Molecular Quantity Variations in Human-Mandibular-Bone Osteoid.

Osteoid is a layer of new-formed bone that is deposited on the bone border during the process of new bone formation. This deposition process is crucial for bone tissue, and flaws in it can lead to bone diseases. Certain bone diseases, i.e. medication related osteonecrosis, are overexpressed in mandibular bone. Because mandibular bone presents different properties than other bone types, the data concerning osteoid formation in other bones are inapplicable for human-mandibular bone. Previously, the molecular distribution of other bone types has been presented using Fourier-transform infrared (FTIR) spectroscopy. However, the spatial distribution of molecular components of healthy-human-mandibular-bone osteoid in relation to histologic landmarks has not been previously presented and needs to be studied in order to understand diseases that occur human-mandibular bone. This study presents for the first time the variation in molecular distribution inside healthy-human-mandibular-bone osteoid by juxtaposing FTIR data with its corresponding histologic image obtained by autofluorescence imaging of its same bone section. During new bone formation, bone-forming cells produce an osteoid constituted primarily of type I collagen. It was observed that in mandibular bone, the collagen type I increases from the osteoblast line with the distance from the osteoblasts, indicating progressive accumulation of collagen during osteoid formation. Only later inside the collagen matrix, the osteoid starts to mineralize. When the mineralization starts, the collagen accumulation diminishes whereas the collagen maturation still continues. This chemical-apposition process in healthy mandibular bone will be used in future as a reference to understand different pathologic conditions that occur in human-mandibular bone.

Long bone histomorphogenesis of the naked mole-rat: Histodiversity and intraspecific variation.

Lacking fur, living in eusocial colonies and having the longest lifespan of any rodent, makes naked mole-rats (NMRs) rather peculiar mammals. Although they exhibit a high degree of polymorphism, skeletal plasticity and are considered a novel model to assess the effects of delayed puberty on the skeletal system, scarce information on their morphogenesis exists. Here, we examined a large ontogenetic sample (n = 76) of subordinate individuals to assess the pattern of bone growth and bone microstructure of fore- and hindlimb bones by using histomorphological techniques. Over 290 undecalcified thin cross-sections from the midshaft of the humerus, ulna, femur, and tibia from pups, juveniles and adults were analyzed with polarized light microscopy. Similar to other fossorial mammals, NMRs exhibited a systematic cortical thickening of their long bones, which clearly indicates a conserved functional adaptation to withstand the mechanical strains imposed during digging, regardless of their chisel-tooth predominance. We describe a high histodiversity of bone matrices and the formation of secondary osteons in NMRs. The bones of pups are extremely thin-walled and grow by periosteal bone formation coupled with considerable expansion of the medullary cavity, a process probably tightly regulated and adapted to optimize the amount of minerals destined for skeletal development, to thus allow the female breeder to produce a higher number of pups, as well as several litters. Subsequent cortical thickening in juveniles involves high amounts of endosteal bone apposition, which contrasts with the bone modeling of other mammals where a periosteal predominance exists. Adults have bone matrices predominantly consisting of parallel-fibered bone and lamellar bone, which indicate intermediate to slow rates of osteogenesis, as well as the development of poorly vascularized lamellar-zonal tissues separated by lines of arrested growth (LAGs) and annuli. These features reflect the low metabolism, low body temperature and slow growth rates reported for this species, as well as indicate a cyclical pattern of osteogenesis. The presence of LAGs in captive individuals was striking and indicates that postnatal osteogenesis and its consequent cortical stratification most likely represents a plesiomorphic thermometabolic strategy among endotherms which has been suggested to be regulated by endogenous rhythms. However, the generalized presence of LAGs in this and other subterranean taxa in the wild, as well as recent investigations on variability of environmental conditions in burrow systems, supports the hypothesis that underground environments experience seasonal fluctuations that may influence the postnatal osteogenesis of animals by limiting the extension of burrow systems during the unfavorable dry seasons and therefore the finding of food resources. Additionally, the intraspecific variation found in the formation of bone tissue matrices and vascularization suggested a high degree of developmental plasticity in NMRs, which may help explaining the polymorphism reported for this species. The results obtained here represent a valuable contribution to understanding the relationship of several aspects involved in the morphogenesis of the skeletal system of a mammal with extraordinary adaptations.

Quantifying maxillary development in chimpanzees and humans: An analysis of prognathism and orthognathism at the morphological and microscopic scales.

Facial orientation (projection and degree of prognathism) and form in hominins is highly variable, likely related to evolutionary modifications of the microscopic process of bone modeling (the simultaneous cellular activities of bone formation and resorption) during ontogeny. However, in anteriorly projected faces such as those of early hominins, little is known about the link between bone modeling and facial developmental patterns. Similarly, these aspects have been infrequently investigated in extant great apes. In this study, quantitative methods were applied to a cross-sectional ontogenetic sample of 33 chimpanzees (Pan troglodytes verus) and 59 modern humans (Homo sapiens) to compare the development of maxillary prognathism to orthognathism at both microscopic and macroscopic (or morphological) scales using surface histology and geometric morphometric techniques. Chimpanzees express on average lower amounts of bone resorption than humans on the maxillary periosteum throughout ontogeny; however, the premaxilla is consistently resorbed from early stages on. The presence of bone resorption in the chimpanzee premaxilla, such as that seen in some early hominins, suggests a more ape-like pattern of maxillary bone modeling in these specimens. However, this shows that similarities in bone modeling patterns can lead to variations in shape, suggesting that other aspects of facial growth (such as modifications of rates and timings of development, as well as sutural growth) also played a crucial role in facial evolution.

Trabecular bone properties in the ilium of the Middle Paleolithic/Middle Stone Age Border Cave 3 Homo sapiens infant and the onset of independent gait.

The Border Cave 3 (BC3) infant skeleton has been understudied, despite its importance as an example of a well-preserved and fairly complete immature skeleton of early Homo sapiens which potentially provides a rare window into various aspects of ontogenetic development, including locomotor activity (e.g., timing of gait events). Trabecular structure in the BC3 ilium was evaluated to investigate whether it matches that of an equivalently aged infant from a postindustrialized society. Microcomputed tomography (µCT) scans were acquired from the BC3 infant and from an ontogenetic series of 25 postindustrial infants that were divided into three age classes (ACs) ranging from neonates to toddlers (<36 months). All ilia were qualitatively compared and then digitally subdivided into 10 volumes of interest (VOIs) based on anatomical reference points. The VOIs were quantified and ontogenetic differences in trabecular structure were statistically evaluated. Across the comparative ontogenetic series, trabecular architectural properties overlapped in all regions. However, trabecular thickness increased significantly after the first year of life. The BC3 infant demonstrated generally similar trabecular structure to that observed in the age-equivalent postindustrial infants (AC2), including relatively strong development of the trabecular chiasma qualitatively. However, some interesting distinctions were observed in BC3, such as low strut thickness compared with infants from the postindustrial sample, that bear further exploration in future studies. Evaluation of only one individual from the Middle Stone Age (MSA), coupled with the relatively small comparative sample, limit our ability to distinguish more meaningful biological differences in trabecular structure throughout ontogeny from idiosyncratic characteristics. Nonetheless, results of this study extend ongoing research on infant locomotor and morphological development to archeological populations in the Middle Stone Age. Further cross-cultural studies consisting of larger comparative postindustrial samples may provide additional information on trabecular structure in the infant ilium during this important developmental timeframe.

Ontogenetic changes of tissue compartmentalization and bone type distribution in the humerus of Soay sheep.

We studied ontogenetic changes of histomorphological features and bone type distribution in the humeral midshaft region of Soay sheep from three postnatal age classes (13, 25, and 33 months). Our study demonstrated a marked change of bone type distribution in the humeri with age. In the cortical midshaft region of 13-month-old individuals, periosteal fibrolamellar bone was the dominating bone type. This indicates a rapid bone growth during the first year of life, which was only interrupted by a seasonal growth arrest in the animals' first winter. In individuals from the two older age classes, periosteal lamellar-zonal bone and intermediate fibrolamellar bone had been formed at the periosteal surface, and endosteal lamellar-zonal bone at the endosteal surface. These bone types are indicative of a reduced bone growth rate. A marked reduction in radial growth was already recorded in the 25-month-old individuals. Distribution and extent of secondary bone showed a marked bilateral symmetry in the humeri of individual sheep. The presence of secondary bone was largely restricted to the anterior (cranial) and the medial cortical areas. This characteristic distribution of remodeling activity within the humeral cortex of sheep is consistent with the view that remodeling activity is largely caused by compressive stress. Our study further demonstrated the presence of a considerable cortical drift in the sheep humeri over the study period, with endosteal resorption occurring predominantly in the posterior (caudal) quadrant and formation of a prominent endosteal lamellar pocket in the anterior (cranial) and medial cortical quadrants.

LPS-induced inflammation disorders bone modeling and remodeling by inhibiting angiogenesis and disordering osteogenesis in chickens.

Inflammation plays a negative role in the growth and development of bone. However, the underlining mechanisms of inflammation caused abnormal bone development and even bone disease are still poorly understood, especially in chickens. In this study, we explored the influence of inflammation on bone formation in broilers for the first time by using lipopolysaccharide (LPS) to establish systemic inflammatory models in chickens with tibia as the research object. The measurements of production and tibial parameters showed an inefficient production performance and lower growth rate in LPS group. We also found a large amount of platelets, inflammatory cells in chickens' blood and higher levels of inflammatory factors in serum after LPS injection, meanwhile, increase in thrombus, chondrocyte nucleolysis, and osteoclasts and a reduction in blood vessels were observed in growth plate through histological observation. The qPCR analysis showed that the mRNA expression levels of NF-κB, TLR4, TF, TPO, and its receptor C-MPL enhanced, while VEGFA was inhibited in LPS group. In addition, in OPG/RANKL system, OPG was decreased while RANKL enhanced. It was also observed that the mRNA levels of MMP-9 and its inducing factor CD147 enhanced in LPS group. The western blot results were basically in consistent with mRNA test. Thus, we infer that inflammation can inhibit bone modeling and remodeling by affecting angiogenesis and osteogenesis, and result in negative effect on bone formation furtherly.

The Cells of Bone and Their Interactions.

Bone tissue is comprised of a collagen-rich matrix containing non-collagenous organic compounds, strengthened by mineral crystals. Bone strength reflects the amount and structure of bone, as well as its quality. These qualities are determined and maintained by osteoblasts (bone-forming cells) and osteoclasts (bone-resorbing cells) on the surface of the bone and osteocytes embedded within the bone matrix. Bone development and growth also involves cartilage cells (chondrocytes). These cells do not act in isolation, but function in a coordinated manner, including co-ordination within each lineage, between the cells of bone, and between these cells and other cell types within the bone microenvironment. This chapter will briefly outline the cells of bone, their major functions, and some communication pathways responsible for controlling bone development and remodeling.

The role of nervous system in adaptive response of bone to mechanical loading.

Bone tissue is remodeled through the catabolic function of the osteoclasts and the anabolic function of the osteoblasts. The process of bone homeostasis and metabolism has been identified to be co-ordinated with several local and systemic factors, of which mechanical stimulation acts as an important regulator. Very recent studies have shown a mutual effect between bone and other organs, which means bone influences the activity of other organs and is also influenced by other organs and systems of the body, especially the nervous system. With the discovery of neuropeptide (calcitonin gene-related peptide, vasoactive intestinal peptide, substance P, and neuropeptide Y) and neurotransmitter in bone and the adrenergic receptor observed in osteoclasts and osteoblasts, the function of peripheral nervous system including sympathetic and sensor nerves in bone resorption and its reaction to on osteoclasts and osteoblasts under mechanical stimulus cannot be ignored. Taken together, bone tissue is not only the mechanical transmitter, but as well the receptor of neural system under mechanical loading. This review aims to summarize the relationship among bone, nervous system, and mechanotransduction.

Ontogeny of the human maxilla: a study of intra-population variability combining surface bone histology and geometric morphometrics.

Bone modeling is the process by which bone grows in size and models its shape via the cellular activities of the osteoblasts and osteoclasts that respectively form and remove bone. The patterns of expression of these two activities, visible on bone surfaces, are poorly understood during facial ontogeny in Homo sapiens; this is due mainly to small sample sizes and a lack of quantitative data. Furthermore, how microscopic activities are related to the development of morphological features, like the uniquely human-canine fossa, has been rarely explored. We developed novel techniques for quantifying and visualizing variability in bone modeling patterns and applied these methods to the human maxilla to better understand its development at the micro- and macroscopic levels. We used a cross-sectional ontogenetic series of 47 skulls of known calendar age, ranging from birth to 12 years, from a population of European ancestry. Surface histology was employed to record and quantify formation and resorption on the maxilla, and digital maps representing each individual's bone modeling patterns were created. Semilandmark geometric morphometric (GM) methods and multivariate statistics were used to analyze facial growth. Our results demonstrate that surface histology and GM methods give complementary results, and can be used as an integrative approach in ontogenetic studies. The bone modeling patterns specific to our sample are expressed early in ontogeny, and fairly constant through time. Bone resorption varies in the size of its fields, but not in location. Consequently, absence of bone resorption in extinct species with small sample sizes should be interpreted with caution. At the macroscopic level, maxillary growth is predominant in the top half of the bone where bone formation is mostly present. Our results suggest that maxillary growth in humans is highly constrained from early stages in ontogeny, and morphological changes are likely driven by changes in osteoblastic and osteoclastic rates of expression rather than differences in the bone modeling patterns (i.e. changes in location of formation and resorption). Finally, the results of the micro- and macroscopic analyses suggest that the development of the canine fossa results from a combination of bone resorption and bone growth in the surrounding region.

Consumption of Very Low Mineral Water Is Associated with Lower Bone Mineral Content in Children.

BACKGROUND: Our previous study found that consumption of very low mineral drinking water may retard height development in schoolchildren; however, its association with bone modeling remained unknown. OBJECTIVES: The aim of this study was to investigate the influence of very low mineral water on biomarkers of bone modeling in children. METHODS: A retrospective cohort study was conducted among 2 groups of 10-13-y-old children who had consumed drinking water with normal mineral contents (conductivity 345 µs/cm, the NW group including 119 boys and 110 girls) or very low mineral contents (conductivity 40.0 µs/cm, the VLW group including 223 boys and 208 girls) in school for 4 y. Differences in daily total mineral intakes, developmental parameters, serum biomarkers of osteoblast activity, and bone formation and resorption between the 2 groups were analyzed with independent t test and chi-square test. Associations of developmental parameters and serum biomarkers with Ca intake from drinking water were analyzed with multiple linear regression and binary logistic regression. RESULTS: Compared with the NW group, the VLW group had lower daily Ca intake, height increase, bone mineral content (BMC), osteoblast activity [serum bone alkaline phosphatase (BALP)] (means ± SDs: 433 ± 131 mg, 16.6 ± 8.27 cm, 1.92 ± 0.431 kg, and 9.28 ± 1.42 µg/L compared with 497 ± 155 mg, 22.3 ± 8.45 cm, 2.14 ± 0.354 kg, and 11.0 ± 0.823 µg/L, respectively, P < 0.001), and higher bone resorption [serum crosslinked C-telopeptide of type I collagen (CTX), mean ± SD: 142 ± 46.9 nmol/L compared with 130 ± 40.6 nmol/L, P = 0.001). Ca intake from drinking water was positively associated with height increase, BMC, and BALP (ß: 0.0667, 95% CI: 0.0540, 0.0793; ß: 3.22, 95% CI: 2.37, 4.08; and ß: 23.9, 95% CI: 20.6, 27.2), respectively, P < 0.001), and was negatively associated with CTX (ß: -0.206, 95% CI:-0.321, -0.0904, P < 0.001). CONCLUSIONS: These changes suggested that consumption of very low mineral water may be associated with osteoblast inhibition, bone resorption activation, bone mineral reduction, and height development retardation. The health risk of consuming very low mineral water should be considered in children.

Accumulation of microdamage in subchondral bone at the femoral head in patients with end-stage osteoarthritis of the hip.

In end-stage osteoarthritis (OA) of the hip, the effect of bone metabolism with and without cartilage is unclear. In this study, we aimed to investigate histomorphology and microdamage in the subchondral bone of the femoral head in areas with and without articular cartilage in patients with end-stage OA. Nineteen femoral heads were evaluated in 10 women who underwent total hip arthroplasty for OA and in nine cadaveric controls (CNT). Chondral thickness and subchondral bone plate thickness (SBP.Th) were measured in 5-mm-wide areas where cartilage was lost (area A) or preserved (area B) in OA and in corresponding areas in the load-bearing portion of the femoral head in the CNT. Histomorphometry and microdamage in 5 × 5-mm areas of cancellous bone were assessed. SBP.Th and bone volume were significantly greater in area A than in area B or in the CNT. Osteoid volume was significantly greater in area A than in area B or in the CNT. There was no significant difference in eroded surface between area A and CNT. Microcrack density was significantly greater in area A than in area B or in the CNT. Although accumulation of microdamage was caused by concentration of stress on the subchondral bone in the cartilage loss area in end-stage OA, remodeling for microdamage repairing mechanism was not enhanced. It was considered that the subchondral cancellous bone volume was increased because of modeling, not remodeling, by stress concentration due to articular cartilage loss.

The role of Rho-GEF Trio in regulating tooth root development through the p38 MAPK pathway.

Trio, the Rho guanine nucleotide exchange factor (Rho-GEF), plays diverse roles in cell migration, cell axon guidance and cytoskeleton reorganization. Conserved during evolution, Trio encodes two guanine nucleotide exchange factor domains (GEFs) and activates small GTPases. The Rho-family small GTPases RhoA and Rac1, which are target molecules of Trio, have been described to engage in craniofacial development and tooth formation. However, the exact role of Trio in tooth development remains elusive. In this study, we generated Wnt1-cre;Triofl/fl mice to address the potential function of Trio in tooth development. Wnt1-cre;Triofl/fl mice showed short root deformity as well as decreased expression of odontogenic makers such as RUNX2, OSX, OCN, and OPN. In vitro, Trio was silenced in human stem cells of dental papilla (SCAPs). Compared with the control group, the proliferation and migration ability in the experimental group was disrupted. After knocking down Trio in SCAPs, the cells showed phenotypes of poor odontogenic differentiation and weak mineralized nodules. To study the underlying mechanism, we investigated the p38 MAPK pathway and found that loss of Trio blocked the cascade transduction of p38 MAPK signaling. In conclusion, we identified Trio as a novel coordinator in regulating root development and clarified its relevant molecular events.

Long bone histology of the subterranean rodent Bathyergus suillus (Bathyergidae): ontogenetic pattern of cortical bone thickening.

Patterns of bone development in mammals are best known from terrestrial and cursorial groups, but there is a considerable gap in our understanding of how specializations for life underground affect bone growth and development. Likewise, studies of bone microstructure in wild populations are still scarce, and they often include few individuals and tend to be focused on adults. For these reasons, the processes generating bone microstructural variation at intra- and interspecific levels are not fully understood. This study comprehensively examines the bone microstructure of an extant population of Cape dune molerats, Bathyergus suillus (Bathyergidae), the largest subterranean mammal endemic to the Western Cape of South Africa. The aim of this study is to investigate the postnatal bone growth of B. suillus using undecalcified histological sections (n = 197) of the femur, humerus, tibia-fibula, ulna and radius, including males and females belonging to different ontogenetic and reproductive stages (n = 42). Qualitative histological features demonstrate a wide histodiversity with thickening of the cortex mainly resulting from endosteal and periosteal bone depositions, whilst there is scarce endosteal resorption and remodeling throughout ontogeny. This imbalanced bone modeling allows the tissues deposited during ontogeny to remain relatively intact, thus preserving an excellent record of growth. The distribution of the different bone tissues observed in the cortex depends on ontogenetic status, anatomical features (e.g. muscle attachment structures) and location on the bone (e.g. anterior or lateral). The type of bone microstructure and modeling is discussed in relation to digging behavior, reproduction and physiology of this species. This study is the first histological assessment describing the process of cortical thickening in long bones of a fossorial mammal.

Bone Matrix Maturation in a Rat Model of Intra-Cortical Bone Remodeling.

Matrix maturation within cortical bone is an important but oft-neglected component of bone remodeling because of the lack of a suitable small animal model. Intra-cortical remodeling can be induced in rodents by feeding virgin or lactating animals a low-calcium diet. The current study aimed to determine which of these two models is most suitable for studying intra-cortical matrix maturation. We compared intra-cortical remodeling in female rats fed a normal calcium diet (virgin/normal Ca), a low-calcium diet (virgin/low Ca), or a low-calcium diet during lactation (lactation/low Ca). The low-calcium diet was administered for 23 days (induction phase) followed by return to normal calcium for 30 days (recovery phase). At the end of induction, the virgin/normal Ca and virgin/low-Ca animals had no difference in cortical porosity, but the lactation/low-Ca animals had elevated cortical porosity at various diaphyseal sites in the femur and tibia. The distal femoral site had the greatest amount of induced porosity in the size range of rat secondary osteons. Neither global mineralization nor tissue age-specific mineral-to-matrix ratio in the bone formed during recovery were affected in the lactation/low-Ca rats. Serum calcium levels did not differ from controls, but phosphate levels were slightly elevated, consistent with the rapid recovery of lost bone mass. We conclude that the lactation/low-Ca model represents a means to increase intra-cortical remodeling in adult rats with no apparent detrimental effect on matrix maturation. This model will provide researchers with a new tool to study matrix maturation throughout the cortex.

Cathepsin K Inhibition: A New Mechanism for the Treatment of Osteoporosis.

Cathepsin K (CatK), a cysteine protease, is highly expressed by osteoclasts and very efficiently degrades type I collagen, the major component of the organic bone matrix. Robust genetic and pharmacological preclinical studies consistently demonstrate that CatK inhibition increases bone mass, improves bone microarchitecture and strength. Recent advances in the understanding of the molecular and cellular mechanisms involved in bone modeling and remodeling suggest that inhibition of CatK decreases bone resorption, but increases the number of cells of osteoclast lineage. This in turn maintains the signals for bone formation, and perhaps may even increase bone formation on some cortical surfaces. Several CatK inhibitors, including relacatib, balicatib, odanacatib and ONO-5334 had entered clinical development for metabolic bone disorders with increased bone resorption, such as postmenopausal osteoporosis. However, odanacatib (ODN) is the only candidate continuing in development. ODN is a highly selective oral CatK inhibitor dosed once-weekly in humans. In a Phase 2 clinical trial, postmenopausal women treated with ODN had sustained reductions of bone resorption markers, while bone formation markers returned to normal after an initial decline within the first 2 years on treatment. In turn areal bone mineral density increased continuously at both spine and hip for up to 5 years. ODN has also been demonstrated to improve bone mass in women with postmenopausal osteoporosis previously treated with alendronate and in men with osteoporosis. ODN is currently in a worldwide Phase 3 fracture outcome trial for the treatment of postmenopausal osteoporosis with interim results supporting its anti-fracture efficacy at the spine, hip and non-vertebral sites.

Sclerostin Inhibition in the Management of Osteoporosis.

The recognition of the importance of the Wnt-signaling pathway in bone metabolism and studies of patients with rare skeletal disorders characterized by high bone mass identified sclerostin as target for the development of new therapeutics for osteoporosis. Findings in animals and humans with sclerostin deficiency as well as results of preclinical and early clinical studies with sclerostin inhibitors demonstrated a new treatment paradigm with a bone building agent for the management of patients with osteoporosis, the antifracture efficacy, and long-term tolerability of which remain to be established in on-going phase III clinical studies. In this article we review the currently available preclinical and clinical evidence supporting the use of sclerostin inhibitors in osteoporosis.

The response of anosteocytic bone to controlled loading.

The bones of the skeleton of most advanced teleost fish do not contain osteocytes. Considering the pivotal role assigned to osteocytes in the process of modeling and remodeling (the adaptation of external and internal bone structure and morphology to external loads and the repair of areas with micro-damage accumulation, respectively) it is unclear how, and even whether, their skeleton can undergo modeling and remodeling. Here, we report on the results of a study of controlled loading of the anosteocytic opercula of tilapia (Oreochromis aureus). Using a variety of microscopy techniques we show that the bone of the anosteocytic tilapia actively adapts to applied loads, despite the complete absence of osteocytes. We show that in the directly loaded area, the response involves a combination of bone resorption and bone deposition; we interpret these results and the structure of the resultant bone tissue to mean that both modeling and remodeling are taking place in response to load. We further show that adjacent to the loaded area, new bone is deposited in an organized, layered manner, typical of a modeling process. The material stiffness of the newly deposited bone is higher than that of the bone which was present prior to loading. The absence of osteocytes requires another candidate cell for mechanosensing and coordinating the modeling process, with osteoblasts seeming the most likely candidates.

Personalized and precision orthodontic therapy.

OBJECTIVE: To bring together orthodontic stakeholders from academics, industry, and private practice for a series of thematically focused workshops to explore and develop the transfer of novel approaches into clinical orthodontic practice. SETTING AND SAMPLE POPULATION: Twenty-seven invited speakers, eight poster presenters, and participants of the Consortium for Orthodontic Advances in Science and Technology (COAST) 2014 Innovators' Workshop at the Eaglewood Resort and Spa, Itasca, Illinois, September 11-14, 2014. MATERIAL AND METHODS: Five themed sessions involving between 4-7 presentations followed by panel discussions were organized. The aims of the discussion sessions were to highlight important findings and consider the strength of evidence for these, indicate next steps and needed research or technological developments to move forward, and to weigh the expected benefits from these findings and steps to implement in clinical practice. RESULTS: Among important areas for attention identified were need for multiscale and multispecies modeling and experimentation for interspecies translation of results; large-scale collaborative efforts within the profession to address the need for adequate sample sizes for future genetic studies of complex traits such as malocclusion; a consortium approach to improve new technologies such as intra-oral scanning and 3D imaging by establishing standards; and harnessing the growing body of knowledge about bone biology for application in orthodontics. CONCLUSIONS: With increased awareness of the potential of current and emerging technologies, translation of personalized and precision approaches in the field of orthodontics holds ever-increasing promise.

Resorption controls bone anabolism driven by parathyroid hormone (PTH) receptor signaling in osteocytes.

The contribution of remodeling-based bone formation coupled to osteoclast activity versus modeling-based bone formation that occurs independently of resorption, to the anabolic effect of PTH remains unclear. We addressed this question using transgenic mice with activated PTH receptor signaling in osteocytes that exhibit increased bone mass and remodeling, recognized skeletal effects of PTH elevation. Direct inhibition of bone formation was accomplished genetically by overexpressing the Wnt antagonist Sost/sclerostin; and resorption-dependent bone formation was inhibited pharmacologically with the bisphosphonate alendronate. We found that bone formation induced by osteocytic PTH receptor signaling on the periosteal surface depends on Wnt signaling but not on resorption. In contrast, bone formation on the endocortical surface results from a combination of Wnt-driven increased osteoblast number and resorption-dependent osteoblast activity. Moreover, elevated osteoclasts and intracortical/calvarial porosity is exacerbated by overexpressing Sost and reversed by blocking resorption. Furthermore, increased cancellous bone is abolished by Wnt inhibition but further increased by blocking resorption. Thus, resorption induced by PTH receptor signaling in osteocytes is critical for full anabolism in cortical bone, but tempers bone gain in cancellous bone. Dissecting underlying mechanisms of PTH receptor signaling would allow targeting actions in different bone compartments, enhancing the therapeutic potential of the pathway.

Periosteal PTHrP regulates cortical bone modeling during linear growth in mice.

The modeling of long bone surfaces during linear growth is a key developmental process, but its regulation is poorly understood. We report here that parathyroid hormone-related peptide (PTHrP) expressed in the fibrous layer of the periosteum (PO) drives the osteoclastic (OC) resorption that models the metaphyseal-diaphyseal junction (MDJ) in the proximal tibia and fibula during linear growth. PTHrP was conditionally deleted (cKO) in the PO via Scleraxis gene targeting (Scx-Cre). In the lateral tibia, cKO of PTHrP led to a failure of modeling, such that the normal concave MDJ was replaced by a mound-like deformity. This was accompanied by a failure to induce receptor activator of NF-kB ligand (RANKL) and a 75% reduction in OC number (P ≤ 0.001) on the cortical surface. The MDJ also displayed a curious threefold increase in endocortical osteoblast mineral apposition rate (P ≤ 0.001) and a thickened cortex, suggesting some form of coupling of endocortical bone formation to events on the PO surface. Because it fuses distally, the fibula is modeled only proximally and does so at an extraordinary rate, with an anteromedial cortex in CD-1 mice that was so moth-eaten that a clear PO surface could not be identified. The cKO fibula displayed a remarkable phenotype, with a misshapen club-like metaphysis and an enlargement in the 3D size of the entire bone, manifest as a 40-45% increase in the PO circumference at the MDJ (P ≤ 0.001) as well as the mid-diaphysis (P ≤ 0.001). These tibial and fibular phenotypes were reproduced in a Scx-Cre-driven RANKL cKO mouse. We conclude that PTHrP in the fibrous PO mediates the modeling of the MDJ of long bones during linear growth, and that in a highly susceptible system such as the fibula this surface modeling defines the size and shape of the entire bone.