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The underlying mechanisms of human bone morphogenesis leading to a topologically specific shape remain unknown, despite increasing knowledge of the basic molecular aspects of bone formation and its regulation. The formation of the alveolar bone, which houses the dental primordia, and later the dental roots, may serve as a model to approach general questions of bone formation. Twenty-five heads of human embryos and fetuses (Radlanski-Collection, Berlin) ranging from 19mm to 270mm (crown-rump-length) CRL were prepared as histological serial sections. For each stage, virtual 3D-reconstructions were made in order to study the morphogenesis of the mandibular molar primordia with their surrounding bone. Special focus was given to recording the bone-remodeling pattern, as diagnosed from the histological sections. In early stages (19-31mm CRL) developing bone was characterized by appositional only. At 41, in the canine region, mm CRL bony extensions were found forming on the bottom of the trough. Besides general apposition, regions with resting surfaces were also found. At a fetal size of 53mm CRL, septa have developed and led to a compartment for canine development. Furthermore, one shared compartment for the incisor primordia and another shared compartment for the molars also developed. Moreover, the inner surfaces of the dental crypts showed resorption of bone. From this stage on, a general pattern became established such that the compartmentalizing ridges and septa between all of the dental primordia and the brims of the crypts were noted, and were due to appositional growth of bone, while the crypts enlarged on their inner surfaces by resorption. By 160mm CRL, the dental primordia were larger, and all of the bony septa had become reduced in size. The primordia for the permanent teeth became visible at 225mm CRL and shared the crypts of their corresponding deciduous primordia., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Eruption requires synchrony of the tooth with the surrounding tissues, particularly the bone. One important step during eruption is remodelling of the alveolar bone at the base of the tooth and along the roots. Expression of BMP6 was reported to be increased in the basal half of the dental follicle prior to eruption and inhibition of BMP6 affected bone formation at the base of the alveolar crypt. The aim of this study was to further investigate BMP6 protein in relation to tooth eruption and the corresponding bone remodelling using temporospatial correlations of BMP6 localization with morphogenetic events (proliferation, differentiation, apoptosis and bone apposition/resorption), other BMPs (BMP2 and BMP7) and three-dimensional images of tooth-bone development. BMP6 expression pattern was mapped in the mandibular molar teeth and related structures around eruption. Localization of BMP6 dominated in osteoblasts, in regions of bone formation within the alveolar crypt. These findings positively correlated with proliferation at the tooth base region, osteocalcin expression in the osteoblasts/osteocytes and BMP2 and BMP7 presence in the alveolar bone surrounding the tooth. Osteoclast activity and apoptotic elimination in the root region gradually decreased before eruption and totally ceased at eruption stages. Generally, BMP6 positively correlated with BMP2, BMP7 and osteocalcin-positive osteoblasts, and areas of bone remodelling. Moreover, BMP6 was found in the periodontium and cementoblasts. BMP6 expression in the alveolar bone accompanied tooth eruption. Notably, the expression pattern of BMP6 in the bone did not differ around individual molar teeth at the same stage of development. The expression of BMP6 in periodontal ligaments may contribute to interaction between the tooth and bone during the eruption and anchoring process.

From a morphogenetic point of view, the mental foramen of the mandible is a highly suitable model to study the interactions of different tissues such as nerves, vessels, mesenchymal cells, cartilage, and bone. In previous work, we provided a three-dimensional description of the mental foramen at different developmental stages, and now we complement those studies with a three-dimensional visualization of different bone remodeling activities around the mental foramen. Histological serial sections of human embryos and fetuses, ranging in size from 25 to 117 mm crown-rump-length (CRL), were used to characterize the bone remodeling activity (apposition, inactivity, and resorption). We quantified and reconstructed this activity in three dimensions, and included information on the spatial relationship of the nerves, vessels, and dental primordia. In general, the mandible showed strong apposition at its outer surfaces. The brim of the mental foramen, however, displayed changing remodeling activity at different stages. In the depth of the bony gutter, which provides space for the nerve and the blood vessels, we found bone resorption beneath the inferior alveolar vein. Bone was also resorbed in proximity to the dental primordia. In future studies, we will relate gene expression data to these morphological findings in order to identify molecular mechanisms that regulate this complex system.

Human embryos and fetuses ( n=25) ranging from 12 to 117 mm CRL (crown-rump-length) were serially sectioned and the mandibles were reconstructed in 3D. In addition, characteristic areas of apposition, resorption and resting zones were projected onto the surface of the mandibular reconstructions after histological evaluation of the remodeling processes. Furthermore, morphometric data were taken to describe growth processes in horizontal views. In this way the changing outlines as seen in 3D could be correlated with the remodeling patterns and with the changes in growth. In these stages the mandible showed a general appositional growth, but resorption areas were found at the posterior margins of the mental foramen and at the lateral and medial posterior bony planes at concave surfaces. The bulging of bone underneath and over Meckel's cartilage could be recognized as active appositional growth areas. Meckel's cartilage itself lay in a trough which could be characterized by less apposition and even resorption. Questions were raised in how much the gap between our present knowledge of genetic expression of signaling molecules and the precise morphologic description of the mandibles can be bridged.

Material and Method: Based on histological serial sections of human fetuses (22-117 mm crown-rump length) the remodeling of the bone surfaces of the fetal mandible was characterized and visualized in 3D reconstructions., Results: In the embryo of 22 mm crown-rump length the mandible was completely covered by cells producing bone apposition, but beginning with the embryo of 25 mm crown-rump length, morphological differentiations of these cells leading to bone modeling were visible. These modeling processes were found to be much more complicated than described in the literature so far., Conclusion: Bone growth of the fetal mandible is a complex process comprising not only lingual resorption and buccal apposition. Instead, we found well differentiated remodeling processes, represented by variable portions of apposition, resorption and resting areas seamed by lining cells.

Quantitative analysis of remodeling activity was done using microradiographs of horizontal ground sections of human alveolar bone obtained from autopsies. The results demonstrated no significant age- or sex-dependent variations. The local distribution of remodeling activity in younger individuals pointed to a tipping mesial movement of the teeth. In older individuals this distribution showed a more random pattern.

Orthodontic tooth movement of upper first molars was performed in twelve aged (500 days old) rats. It was demonstrated by histomorphologic findings as well as by vital polychrome staining that the remodelling process of the periodontal tissues in the aged animals was qualitatively similar to that in younger ones. The first molar in all animals was tipped mesially, while its mesial root was intruded. According to the vital polychrome staining the bone formation rate at the mesio-apical bone surface of the mesial root was determined as 7-8 microns per day. After 14 days comprehensive root resorption in the pressure zone distal of the bifurcation was found.