CURRENT ASPECTS OF THE ROLE OF GLYCOSAMINOGLYCANS OF THE EXTRACELLULAR MATRIX IN THE DEVELOPMENT OF GENERALIZED PERIODONTITIS AND THE COURSE OF REPAIR PROCESSES

The prevalence of periodontal disease, in particular of generalized periodontitis, has increased up to 98.5% over the past decades. The topical issue of modern dentistry is to ﬁ nd the cause-effect relations of the development of in ﬂ ammatory and dystrophic in ﬂ ammatory periodontal diseases. It has been established that sulfated and non-sulfated glycosaminoglycans (GAGs) support the structure of periodontal tissues. The group of sulfated glycosaminoglycans (sGAGs) is represented in the bone tissue of the alveolar ridges by chondroitin sulfates, dermatan sulfate, keratan sulfate and heparan sulfate. Hyaluronic acid, which belongs to non-sulfated glycosaminoglycans, is present in a small amount. The role of bio ﬁ lm proteinase is important in the pathogenesis of gingivitis and periodontitis, when the activity of acidic and faintly acid proteinases of dental deposits and gum tissues increases 4-5 times. This process is accompanied by degradation of glycoproteins and other proteins of periodontal tissues. The enzymes of beta-glucuronidase, hyaluronidase, beta-N-Acetylhexosaminidase and chondroitin sulfatase are actively involved in the cleavage of acid glycosaminoglycans and glycoproteins of the intercellular substance, periodontal cell membranes, and thus the destruction of circular ligament and periodontal tissues in general. Healing, as a complex dynamic process, is implemented with the inclusion of soluble mediators, blood cells, components of the extracellular matrix and resistant cells involved in recovery and tissue integration. Therefore, the role of GAGs in the processes of periodontal healing is active: 1. Inhibition of synthesis of lipids; 2. Inhibition of activity of proteolytic enzymes; 3. Inhibition of synergistic effect of enzymes and oxygen radicals; 4. Reduction of biosynthesis of in ﬂ ammation mediators due to masking of secondary antigenic determinants and inhibition of chemotaxis; 5. Inhibition of apoptosis; 6. Construction of collagen ﬁ bers; 7. Regulation of cell proliferation; 8. Regulation of biosynthesis of the intercellular matrix components; 9. Improvement of microcirculation processes; 10. Rearrangement in structures of proteoglycans; 11. Regulation of chondro-and osteogenesis. The references present a generalized formulation of the main mechanisms of effect of periodontal structures glycosaminoglycans, which is relevant and requires further studying.

The number of fundamental works of domestic and foreign authors has increased over the past decades. They deal with establishing cause-effect relations of infl ammatory and dystrophic infl ammatory diseases of periodontal tissues with the participation of infectious, immune, hereditary, traumatic and other agents, against the background of anatomical and topographical specifi city of oral tissues (Biloklytska et al., 2004;Danylevskyi et al., 2008;Persson 2008;Hodovana, 2009;Zabolotnyi et al., 2011) [3,8,31,15,46]. However, not enough attention is paid in the domestic literature to the study of the role of individual components of the intercellular matrix of periodontal bone tissue under normal conditions, under pathological conditions and at the stages of healing. A few studies of foreign authors are conducted in the direction of studying the course of metabolic processes in the organic matrix of bone tissue, in particular of one of its components -proteoglycans, which ensure consolidation of collagen fi bers and their connection with mineral crystals (Bartold, 1990;Chen et al., 2004;Grzesik et al., 2002;Iozzo, 1998;Jones et al., 2000;Pins et al., 1997) [1,5,14,18,20,32].
The structure of extracellular matrix of periodontal tissue, as a complex network in the form of a semi-liquid cohesive gel, consists mainly of collagen proteins, proteoglycans and glycoproteins. Fibroblasts, chondroblasts, osteoblasts, odontoblasts, cementoblasts, etc. are involved in the formation of this matrix. At the same time, the matrix contains molecules that can form complexes. Thus, a specialized form of the extracellular matrix of tissues is a basement membrane under normal conditions, which forms a discrete structure that separates one cell layer from another (Graber et al., 1999;Hodovana, 2009; Kordiiak, 2011) [12,15,24].  [19,34,41].
Along with collagen proteins the intercellular matrix also contains non-collagen ones -elastin, glycoproteins, proteoglycans, and others. Glycoproteins are complex proteins, which include the carbohydrate component. The protein in these compounds is a peculiar basis, to which the hydrocarbon (glycan) chains are very fi rmly attached. In accordance with the peculiarities of the chemical structure, glycoproteins can be divided into genuine (true) glycoproteins and proteoglycans (glycosaminoproteoglycans). The main difference between them is that the carbohydrate groupings of true glycoproteins typically have 15-20 monosaccharide components that do not form repeated oligosaccharide fragments, while in proteoglycans these groupings are made of a very large number of repeated units, which, basically, have a peculiar disaccharide nature. Most typically this disaccharide contains glucosamine or galactosamine in sulfated or non-sulfated form and uronic acid (glucuronic or iduronic acid) (Jackson et al., 1991;Rees et al., 2002;Sugahara and Kitagawa, 2000) [19,34,41].
Osteoprotegerin actively participates in the processes of the alveolar ridge bone remodeling. This is a glycoprotein, which belongs to the family of receptors of the tumor necrosis factor and suppresses the mobilization, proliferation and activation of osteoclasts (Riggz and Melton, 2000;Varki, 2009) [35,45].
Another component of the extracellular matrix of periodontal tissues is non-collagen proteins -proteoglycans. This class of complex proteins is constructed from different core proteins. Oligosaccharides, linked to glycosaminoglycan chains (GAGs), joint to them via N-and O-glycosidic bonds. Different proteoglycans vary in sizes of molecules, relative protein content and a set of GAGs. Proteoglycans act as receptors for the construction of extracellular matrix, facilitate cell adhesion and regulate cell growth processes. They are able to form complexes with some proteins, for example, growth factors. The proteins in the formed complexes are protected from proteolytic enzymes. These complexes serve as  [11,32].
Small polypeptides usually play the role of growth factors in periodontal tissues. They stimulate or inhibit proliferation of some types of cells (transforming growth factor beta, bone morphogenetic protein, endothelial growth factor, insulin-like growth factor, fi broblast growth factor, platelet growth factor, etc.) Transforming growth factor beta is a family of glycoproteins that activates the synthesis of extracellular matrix proteins, for example, type I collagen and metalloproteinases, and acts as a chemotactic factor for monocytes and fi broblasts. In addition to that, it inhibits proliferation and T and B lymphocytes function, endothelial cells. Among the complex net of cytokines that infl uence the function of odontoblasts in the process of repair, the transforming growth factor beta functions as a powerful immunosuppressant, an inductor of protein synthesis and supports homeostasis in the endoperiodontal focus during infl ammation. Bone morphogenetic protein -is an acid glycophosphoprotein with high levels of glycine and serine, contains three disulfi de bonds. Restoration of disulfi de bonds causes inactivation of bone morphogenetic protein. It is secreted by odontoblasts in the tooth pulp in response to external stimuli for the formation of replacing dentine, and also plays a very active role in the periodontal bone tissue, causing differentiation of stem cells into osteogenic ones. Endothelial growth factor is a glycoprotein that binds only to vascular endothelium cells and stimulates their proliferation. The endothelial growth factor has the ability to activate a specifi c protein that includes a kinase complex. Phosphorylated proteins, formed as a result of this process, stimulate the migration of cells. Therefore, when the components of the periodontal complex are Протеоглікани, зокрема версікан, біглікан, декорин і синдекан, у великій кількості представлені у тканинах пародонта (цементі кореня, дентині та пульпі зуба, періодонтальній зв'язці, компактній чаcтині альвеоли, слизовій ясен) (Gotte, 2003) [11]. У зв'язуванні протеогліканів зі специфічними білками головна роль належить молекулам глікозаміногліканів. Глікозаміноглікани (ГАГ), які належать до гетерополісахаридів, представлені у вигляді лінійних структур та побудовані з дисахаридних одиниць, які повторюються. Молекула дисахариду складається з уронової кислоти й аміносахару, аміногрупа якого зазвичай ацетильована. Наявність сульфатних і карбоксильних груп у ГАГ наділяє їх великим негативним зарядом та здатністю зв'язувати воду. Завдяки високій щільності негативного заряду на їхній поверхні, вони зв'язують катіони Ca 2+ , Na + , K + і беруть участь у мінеральному обміні. Стуктуру тканин пародонта підтримують такі сульфатовані ГАГ: хондроїтин-4-сульфат, хондроїтин-6-сульфат, дерматансульфат, damaged (bone tissue of the alveolus, gingival mucosa, periodontal ligament, tooth pulp) under the infl uence of the endothelial growth factor, there is a rapid movement, an increase and differentiation of cells with activation of alkaline phosphatase. The endothelial growth factor also causes the expansion of the blood vessels, which is an important condition for maintaining blood fl ow in the tissues in case of infl ammation. It increases the synthesis of interleukin-1, tumor necrosis factor, which have a signifi cant effect on vasodilatation in pathological processes, which is accompanied by an increase in osmotic pressure, pain and irreversible changes in tissues. The insulin-like growth factor has an autocrine and paracrine effect. Its participation in the rapid growth of cells, their differentiation and mineralization of tissues is permissible. The fi broblast growth factor is a family of structurally bound polypeptides, represented by nine proteins with manifestations of heparin affi nity. This growth factor causes vasodilatation, participates in the differentiation of fi broblasts in the formation of a fi brous capsule around the focus of infl ammation. The platelet growth factor infl uences numerous cells inducing the synthesis of alkaline phosphatase and proteoglycans in odontoblastic cells of the tooth pulp and periodontal bone tissue ( [20,17,33].
In periodontal tissues, the non-sulfated GAG -hyaluronic acid forms complexes with proteins and serves as biological cement, fi lling the space between cells. The main function of hyaluronic acid in the connective tissue is believed to be water binding.
As a result of this binding, the intercellular substance becomes like a gelatinous matrix capable of "supporting" the cells. Hyaluronic acid's role in the regulation of tissue permeability is also important. Hyaluronic acid's grid in the form of a gel is a kind of fi lter that holds up microbial and other large molecules that get into the body. The rupture of glycoside bonds in the chains of hyaluronic acid causes its depolymerization. As a result, the fi ltering system is violated, various molecules get in between the cells, including large ones, intercellular water is accumulated, which is kept by whole polymer (edema develops). A special enzyme of hyaluronidase secretes into the intercellular space in the cells of the body, and can increase intercellular permeability. Therefore, hyaluronidase is called the permeability factor. Some bacteria contain hyaluronidase-like enzyme, which allows them to penetrate into the intercellular space from the bloodstream (Giannobile [10,19,20,29,30]. In the pathogenesis of gingivitis and periodontitis, the role of the biofi lm proteinases is important, when the activity of acid and faintly acid proteinases of dental deposits and gum tissues increases 4-5 times. The degradation of glycoproteins and other proteins of periodontal tissues accompany this process (Kordiiak, 2011) [24]. The enzymes of beta-glucuronidase, hyaluronidase, beta-N-acetylhexosaminidase and chondroitin sulfatase are actively involved in the cleavage of acid GAGs and glycoproteins of the intercellular substance, periodontal cell membranes, and thus cause the destruction of circular ligament and periodontal tissues in general (Mc-Culloch, 1994;Shyrobokov et al. 2003) [29,37]. The degradation of the components of extracellular matrix and the destruction of the  [39,13]. Ця група ферментів активно задіяна у процесах деградації ланцюгів взаємодії факторів росту, цитокінів, речовин, які беруть участь в апоптозі і клітинній адгезії. Разом з іншими позаклітинними протеїназами ММП задіяні у запальному процесі, реалізації імунної відповіді, коагуляції, фізіологічній і постраневій перебудові тканин. Однак в умовах патологічного процесу ММП викликають пошкодження тканин на усіх рівнях (Suomalainen et al., 1991) [43]. Причиною підвищення активності ММП за таких умов вважають дисбаланс між ММП та їхніми локально діючими інгібіторами -тканинними інгібіторами матриксних металопротеїназ (ТІМП) (Ingman et al., 1996) [16].
Отже, згідно з аналізом літературних даних активною є роль сульфатованих і несульфатованих ГАГ у процесах репаративного остеогенезу тканин пародонта. Загоєння як комплексний динамічний процес реалізується із включенням розчинних медіаторів, клі-periodontal tissue is also caused by the activity of matrix metalloproteinases (MMPs), which represent a large group of structurally related enzymes breaking down most of the proteins of extracellular matrix and basement membrane. Destructive processes in the aggressive course of periodontitis, which last for several months, lead to irreversible loss of periodontal tissues at all levels. However, MMPs have an important role in the development of osteoporotic processes in bone tissue (Sorsa et al., 2004; Grinin et al., 2011) [39,13]. This group of enzymes is actively involved in the processes of degradation of the interaction chains of growth factors, cytokines, substances that participate in apoptosis and cellular adhesion. Together with other extracellular proteinases, MMPs are involved in the infl ammatory process, implementation of the immune response, coagulation, physiological and post-traumatic tissue reconstruction. However, in the presence of pathological process MMPs cause tissue damage at all levels (Suomalainen et al., 1991) [43]. The reason for the increase in the MMPs activity under such conditions is the imbalance between MMPs and their locally active inhibitors -tissue inhibitors of matrix metalloproteinases (TIMPs) (Ingman et al., 1996) [16].
There are reports in literary sources about studying the GAG level in the blood at various pathological conditions accompanied by the infl ammatory process (Klishov et al., 1990) [23].
In particular, there is data indicating the informative value of the metabolic indexes of these compounds in the regeneration of bone tissue (Riggz et al., 2000) [35]. DeCarlo A.A. and Whitelock J.M. [4] demonstrated a deeper understanding of the role of growth factors, cytokines and extracellular matrix molecules in the healing processes in their work, where the authors studied heparan-sulfate extracellular molecule, which was named perlecan. Its important role in the potential of reparative processes of the alveolar ridge bone tissue was studied as well, namely, the stimulating effect on cell adhesion, proliferation, differentiation and angiogenesis (Iozzo and San Antonio, 2001) [17].
Thus, a generalized formulation of the main mechanisms of action of sulfated and non-sulfated GAGs of periodontal structures is presented in the literature: 1. Inhibition of synthesis of lipids; 2. Inhibition of activity of proteolytic enzymes; 3. Inhibition of synergistic effect of enzymes and oxygen radicals; 4. Reduction of biosynthesis of infl ammation mediators due to masking of secondary antigenic determinants and inhibition of chemotaxis; 5. Inhibition of apoptosis; 6. Construction of collagen fi bers; 7. Regulation of cell proliferation; 8. Regulation of biosynthesis of the intercellular matrix components; 9. Improvement of microcirculation processes; 10. Rearrangement in structures of proteoglycans; 11. Regulation of chondro-and osteogenesis. The foregoing makes it possible to understand to what extent research in the fi eld of molecular and cellular biology has infl uenced the understanding of the course of pathological processes in bone tissue, the course of reparative osteogenesis processes and the possibility of their modulation. The most promising in modern periodontology are considered to be the approaches with the use of natural regulators of physiological and pathological processes, which are deprived of any toxic effects on cells Proc. Shevchenko Sci. Soc. Medical sciences 2017, 2 (L) Огляд Review агентом є сульфатовані і несульфатовані ГАГ, область застосування яких у пародонтологічній практиці є актуальною й потребує продовження дослідження. and tissues. Sulfated and non-sulfated GAGs are those promising agents, which application in periodontal practice is relevant and requires further study