Periodontology 2000, Vol. 67, 2015, 211–233 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Printed in Singapore. All rights reserved PERIODONTOLOGY 2000 Cementum proteins: role in cementogenesis, biomineralization, periodontium formation and regeneration HIGINIO ARZATE,MARGARITA ZEICHNER-DAVID &GABRIELA MERCADO-CELIS Destruction of periodontal tissues is a cardinal sign of tissue regeneration) have been developed to guide periodontal disease, and many factors, such as infec- and control regeneration using bioresorbable mem- tions, trauma, orthodontic tooth movement and sys- branes (3, 138, 142) and bone grafts (175). Although temic and genetic diseases, can contribute to this effective to a certain point, these strategies have the process. In periodontal disease, bacteria on the sur- problem that they are not predictable and do not face of the teeth produce a chronic inflammation of completely restore the architecture of the original the gingiva. Cells on the surface of the tooth root and periodontium. To achieve complete repair and regen- the cementum covering the root are destroyed, and eration it is necessary to recapitulate the develop- the epithelium from the oral mucosa grows down- mental process with complete formation of wards, producing a gingival crevice. Bacteria deposit cementum, bone and periodontal ligament fibers. in this crevice and the ensuing inflammatory process The past 20 years of research have seen tremen- may eventually result in the breakdown of periodon- dous advances in our knowledge of the cellular and tal tissues, including the cementum, periodontal liga- molecular events involved in the process of devel- ment and alveolar bone. oping the periodontium. This knowledge has trans- The process of periodontal tissue regeneration is lated into new therapeutic strategies for periodontal initiated at the moment that the damage takes place regeneration using molecular approaches (45, 67, by the production of growth factors and cytokines by 110–112, 116, 129, 146, 158, 210, 223, 240). Amongst the damaged and inflammatory cells. Periodontal these strategies are the use of growth factors, such treatment can enhance periodontal healing (60). Root as platelet-derived growth factor and insulin-like planing or root conditioning is being used as a strat- growth factors (32, 54, 90, 120, 163, 181, 222), trans- egy to increase mesenchymal cell migration and forming growth factor-beta1 (127), basic fibroblast attachment to the exposed root surface. Treatment growth factor (191), dexamethasone (181) and bone with acid, in particular citric acid, has been found to morphogenetic proteins (109, 114, 154, 176–178). It widen the orifices of dentinal tubules, thereby accel- is believed that these molecules are produced dur- erating cementogenesis and enhancing cementum ing cementum formation and are then stored in the apposition and connective tissue attachment (125). cementum matrix to induce periodontal ligament However, when periodontal ligament cells are regeneration when needed (200). However, one of removed from the cementum or are unable to regen- the problems of application of these factors for peri- erate, bone tissue may invade the periodontal liga- odontal repair is the nonspecific activity of some of ment space and establish a direct connection the factors on different cell lineages and the rapid between the tooth and the wall of the alveolar socket, loss of the topically applied factors over time (15, resulting in ankylosis. This nonflexible type of tooth 120). support can lead to loss of function and eventually to As our understanding of the structure, function and resorption of the root (15). Strategies (such as guided composition of cementum increases, so does the 211 Arzate et al. potential for new therapies for periodontal regenera- all animal teeth. Initial examination of cementum on tion using molecules formed by these tissues. One the roots of human teeth is attributed to Ringelmann such example has been the use of enamel proteins to in 1824, followed by physiologists Jan Evangelista Pur- induce cementum and bone regeneration (50, 51, 72– kinje and his pupils, Fraenkel and Raschkow, in 1835, 74, 84, 85). A preparation of porcine enamel protein and later by the classic histologist Anders Adolf Retzi- â has been marketed (Emdogain ) and is currently us, in 1836, who noticed the presence of ‘striaes’ in being used by practicing dentists (42, 52, 55, 105, 237, cementum (19, 37, 61, 186). In almost all mammalian 239). Outcomes from studies using Emdogain suggest species the number of incremental structures in the that its clinical action is the result of contamination dental cementum (annulations) can be correlated with growth factors such as transforming growth fac- with age and are used as such in archeology and tor-beta (107, 143) and bone morphogenetic proteins forensics (61). (100). However, studies using recombinant amelo- In a very simplistic way we can define cementum genin, including results obtained in our laboratory, as an extracellular matrix composed of calcified col- indicate that amelogenin and ameloblastin also have lagenous Sharpey’s fibrils, collagen, glycosaminogly- signaling properties that induce phenotypic changes cans, proteoglycans and inorganic hydroxyapatite. In in cells, and these changes can fluctuate depending the same way we can say that the major functional on the target cell (20, 219, 237, 239, 240). role of cementum is to serve as the anatomical struc- It is the purpose of this review to focus on the role tural site for the attachment of Sharpey’s fibers of the of cementum and its specific components in the for- periodontal ligament. However, the more we study mation, repair and regeneration of the periodontium. this tissue, the more complex we find its structure As cementum is a matrix rich in growth factors that and function. Cementum biology goes back to Gott- could influence the activities of various types of peri- lieb, in 1942, who stated that “the continuous deposi- odontal cells, this review will examine the characteris- tion of cementum layers seems to be of great tics of cementum, its composition and the role of importance and work as a barrier against the down- cementum components, especially the cementum growth of the epithelium. Newly deposited cemen- protein-1, during the process of cementogenesis, and tum seems to have the highest vitality and act as the their potential usefulness for regeneration of the best barrier. If the ideas about the biology of cemen- periodontal structures in a predictable therapeutic tum are correct, it is then our task to find out just manner. how nature provides for continuous cementum depo- sition and having done so, to imitate the procedure” (62). These studies introduced the notion that not What is cementum? only does cementum act as a barrier to delimit epi- thelial growth that can impair attachment but also Cementum can be described as the mineralized tis- that the presence of a continuous cementum layer is sue that covers the roots of teeth and serves to necessary to act as a microbial barrier and that attach the tooth to alveolar bone via collagen fibers defects in this tissue could result in periodontitis (62, of the periodontal ligament. Morphological, histo- 63). This idea was further supported by observations logical and functional differences appear to exist that the root surfaces of patients with hypophospha- along the length of the root, leading cementum to tasia contained areas completely devoid of cemen- be classified as follows: intermediate cementum tum or covered with a hypoplastic form of a (found in the cemento–enamel junction), acellular cementum-like material. These patients developed cementum (found in the coronal and mid-portions early-onset periodontitis, suggesting that abnormali- of the root) and cellular cementum (present in the ties in the deposition or maintenance of cementum apical and inter-radicular portions of the root con- can result in a defective periodontium highly suscep- taining cementoblasts) (21, 33, 71, 75, 183, 187, 207, tible to microbial invasion and destruction (160). 240). Based on the different functions attributed to Studies on dental cementum can be traced back to cementum it is clear that a thorough understanding Malpighi in the 1600s (61). In general, 18th century of the biological properties of cementum is required anatomists regarded human teeth as composed only to determine its role in periodontal formation and of enamel and dentin. However, the studies of Tenon therefore periodontal regeneration. Furthermore, the on horses’ teeth, of Blake on elephants’ teeth and of principles attributed to cementum regeneration Cuvier on the teeth of many species resulted in the might be used in the regeneration of other mineral- recognition that cementum was a constituent part of ized tissues. 212 Cementum proteins Cementum composition pericementocyte area), suggesting that they play major regulatory roles during cementum mineraliza- In order to understand the process of cementogenesis tion (30). In a similar manner, it was also determined it is important to know the composition of cemen- that the large chondroitin sulfate glycosaminoglycan, tum. As in bone and dentin, the major organic com- present in cementum, contains the large hyaluronan- ponent of cementum is collagen (18). The major type binding proteoglycan, versican, and the small intersti- of collagen is type I collagen, which accounts for 90% tial proteoglycans, decorin and biglycan. Versican is of all collagens and plays a structural