Biological Function of Glycosaminoglycans

MICHAEL ROTH ELENI PAPAKONSTANTINOU AND GEORGE KARAKIULAKIS  

Chondroitin sulfates activate ECM-degrading enzymes, such as MMPs, and are therefore involved in the degradation of aggrecan by MMP-2 (30,31), MMP-13 

Chondroitin sulfates have been used in clinical trials of osteoarthritis, where they improved knee mobility and reduced pain, by providing better lubrication (41,42). This effect is claimed to be achieved not only by local injection but also by increased dietary intake of chondroitin sulfates (43,44). However, the effect was only achieved when the compounds were taken regularly over a period of at least 6 months (43,44), and therefore, oral administration must be approached with caution, also taking into account bioavailability aspects. In a much smaller study, chondroitin sulfates were administered to patients with osteoarthritis who also suffered from psoriasis, and the outcome showed reduced skin thickness, less skin inflammation, and flaking (45). 

Dermatan sulfate is necessary for thrombopoietin-induced megakaryo-cytopoiesis (55) and triggers the maturation of mesenchymal and neuronal stem cells (27,55-57). In this context, decorin and versican are rich in dermatan sulfate and neutralize phospholipase A2, which is a proinflammatory and profibrotic factor (58). Dermatan sulfate also regulates the differentiation of bone forming cells (59), which involves the blockade of NF-kB inhibitors (60) leading to the expression of endothelial and intercellular adhesion molecule-1 (61). Therefore, dermatan sulfate is the only chondroitin sulfate that modifies the action of transcription factors without being attached to a proteoglycan. 

Heparin and heparan sulfate are the best known GAGs as they have been used since decades to treat diseases that are associated with increased blood clotting (69-72). The molecular mass of heparin ranges from 6 to 50 kDa, but can reach up to 100 kDa, and those used therapeutically have a molecular weight of 12-15 kDa. 

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Question What is the (biological) function of the carboxyl and sulfate groups on glycosaminoglycans ... 

Ogston AG. The biological functions of the glycosaminoglycans. In BalaisEA.editot. Chemistry andmolecular biology of the intercellular matrix. London Academic Press 1970. p. 1231-9. 

HA is an unsulfated glycosaminoglycane composed of repeating disaccharide units of D-glucuronic acid and A-acetylglucosaminc linked a-( 1 —4) and p-( 1—3), respectively. HA has special importance because it is a component of the ECM [53] in the soft tissues of mammals, where it mainly ensures water retention [54], This enables the transport of nutrients to, and removal of waste from, cells that do not have a direct blood supply, such a cartilage cells. Moreover, HA is present in the synovial joint fluid, the vitreous humor of the eye, cartilage, blood vessels, and the unbilical cord. More detailed information about the biological functions and physicochemical properties of HA can be found elsewhere [55, 56],... 

Shriver, Z., Liu, D., and Sasisekharan, R. (2002). Emerging views of heparan sulfate glycosaminoglycan structure/activity relationships modulating dynamic biological functions. Trends Cardiovasc. Med. 12, 71—II. 

Ali, S., Palmer, A.C.V., Banerjee, B., Fritchley, S.J., and Kirby, J.A. (2000) Examination of the function of RANTES, MIP-1 alpha, and MIP-1 beta following interaction with heparin-like glycosaminoglycans. The Journal of Biological Chemistry, 275, 11721-11727. 

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