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ABOUT HYALURONAN

'Hyaluronan' is the accepted scientific nomenclature for hyaluronic acid and physiological salts of hyaluronate, the conjugate base of hyaluronic acid.  This nomenclature is preferred since the counterion for hyaluronate in the body may be either sodium or potassium (Fraser et al. 1997).

Hyaluronan structure

Hyaluronan is a nonsulfated glycosaminoglycan (complex carbohydrate) polymer consisting of repeats of the disaccharide unit D-glucuronic acid beta-1,3-N-acetyl-D-glucosamine-beta-1,4.  Hyaluronan therefore refers to a large number of molecules of different molecular weights, from several hundred (a disaccharide) to several million (tens of thousands of repeats of the disaccharide) Daltons (Tammi et al. 2002).  The physical and biological properties of low-molecular-weight hyaluronan and high-molecular-weight hyaluronan are entirely different from one another.  In general, higher-molecular-weight hyaluronan is regarded as anti-inflammatory and lower-molecular-weight hyaluronan as pro-inflammatory (Bollyky et al. 2007and Krasinski et al 2007). 

Where hyaluronan is found

Hyaluronan is essentially ubiquitous within the body.  It is part of the pericellular matrix of many cell types.  High amounts of hyaluronan are found in the skin, connective tissues and synovial fluid.  It is also a principal constituent of the vitreous of the eye, and the extracellular matrix (DeAngelis 2002).  Hyaluronan exists in all mammals and is identical in all species and tissues. 

Hyaluronan and joints

In diarthrodial joints, hyaluronan is the principal macromolecular component of synovial fluid and one of the chief constituents of articular cartilage (Cohen et al. 1998).  The compression of hyaluronan and its elastic rebound are absolutely required for the nutrition of articular cartilage.  This explains why moderate exercise is necessary for the maintenance of joint health, since, without this compression-rebound cycle, no nutrients are carried to articular cartilage, which lacks a direct blood supply (Suh et al. 1995).  Thus osteoarthritis is increasingly viewed as a metabolic disease (Lajeunesse et al. 2005), the onset of which can be hastened by joint trauma, overuse and inflammation, all associated with a decrease in the molecular weight of endogenous hyaluronan (Takahashi et al. 2004; Tehranzadeh et al. 2005).

Hyaluronan physicochemical properties

Among the more remarkable characteristics of hyaluronan are its viscoelasticity.  It is extraordinarily hydrophilic, carrying with it up to 1000 times its weight in water (Laurent and Fraser 1992).  Its ability to bind and retain water play an important role in tissue hydration, lubrication, and cellular function. 

Hydration is important to the absorption of many bioactive molecules, including hyaluronan.  For this reason, it is unclear whether meaningful amounts of dry hyaluronan supplements are absorbed, since full hydration of a desiccated hyaluronan molecule can take significantly longer than the transit time of a dry supplement through the gastrointestinal tract.

Hyaluronan's actions

Hyaluronan appears to have multiple complementary mechanisms of action.  Hyaluronan is known to directly affect the composition of synovial fluid, making the synovial fluid more viscous and the joint more resistant to physical trauma (Marshall 2000).  A hyaluronan derivative has been shown to stimulate fibroblasts to produce Type II collagen (Wang et al. 2007).  Apart from its structural role, hyaluronan can influence cell proliferation, differentiation, and migration, angiogenesis, as well as inflammation and immune cell function.

Hyaluronan and the control of inflammation and pain
Hyaluronan provides a surface to which activated lymphocytes can attach.  The result of this attachment can include the attenuation of the inflammatory response (Bollyky et al. 2007).  High molecular weight hyaluronan has been shown to be anti-inflammatory (Stancikova et al. 2004).  The interruption of chronic substance-P-mediated pain signaling may result from hyaluronan administration (Moore and Willoughby 1995), and topical high molecular weight hyaluronan has been shown to reduce radicular pain post laminectomy in a preclinical model (Massie et al. 2005).

Hyaluronan in FDA-approved therapeutic products
Hyaluronan is currently in clinical use in a number of FDA-approved therapeutic products (US FDA 2007):

• Intraarticular injections of hyaluronan for osteoarthritis (visco-supplementation)
• Dermal injection of hyaluronan in cosmetic surgery (dermal filler)
• Topical gel for dermal application (anti-inflammatory)

References
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Cogent Solutions Group (2007). Unpublished data.
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Moore AR and Willoughby DA (1995). Int J Tissue React 17, 153.
Pritzker, K.P.H. et al., Osteoarthritis and Cartilage 14, 13 (2006) 
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US FDA (2007). Compiled from www.fda.gov (viewed 15 October 2007).
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Welch I (2007). Manuscript in preparation.
Wheeler P and Batt ME (2005). Br J Sports Med 39, 65.

Compiled by G.D. McClure Jr., Ph.D., Chief Scientific Officer,
Cogent Solutions Group.

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