and cell viability, while preserving ATP levels and ameliorating apoptosis.7
Furthermore, studies have shown that the concentration and level of HA decline significantly in inflammatory arthritis,8 which can be counteracted with high molecular weight HA supplementation. This measure has proved effective in promoting chondrocyte HA and proteoglycan synthesis, reducing the production of substances that break down collagen such as proinflammatory mediators and enzymes called matrix metalloproteinases (MMPs), and maintaining joints in good condition.8
Temporomandibular Joint (TMJ) Syndrome
As with osteoarthritis, the level of HA is significantly lower in the synovial fluid from patients with inflammation of the temporomandibular joint, which connects the jaw to the skull.9 Hyaluronic acid has a natural affinity for joint tissue. In one study, the intra-articular administration of sodium hyaluronate into the temporomandibular joint in patients with Wilkes stage II disease (a classification used to define TMJ severity according to 5 stages) showed better efficacy in reducing pain and improving joint function compared with the oral administration of pain-relief tablets.10
Promoting Healthy Skin
In 2003, the FDA approved hyaluronic acid injections for filling soft tissue defects such as facial wrinkles. HA and collagen are both vital components of skin tissue. However, there is a progressive reduction in the number of hyaluronic acid granules in human skin, deteriorating to a complete absence in individuals over 60. It is believed these variations account for the decreased turgidity, wrinkled appearance, and altered elasticity of skin tissue.11 The regulation of major skin cells known as fibroblasts is central to both healing and scarring processes. Laboratory studies show that supplementing fibroblasts with HA causes a significant increase in their ability to renew skin tissue, resulting in increased proliferation within the collagen matrix.12
The anti-inflammatory effects of HA also carry important implications for collagen regeneration in maintaining healthy skin. The cutaneous benefits of HA can be seen in studies where it has been shown to block IL-1b, a cytokine that inhibits collagen biosynthesis at the transcriptional level.13 IL-1 also inhibits the expression of insulin-like growth factor-1, a highly potent stimulator of collagen synthesis, while HA counteracts this process.14 HA also suppresses MMP-1, which preferentially breaks down major components of collagen in the skin,15 and reduces levels of an inflammatory chemokine called RANTES16. Both processes are mediated partly by the interaction of HA with its receptor called CD4416 that is found in abundance in the oral mucosa, making the use of an HA lozenge particularly useful for maintaining healthy skin.
The effectiveness of HA also extends to skin disorders such as oral lichen planus (OLP), a common inflammatory disease of the skin and mouth. In a study of 124 patients with oral lichen planus, HA significantly reduced soreness scores compared with placebo for up to 4 hours.17 Patients treated for up to 28 days with HA showed a significant reduction in the size of the erosive/ulcerated area compared with baseline. The researchers concluded that HA may be a “useful addition to the treatment option for OLP.”
In the above study, HA was used in direct contact with the mucus membranes. A 30 mg lozenge provides an ideal delivery system for this type of use since it delivers more HA for equal or longer periods of time to target tissues.
Managing Ocular Health
Another important body system where HA distribution declines dramatically with aging is in human eye tissue.18 Researchers have speculated that this decline may play a role in age-related ocular disorders.18
UV light is the most common cause of radiation injury to the eye. While the cornea absorbs most UVB light to protect the inner eye, exceeded threshold levels induce corneal inflammation (photokeratitis). UVB light also triggers different signaling cascades that cause apoptosis of corneal cells. However, researchers have recently shown for the first time that high molecular weight HA protects human corneal epithelial cells against UVB-induced apoptosis as well as decreasing UVB-induced release of the proinflammatory mediators IL-6 and IL-8.19 Corneal cells express CD44 receptors on their plasmic membranes, which is a specific point of interaction for HA. It is believed that this may be a key factor in understanding how HA protects against UVB radiation.19 HA supplementation can also be useful to people with dry eyes as well as people suffering eye discomfort after computer use.20-22
Maintaining a Healthy Oral Cavity
Another emerging benefit for the use of HA is in the treatment of plaque-induced gingivitis. HA has shown anti-inflammatory and antibacterial effects in both gingivitis and periodontitis. It is important to remember that oral disease processes contribute to cardiovascular disease and total inflammatory burden in the body, including elevated C-reactive protein, and the condition of the mouth and gums is therefore important to overall health. Due to its tissue-healing properties, HA may be a useful adjunct in diseases of the oral cavity.23-24 The availability of HA in a lozenge preparation, which is well absorbed across the oral mucosa, enhances its effectiveness for optimizing dental hygiene.
HA has also been shown to be of benefit in recurrent aphthous ulcers, or canker sores, which are painful open sores inside the mouth or upper throat caused by breaks in the mucous membrane.25 In addition, in vivostudies show that sodium hyaluronate effectively accelerates the healing process after tooth extraction by stimulating the expression of bone-forming proteins.26
Another oral condition that may cause difficulties in speech and eating as well as increasing the susceptibility of periodontal tissue to infection is known as xerostomia, or dry mouth, which is a common complaint in the elderly. Elderly patients with dry mouth, not caused by any history of connective tissue disease, have been shown to have lower HA levels in their saliva compared with age-matched controls.27 Oral use of hyaluronic acid improved hyposalivation and unpleasant oral complaints associated with dry mouth.28
HA is a vital component of cellular structure and offers a multitude of benefits including anti-inflammatory and antioxidant effects, pain-relief, joint lubrication and cartilage-protection, collagen regeneration, and enhancement of cell viability. Most of these actions are mediated via the HA-specific CD44 receptor present on endothelial, epithelial, and smooth muscle cell membranes. Since HA declines naturally with age, oral HA supplementation with a new lozenge offers an efficient alternative, which is well absorbed through the highly vascularized oral mucosa that is rich in CD44 receptors. As a result, oral HA supplementation offers an effective solution for joint protection, maintaining healthy skin and eyes, and is a useful adjunct for good dental hygiene.
- Volpi N, Schiller J, Stern R, Soltés L. Role, metabolism, chemical modifications and applications of hyaluronan. Curr Med Chem. 2009;16(14):1718-1745.
- Sun SF, Chou YJ, Hsu CW, Chen WL. Hyaluronic acid as a treatment for ankle osteoarthritis. Curr Rev Musculoskelet Med. 2009 Mar 13.
- Kalman DS, Heimer M, Valdeon A, Schwartz H, Sheldon E. Effect of a natural extract of chicken combs with a high content of hyaluronic acid (Hyal-Joint) on pain relief and quality of life in subjects with knee osteoarthritis: a pilot randomized double-blind placebo-controlled trial. Nutr J. 2008 Jan 21;7:3.
- Adams ME, Lussier AJ, Peyron JG. A risk-benefit assessment of injections of hyaluronan and its derivatives in the treatment of knee osteoarthritis. Drug Saf. 2000;23:115-130.
- Strauss EJ, Hart JA, Miller MD, Altman RD, Rosen JE. Hyaluronic Acid Viscosupplementation and Osteoarthritis: Current Uses and Future Directions. Am J Sports Med. 2009 Feb 3.
- Akmal M, Singh A, Anand A, et al. The effects of hyaluronic acid on articular chondrocytes. J Bone Joint Surg Br. 2005;87:1143-1149.
- Grishko V, Xu M, Ho R, et al. Effects of hyaluronic acid on mitochondrial function and mitochondria-driven apoptosis following oxidative stress in human chondrocytes. J Biol Chem. 2009 Apr 3;284(14):9132-9139.
- Matsuno H, Nakamura H, Katayama K, et al. Effects of an oral administration of glucosamine-chondroitin-quercetin glucoside on the synovial fluid properties in patients with osteoarthritis and rheumatoid arthritis. Biosci Biotechnol Biochem. 2009 Feb;73(2):288-292.
- Takahashi T, Tominaga K, Takano H, et al. A decrease in the molecular weight of hyaluronic acid in synovial fluid from patients with temporomandibular disorders. J Oral Pathol Med. 2004 Apr;33(4):224-229.
- Oliveras-Moreno JM, Hernandez-Pacheco E, Oliveras-Quintana T, Infante-Cossio P, Gutierrez-Perez JL. Efficacy and safety of sodium hyaluronate in the treatment of Wilkes stage II disease. J Oral Maxillofac Surg. 2008 Nov;66(11):2243-2246.
- Ghersetich I, Lotti T, Campanile G, Grappone C, Dini G. Hyaluronic acid in cutaneous intrinsic aging. Int J Dermatol. 1994 Feb;33(2):119-122.
- Greco RM, Iocono JA, Ehrlich HP. Hyaluronic acid stimulates human fibroblast proliferation within a collagen matrix. J Cell Physiol. 1998 Dec;177(3):465-473.
- Karna E, Miltyk W, Pałka JA, Jarzabek K, Wołczyński S. Hyaluronic acid counteracts interleukin-1-induced inhibition of collagen biosynthesis in cultured human chondrocytes. Pharmacol Res. 2006 Oct;54(4):275-281.
- Nawrat P, Surazyński A, Karna E, Pałka JA. The effect of hyaluronic acid on interleukin-1-induced deregulation of collagen metabolism in cultured human skin fibroblasts. Pharmacol Res. 2005 May;51(5):473-477.
- Pageon H, Bakala H, Monnier VM, Asselineau D. Collagen glycation triggers the formation of aged skin in vitro. Eur J Dermatol. 2007 Jan-Feb;17(1):12-20.
- Tanaka M, Masuko-Hongo K, Kato T, Nishioka K, Nakamura H. Suppressive effects of hyaluronan on MMP-1 and RANTES production from chondrocytes. Rheumatol Int. 2006 Jan;26(3):185-190.
- Nolan A, Badminton J, Maguire J, Seymour RA. The efficacy of topical hyaluronic acid in the management of oral lichen planus. J Oral Pathol Med. 2009 Mar;38(3):299-303.
- Tate DJ Jr, Oliver PD, Miceli MV, Stern R, Shuster S, Newsome DA. Age-dependent change in the hyaluronic acid content of the human chorioretinal complex. Arch Ophthalmol. 1993 Jul;111(7):963-967.
- Pauloin T, Dutot M, Joly F, Warnet JM, Rat P. High molecular weight hyaluronan decreases UVB-induced apoptosis and inflammation in human epithelial corneal cells. Mol Vis. 2009;15:577-583.
- Johnson ME, Murphy PJ, Boulton M. Effectiveness of sodium hyaluronate eyedrops in the treatment of dry eye. Graefes Arch Clin Exp Ophthalmol. 2006 Jan;244(1):109-112.
- Brignole F, Pisella PJ, Dupas B, Baeyens V, Baudouin C. Efficacy and safety of 0.18% sodium hyaluronate in patients with moderate dry eye syndrome and superficial keratitis. Graefes Arch Clin Exp Ophthalmol. 2005 Jun;243(6):531-538.
- Acosta MC, Gallar J, Belmonte C. The influence of eye solutions on blinking and ocular comfort at rest and during work at video display terminals. Exp Eye Res. 1999 Jun;68(6):663-669.
- Sukumar S, Drízhal I. Hyaluronic acid and periodontitis. Acta Medica (Hradec Kralove). 2007;50(4):225-228.
- Pistorius A, Martin M, Willershausen B, Rockmann P. The clinical application of hyaluronic acid in gingivitis therapy. Quintessence Int. 2005 Jul-Aug;36(7-8):531-538.
- Lee JH, Jung JY, Bang D. The efficacy of topical 0.2% hyaluronic acid gel on recurrent oral ulcers: comparison between recurrent aphthous ulcers and the oral ulcers of Behçet’s disease. J Eur Acad Dermatol Venereol. 2008 May;22(5):590-595.
- Mendes RM, Silva GA, Lima MF, et al. Sodium hyaluronate accelerates the healing process in tooth sockets of rats. Arch Oral Biol. 2008 Dec;53(12):1155-1162.
- Higuchi Y, Ansai T, Awano S, et al. Salivary levels of hyaluronic acid in female patients with dry mouth compared with age-matched controls: a pilot study. Biomed Res. 2009 Feb;30(1):63-68.
- Yuan J, Tohara H, Mikushi S, Hoshino T, Yue B, Uematsu H. The effect of “Oral Wet” for elderly people with xerostomia—the effect of oral rinse containing hialuronan. Kokubyo Gakkai Zasshi. 2005 Mar;72(1):106-110.
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