GAGS - Function

Function

Endogenous heparin is localized and stored in secretory granules of mast cells. Histamine that is present within the granules is protonated (H₂A2+) at pH within granules (5.2-6.0), thus it is believed that heparin, which is highly negatively charged, functions to electrostatically retain and store histamine. In the clinic, heparin is administered as an anticoagulant and is also the first line choice for thromboembolic diseases. Heparan sulfate (HS) has numerous biological activities and functions, including cell adhesion, regulation of cell growth and proliferation, developmental processes, cell surface binding of lipoprotein lipase and other proteins, angiogenesis, viral invasion, and tumor metastasis.

CSGAGs interact with heparin binding proteins, specifically dermatan sulfate interactions with fibroblast growth factor FGF-2 and FGF-7 have been implicated in cellular proliferation and wound repair while interactions with hepatic growth factor/scatter factor (HGF/SF) activate the HGF/SF signaling pathway (c-Met) through its receptor. Other biological functions for which CSGAGs are known to play critical functions in include inhibition of axonal growth and regeneration in CNS development, roles in brain development, neuritogenic activity, and pathogen infection.

One of the main functions of the third class of GAGs, keratan sulfates, is the maintenance of tissue hydration. Within the normal cornea, dermatan sulfate is fully hydrated whereas keratan sulfate is only partially hydrated suggesting that keratan sulfate may behave as a dynamically controlled buffer for hydration. In disease states such as macular corneal dystrophy, in which GAGs levels such as KS are altered, loss of hydration within the corneal stroma is believed to be the cause of corneal haze, thus supporting the long held hypothesis that corneal transparency is a dependent on proper levels of keratan sulfate. Keratan sulfate GAGs are found in many other tissues besides the cornea, where they are known to regulate macrophage adhesion, form barriers to neurite growth, regulate embryo implantation in the endometrial uterine lining during menstrual cycles, and affect the motility of corneal endothelial cells. In summary, KS plays an anti-adhesive role, which suggests very important functions of KS in cell motility and attachment as well as other potential biological processes.

Hyaluronic acid is a major component of synovial tissues and fluid, as well as other soft tissues, and endows their environments with remarkable rheological properties. For example, solutions of hyaluronic acid are known to be viscoelastic, and viscosity changes with sheer stress. At low sheer stress, a solution of 10 g/L of hyaluronic acid may have a viscosity 106 times the viscosity of the solvent, while under high sheer stress, viscosity may drop by as much as 103 times. The aforementioned rheological properties of solutions of hyaluronic acid make it ideal for lubricating joints and surfaces that move along each other, such as cartilage. In vivo, hyaluronic acid forms hydrated coils that form randomly kinked coils that entangle to form a network. Hyaluronan networks retard diffusion and form a diffusion barrier that regulates transport of substances through intercellular spaces. For example, hyaluronan takes part in the partitioning of plasma proteins between vascular and extravascular spaces, and it is this excluded volume phenomenon that affects solubility of macromolecules in the interstitium, changes chemical equilibria, and stabilizes the structure of collagen fibers. Other functions include matrix interactions with hyaluronan binding proteins such as hyaluronectin, glial hyaluronan binding protein, brain enriched hyaluronan binding protein, collagen VI, TSG-6, and inter-alpha-trypsin inhibitor. Cell surface interactions involving hyaluronan are its well-known coupling with CD44, which may be related to tumor progression, and also with RHAMM (Hyaluronan-mediated motility receptor), which has been implicated in developmental processes, tumor metastasis, and pathological reparative processes. Fibroblasts, mesothelial cells, and certain types of stem cells surround themselves in a pericellular "coat", part of which is constructed from hyaluronan, in order to shield themselves from bacteria, red blood cells, or other matrix molecules. For example, with regards to stem cells, hyaluronan, along with chondroitin sulfate, helps to form the stem cell niche. Stem cells are protected from the effects of growth factors by a shield of hyaluronan and minimally sulfated chondroitin sulfate. During progenitor division, the daughter cell moves outside of this pericellular shield where it can then be influenced by growth factors to differentiate even further.