Regeneration of Periodontal Tissues: Cementogenesis Revisited

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Regeneration of Periodontal Tissues: Cementogenesis Revisited Periodontology 2000, Vol. 41, 2006, 196–217 Copyright Ó Blackwell Munksgaard 2006 Printed in Singapore. All rights reserved PERIODONTOLOGY 2000 Regeneration of periodontal tissues: cementogenesis revisited MARGARITA ZEICHNER-DAVID Virtually all types of periodontal disease are caused responsible for the attachment of teeth in the oral by periodontal pocket infections, although several cavityÕ (144). Several excellent reviews have been other factors, including trauma, aging, systemic dis- published describing the embryonic lineage of the eases, genetics, etc., can contribute to the destruction principal periodontal tissues (cementum, periodontal of the periodontium (1, 18, 31, 52, 60, 107, 128, 127, ligament, gingiva and alveolar bone), as well as the 194). Repair of the periodontium and the regener- cells and extracellular matrix components of the ation of periodontal tissues remains a major goal in periodontium (10, 13, 14, 21, 19, 46, 45, 51, 71, 80, 82, the treatment of periodontal disease and is an area 144, 158, 185, 186, 193, 212, 214, 243, 244, 245). still in need of major research attention, as recently Formation of the periodontium is initiated with stated by the American Academy of Periodontology the process of root formation where, following (260). In general, to achieve complete tissue regen- crown formation, the apical mesenchyme continues eration and repair, it is necessary to recapitulate the to proliferate to form the developing periodontium, process of embryogenesis and morphogenesis in- while the inner and outer enamel epithelia fuse volved in the original formation of the tissue. In the below the level of the cervical enamel to produce a case of the periodontium, complete periodontal re- bilayered epithelial sheath, termed the Hertwig’s pair entails de novo cementogenesis, osteogenesis epithelial root sheath. As these cells divide, there is and the formation of periodontal ligament fibers. an apical migration of the Hertwig’s epithelial root Current strategies for periodontal repair are based on sheath cells through the underlying dental ectome- anti-infectious measures such as scaling and root senchymal tissues, dividing them into the dental planing, guided tissue regeneration (with or without papilla and the dental follicle (Fig. 1). As the root bone grafts) or the use of growth factors, none of develops, the first radicular mantle dentin is formed which fully restore the architecture of the original and the epithelial sheath is fenestrated. It is believed periodontium. Several different approaches involving that cells of the Hertwig’s epithelial root sheath tissue engineering are currently being explored to migrate away from the root into the region of the achieve complete, reliable and reproducible regen- future periodontal ligament where they re-associate eration of the periodontium. As tissue engineering is to form the Epithelial Rest of Malassez. However, defined as the science that develops techniques not all Hertwig’s epithelial root sheath cells migrate (based on principles of cell and developmental bio- into the periodontal ligament site; a few undergo logy) for fabricating new tissues to replace or regen- apoptosis and some remain in the root surface erate lost tissues (205), it is important to understand (108). the formation of specific tissues, the physico-chem- Although it is accepted that the Hertwig’s epithelial ical characteristics of the tissues and the molecular root sheath plays an important role in root develop- events leading to the normal function of the tissues. ment, the precise nature of its role remains contro- versial. In 1940, Schour & Massler suggested that the major function of the Hertwig’s epithelial root sheath Development of the periodontium was to induce and regulate root formation, including the size, shape and number of roots (244). Other The periodontium can be defined as Ôan intricate investigators suggested that the role of the Hertwig’s mosaic of cells and proteins that is primarily epithelial root sheath was to induce the differentiation 196 Regeneration of periodontal tissues: cementogenesis revisited Fig. 1. Root development and periodontium formation. continues, and there is formation of the periodontium Histological sections of 7-day postnatal mouse mandibu- with cementum, periodontal ligament and bone. Am, lar molars showing the initial development of the root by ameloblasts; C, cementum; D, dentin; Ds, dental sac; formation of the Hertwig’s epithelial root sheath. At the HERS, Hertwig’s epithelial root sheath; Od, odontoblasts; 14-day postnatal time-point, apical migration of the roots PDL, periodontal ligament. of odontoblasts to form the root dentin (183, 182, 222, chymal transformation to become functional ce- 243, 251), or to differentiate dental sac cells into mentoblasts in charge of producing the acellular cementoblasts (181). The current notion states that cementum (251, 275). Hertwig’s epithelial root sheath cells produce the The gingival tissues appear to be derived from both basement membrane containing chemotactic pro- the oral mucosa and the developing tooth germ (135). teins, which serve to direct the migration of prece- It has been suggested that the dental follicle (con- mentoblast cells (140, 141, 182, 235, 251) and to nective tissue surrounding the developing teeth) induce cementoblast differentiation (191, 232, 234). gives rise to the fibroblasts forming the periodontal Amongst the basement membrane molecules are ligament as well as to the alveolar bone and several extracellular matrix proteins, growth factors, cementoblasts (45, 136, 186, 243), all of which have enamel proteins and adhesion molecules, such as a a common neural crest origin (34). Therefore, it is collagenous-like protein, known as cementum postulated that there are different types of attachment protein (CAP), which has chemotactic cementoblasts: those originating from the Hertwig’s potential capable of recruiting putative cementoblast epithelial root sheath via epithelial–mesenchymal precursors (11, 149, 156, 196, 275). In the second transformation and which form the acellular stage of cementogenesis (when the tooth reaches cementum; and those derived from the dental follicle, occlusion and cellular cementum is formed), the which form the cellular cementum (9, 19, 105, 251, proliferation of cells of the Hertwig’s epithelial root 275). It is also believed that progenitors for perio- sheath is considerably reduced, and some cells are dontal ligament, osteoblast and cementoblast cells entrapped in the newly formed mineral where they adopt a paravascular location in the periodontal may influence phenotypic changes in the dental sac ligament, and these cells, which exhibit some fea- cells (252). It is also suggested that Hertwig’s epi- tures of stem cells, can regenerate functional tissues thelial root sheath cells undergo epithelial–mesen- when the need arises (150–153, 195). Periodontal 197 Zeichner-David ligament stem cells have recently been isolated from may negatively regulate root resorption and induce the human periodontium (162, 224, 225). acellular cementum formation (56). In addition, cells The Epithelial Rest of Malassez cells remain in the of the Epithelial Rest of Malassez may help in ce- periodontal ligament throughout life, suggesting that mentum repair because of their ability to activate they have important, although yet unknown, func- matrix proteins, such as amelogenin, which are also tions, rather than just being leftover structures. Roles expressed during tooth development (76, 81). attributed to the Epithelial Rest of Malassez cells In summary, based on the information presented, it range from bad to good. The Epithelial Rest of appears that the developed or ÔadultÕ periodontium Malassez cells are held responsible for the formation retains its potential for repair/regeneration in the form of periodontal cysts and tumors as a result of peri- of cells of the Epithelial Rest of Malassez, progenitor apical inflammation associated with pulpal necrosis cells and stem cells, which can be induced to differ- (26, 57, 77, 176, 226, 242). It has also been suggested entiate into cementoblast, osteoblast or periodontal that Epithelial Rest of Malassez cells contribute to the ligament cells to regenerate periodontal tissues. formation of the periodontal pocket because of their continuum with the junctional epithelium (176, 238). Molecular factors involved in Some studies report the ability of Epithelial Rest of periodontal development Malassez cells to resorb bone and extracellular mat- rix, and thus implicate the cells in root resorption (15, It is well known that tooth development is regulated by 75, 122). On the other hand, it has also been sug- temporal- and spatial-restricted reciprocal epithelial– gested that the cells of the Epithelial Rest of Malassez mesenchymal interactions. A number of genes that may protect the root from resorption (259). The play a crucial role in tooth development have been finding of Epithelial Rest of Malassez cells being identified and include growth factors and their closely associated with neural endings suggests that receptors, such as transforming growth factor b-1 they have a role in the development of periodontal and )2, bone morphogenetic protein-2 and )4 ligament innervation (126). Studies performed with (BMP-2, )4), activins, fibroblast growth factor-4, )8 1-hydroxyethylidene-1,1-bisphosphonate, a drug that and )9 (FGF-4, )8, )9), hepatocyte growth factor, and interferes with homeostasis in the periodontal liga- midkine and transcription
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