Hyaluronan (also called hyaluronic acid or hyaluronate) is an anionic, non-sulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminoglycans in that it is unsulfated, forms in the plasma membrane instead of the Golgi and can be very large with its molecular weight often reaching the millions. One of the chief components of the extracellular matrix, hyaluronan contributes significantly to cell proliferation and migration, and may also be involved in the progression of some malignant tumors. The average 70 kg (154 lbs) person has roughly 15 grams of hyaluronan in their body, one-third of which is turned over (degraded and synthesised) every day.
Hyaluronic acid is also a component of the group A streptococcal extracellular capsule, and is believed to play a role in virulence.
Hyaluronan in Essential of Glycobiology
Hyaluronan (hyaluronic acid, HA) is a linear naturally occurring polysaccharide formed from repeating disaccharide units of N-acetyl-D-glucosamine and D-glucuronate. Despite its relatively simple structure, HA is an extraordinarily versatile glycosaminoglycan currently receiving attention across a wide front of research areas. It has a very high molar mass, usually in the order of millions of Daltons, and possesses interesting visco-elastic properties based on its polymeric and polyelectrolyte characteristics. HA is omnipresent in the human body and in other vertebrates, occurring in almost all biological fluids and tissues, although the highest amounts of HA are found in the extracellular matrix of soft connective tissues.
Role, Metabolism, Chemical Modifications and Applications of Hyaluronan
Hyaluronan is an important component of articular cartilage, where it is present as a coat around each cell (chondrocyte). When aggrecan monomers bind to hyaluronan in the presence of link protein, large highly negatively-charged aggregates form. These aggregates imbibe water and are responsible for the resilience of cartilage (its resistance to compression). The molecular weight (size) of hyaluronan in cartilage decreases with age, but the amount increases.
Hyaluronan is also a major component of skin, where it is involved in tissue repair. When skin is excessively exposed to UVB rays, it becomes inflamed (sunburn) and the cells in the dermis stop producing as much hyaluronan, and increase the rate of its degradation. Hyaluronan degradation products also accumulate in the skin after UV exposure.
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 receptors, CD44 and RHAMM. 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. Receptor CD44 participates in cell adhesion interactions required by tumor cells.
Although hyaluronan binds to receptor CD44 , there is evidence 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.
The CD44 antigen is a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion and migration. In humans,HA is involved in several key processes, including cell signaling, wound repair and regeneration, morphogenesis, matrix organization and pathobiology.
Role, Metabolism, Chemical Modifications and Applications of Hyaluronan
Prehm demonstrated that hyaluronan synthesis differs from that of other glycosaminoglycans; its chains grow at the reducing end by addition of sugar residues donated by their respective UDP-derivatives. This occurs inside the plasma membrane, and the chain (with the nonreducing end ahead) is translocated to the pericellular space. The other glycos-aminoglycans grow by addition of sugars to the nonreducing end. In some instances the cells can release hyaluronan from the cell surface but the release mechanism is not clarified. The purification of mammalian hyaluronan synthase has been reported by Mian but not confirmed yet in other laboratories despite much effort. We lack knowledge of the molecular mechanism that regulates the biosynthesis of hyaluronan but some stimulatory factors are known. For example, several growth factors such as EGF, PDGF, TGF13, IGF-I, and other cytokines , e.g., IL 1, activate the synthesis.
As shown in the figure, hyaluronan synthesis takes place at the inner surface of the plasma membrane and nascent hyaluronan is extruded onto the plasma membrane while it is still attached to the synthase that produces it.
Effect of Hypoxia on Glycosaminoglycans
Proteoglycans in lung disease
Di Hari G. Garg,Peter J. Roughley,Charles A. Hales
Adv Exp Med Biol. 2005;566:249-56.
Hypoxia-induced alterations in hyaluronan and hyaluronidase.
Gao F, Okunieff P, Han Z, Ding I, Wang L, Liu W, Zhang J, Yang S, Chen J, Underhill CB, Kim S, Zhang L.
Hyaluronan (HA), a large negatively-charged polysaccharide, is a major component of vessel basal membrane. HA is expressed by a variety of cells, including tumor and endothelial cells. We hypothesized that HA could be up-regulated by hypoxia to enhance vessel formation. To determine the effect of hypoxia on the production of HA, tumor cells were treated with either media alone (control) or a hypoxia inducer (CoCl or NaN3) for 24 h. The level of HA in the media was then measured by ELISA. The results showed that both CoCl and NaN3 induced the production of HA. Since the low molecular weight form of HA (SMW) possesses pro-angiogenic properties, we investigated whether hypoxia-induced HA can be processed into SMW. Under hypoxic conditions, the activity of hyaluronidase, the enzyme responsible for degrading HA, was measured by an ELISA-like assay. The activity of hyaluronidase was shown to be up-regulated by hypoxia and, further, could carry out the function of processing HA into SMW. In addition, the hypoxic areas of tumor tissues were stained strongly with biotinylated HA-binding proteins, indicating that the level of HA was high compared to the oxic areas. This study demonstrates that hypoxia can stimulate the production of HA and the activity of hyaluronidase, which may promote angiogenesis as a compensation mechanism for hypoxia.
Hyaluronan: from extracellular glue to pericellular cue. 2004
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 the native high-molecular mass of hyaluronan, can induce inflammatory responses in macrophages and dendritic cells in tissue injury and in skin transplant rejection.
In vivo, HA is degraded by the action of oxygen free radicals and HYALs.
Hyaluronan synthesis and degradation in cartilage and bone. 2007
AA% shows in both HASs and HYALs a ratio Glu/Gln correspondig to an hypoxic environment
Open Question: there is a tissue dependent clustering of the enzymes?
On the basis of AA% similarities we can cluster the synthesis and degradation enzymes in two groups.
HSA1 HYAL1 HYAL2 subset
HSA2 HSA3 HYALP subset
HSA2 HSA3 increase proliferation?
HYALP decreases proliferation increases angiogenesis
Papers HAS3 prostate