Hyaluronan functions

Spicer, A.P. et al., Investigation of hyaluronan function in the mouse through targeted mutagenesis, Glycoconj. J., 19, 341, 2002. 

In aqueous solutions, at a physiological pH, HA is represented by negatively charged hyaluronate macromolecules (pK = 3.21) [15] with extended conformations. In a polyanionic form, hyaluronan functional groups make the biopolymer so hydrophilic that it binds 1000 times more water than is predicted from its molar mass. The heterogeneity and hydrophilicity of HA facilitate its interaction with a variety of tissue constituents inside and outside the cells. In the extracellular space, HA controls the retention of water, ionic and molecular diffusion and provides a 3D-structural meshwork [16]. 

The first chapter describes the history of hyaluronic acid discovery, the main milestones of its research and practical application. The largest chapter. Chapter 2, is dedicated to the biological role of the hyaluronic acid in nature, in particular in the human body. The chapter starts from the phylogenesis of hyaluronic acid, then describes hyaluronan functions in human ontogenesis and especially the role that hyaluronan plays in the extracellular matrix of the different tissues. 

Pain and joint function have been evaluated frequently in clinical trials administering hyaluronan to patients with OA. Results are conflicting, with some suggesting dramatic improvements and others indicating no effect. In one controlled trial, hyaluronan injections relieved pain to a similar extent as oral NSAIDs.29 Hyaluronan provides greater pain relief for a longer time than intraarticular corticosteroids, but corticosteroids work more rapidly.29... 

Huntsman solvent-based collection and refining system, 15 506 Huron-Dow process, 14 42, 53 Huygens principle, 17 424 H values, 23 284 Hyaluronan, 20 577 Hyaluronic acid, 4 706 20 456 classification by structure, 4 723t function as ingredient in cosmetics, 7 829t... 

Such enzymatic catalyzed polycondensations have allowed the synthesis of a number of natural polysaccharides, but has also allowed the production of nonnatural polysaccharides such as cellulose-xylan hybrids and functionalized hyaluronan, chondroitin sulfate, and chondroitin. Such work illustrates the ever-narrowing bridge between natural and synthetic polymers and polymer syntheses. 

Viscosupplementation is a clinical procedure that is being used increasingly in the treatment of osteoarthritis. This technique uses a substance known as hyaluronan to restore the lubricating properties of synovial fluid in osteoarthritic joints.6,41 Hyaluronan is a polysaccharide that can be injected into an arthritic joint to help restore the normal viscosity of the synovial fluid.6 This treatment helps reduce joint stresses, thus limiting the progression of articular destruction seen in osteoarthritis.106 Viscosupplementation has therefore been shown to reduce pain and improve function in osteoarthritis.1,95... 

Hyaluronan also occurs covalently bound to proteins such as inter-alpha trypsin inhibitor, a plasma protein that also functions as a stabilizer of HA-rich structures,21,22 such as the cumulus mass surrounding the mammalian ovum.23... 

Hyaluronan, despite the simplicity of its structure, has a surprisingly wide range of functions. In high concentrations, as found in the ECM of the dermis, it regulates water balance, osmotic pressure, functions as an ion exchange resin, and regulates ion flow. It functions as a sieve, to exclude certain molecules, to enhance the extracellular domain of cell surfaces, particularly the luminal surface of endothelial cells.28 It can also function as a lubricant and as a shock absorber. Hyaluronan can also act as a structural molecule, as in the vitreous of the eye, in joint fluid, and in Wharton s jelly. 

Hyaluronan promotes cell motility, regulates cell-cell and cell-matrix adhesion, promotes proliferation, and suppresses differentiation. It participates in such fundamental processes as embry-ological development and morphogenesis,29,30 wound healing,31,32 repair and regeneration, and inflammation.33-35 Hyaluronan levels increase in response to severe stress, and in tumor progression and invasion.36,37 Recent studies indicate that HA can also exist intracellularly.38-40 The intracellular functions of HA are unknown. 

Selbi W, de la Motte CA, Hascall VC, Day AJ, Bowen T, Phillips AO. Characterization of hyaluronan cable structure and function in renal proximal tubular epithelial cells. Kidney... 

Yokoi N, Komuro A, Nishida K, Kinoshita S. Effectiveness of hyaluronan on corneal epithelial barrier function in dry eye. BrJ Ophthalmol 1997 81 533-536. 

During these years, our work laid the foundation for future studies on the effect of elastoviscous solutions of hyaluronan on the migration, proliferation and function of white blood cells, and how such solutions affect some functions of the immune system. We discovered that hyaluronan regulates the synthesis of glycosaminoglycans in in vitro systems, and regulates inflammation and tissue regeneration in adult animal models and tissues. All these studies laid the theoretical foundation for the therapeutic applications of hyaluronan. 

The therapeutic use of hyaluronan and its derivatives today is based on the function of this molecule in the healthy body as a stabilizer of the molecular structure of intercellular matrix and as a protector of cells and pain receptors. But we have known for a long time that hyaluronan has other biological functions. We know that elastoviscous solutions of hyaluronan and hylan inhibit certain cell functions by stabilizing the cell membranes. Hyaluronan also interacts with certain proteins that have important functions in the regulation of cell activities. In the future, as we learn more about the function of these specific proteins and how hyaluronan may turn on and off the signals given by these molecules to the cells, we may extend the therapeutic uses of hyaluronan significantly. 

Since the merger, I have continued my research in a non-profit organization, the Matrix Biology Institute (MBI). This research institute that I founded in 1986 carries out fundamental research on the function of the intercellular matrix in general and specifically, on the role of hyaluronan in this matrix. 

In recent years, new biological roles have been ascribed to HA along with its essential function as a component of ECM. Due to its unique rheological properties, hyaluronan has found many applications in pharmacy and medicine. Since it has been reported that biological effects of HA depend on its molar mass, methods of... 

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