Exercise promotes gain in bone mass through adaptive responses of the vertebrate skeleton. This mechanism counteracts age- and disease-related skeletal degradation, but remains to be fully understood. In life sciences, zebrafish emerged as a vertebrate model that can provide new insights into the complex mechanisms governing bone quality. To test the hypothesis that musculoskeletal exercise induces bone adaptation in adult zebrafish and to characterize bone reorganization, animals were subjected to increased physical exercise for four weeks in a swim tunnel experiment. Cellular, structural and compositional changes of loaded vertebrae were quantified using integrated high-resolution analyses. Exercise triggered rapid bone adaptation with substantial increases in bone-forming osteoblasts, bone volume and mineralization. Clearly, modeling processes in zebrafish bone resemble processes in human bone. This study highlights how exercise experiments in adult zebrafish foster in-depth insight into aging-related bone diseases and can thus catalyze the search for appropriate prevention and new treatment options.
Excessive skeletal deformations and brittle fractures in the vast majority of patients suffering from osteogenesis imperfecta (OI) are a result of substantially reduced bone quality. Because the mechanical competence of bone is dependent on the tissue characteristics at small length scales, it is of crucial importance to assess how OI manifests at the micro- and nanoscale of bone. In this context, the Chihuahua (Chi/+) zebrafish, carrying a heterozygous glycine substitution in the α1 chain of collagen type I, has recently been proposed as a suitable animal model of classical dominant OI, showing skeletal deformities, altered mineralization patterns, and a smaller body size. This study assessed the bone quality properties of Chi/+ at multiple length scales using micro-computed tomography (micro-CT), histomorphometry, quantitative back-scattered electron imaging, Fourier-transform infrared spectroscopy, nanoindentation, and X-ray microscopy. At the skeletal level, the Chi/+ displays smaller body size, deformities, and fracture calli in the ribs. Morphological changes at the whole bone level showed that the vertebrae in Chi/+ had a smaller size, smaller thickness, and distorted shape. At the tissue level, Chi/+ displayed a higher degree of mineralization, lower collagen maturity, lower mineral maturity, altered osteoblast morphology, and lower osteocyte lacunar density compared to wild-type zebrafish. The alterations in the cellular, compositional, and structural properties of Chi/+ bones bear an explanation for the impaired local mechanical properties, which promote an increase in overall bone fragility in Chi/+. The quantitative assessment of bone quality in Chi/+ thus further validates this mutant as an important model reflecting osseous characteristics associated with human classical dominant OI. © 2018 American Society for Bone and Mineral Research.
Zebrafish are teleosts (bony fish) that share with mammals a common ancestor belonging to the phylum Osteichthyes, from which their endoskeletal systems have been inherited. Indeed, teleosts and mammals have numerous genetically conserved features in terms of skeletal elements, ossification mechanisms, and bone matrix components in common. Yet differences related to bone morphology and function need to be considered when investigating zebrafish in skeletal research. In this review, we focus on zebrafish skeletal architecture with emphasis on the morphology of the vertebral column and associated anatomical structures. We provide an overview of the different ossification types and osseous cells in zebrafish and describe bone matrix composition at the microscopic tissue level with a focus on assessing mineralization. Processes of bone formation also strongly depend on loading in zebrafish, as we elaborate here. Furthermore, we illustrate the high regenerative capacity of zebrafish bones and present some of the technological advantages of using zebrafish as a model. We highlight zebrafish axial and fin skeleton patterning mechanisms, metabolic bone disease such as after immunosuppressive glucocorticoid treatment, as well as osteogenesis imperfecta (OI) and osteopetrosis research in zebrafish. We conclude with a view of why larval zebrafish xenografts are a powerful tool to study bone metastasis. © 2021 American Society for Bone and Mineral Research (ASBMR).
The purpose of this study was to evaluate the cellular compatibility of five endodontic sealers in the first 24 h after mixing. Specimens of N2, Endomethasone, Apexit, AH Plus, and Ketac Endo were extracted with cell culture medium 0, 1, 5, and 24 h after mixing. Eluates were tested for cytotoxicity with immortal 3T3 cells and primary human periodontal ligament fibroblasts using XTT-assays. Data were analyzed for statistically significant differences by means of Dunnett's t tests (p < 0.05). All extracts of N2 completely inhibited cell metabolism (p < 0.05). Similar effects were provoked by the first three eluates of Endomethasone, but the 24-h extract irritated cells significantly less (p < 0.05). Severe cytotoxicity was also observed with all Ketac Endo extracts (p < 0.05). A significant inhibition of mitochondrial activity was induced by the first (3T3) or the first and second eluate (periodontal ligament fibroblasts) of AH Plus (p < 0.05). The subsequent eluates of this sealer and all extracts of Apexit did not reveal any cytotoxic potency.
Dietary phosphorus (P) is essential for bone mineralisation in vertebrates. P deficiency can cause growth retardation, osteomalacia and bone deformities, both in teleosts and in mammals. Conversely, excess P supply can trigger soft tissue calcification and bone hypermineralisation. This study uses a wide range of complementary techniques (X-rays, histology, TEM, synchrotron X-ray tomographic microscopy, nanoindentation) to describe in detail the effects of dietary P on the zebrafish skeleton, after two months of administering three different diets: 0.5% (low P, LP), 1.0% (regular P, RP), and 1.5% (high P, HP) total P content. LP zebrafish display growth retardation and hypomineralised bones, albeit without deformities. LP zebrafish increase production of non-mineralised bone matrix, and osteoblasts have enlarged endoplasmic reticulum cisternae, indicative for increased collagen synthesis. The HP diet promotes growth, high mineralisation, and stiffness but causes vertebral centra fusions. Structure and arrangement of bone matrix collagen fibres are not influenced by dietary P in all three groups. In conclusion, low dietary P content stimulates the formation of non-mineralised bone without inducing malformations. This indicates that bone formation and mineralisation are uncoupled. In contrast, high dietary P content promotes mineralisation and vertebral body fusions. This new zebrafish model is a useful tool to understand the mechanisms underlying osteomalacia and abnormal mineralisation, due to underlying variations in dietary P levels.
Bone continuously adapts to its mechanical environment by structural reorganization to maintain mechanical strength. As the adaptive capabilities of bone are portrayed in its nano-and microstructure, the existence of dark and bright osteons with contrasting preferential collagen fiber orientation (longitudinal and oblique-angled, respectively) points at a required tissue heterogeneity that contributes to the excellent fracture resistance mechanisms in bone. Dark and bright osteons provide an exceptional opportunity to deepen our understanding of how nanoscale tissue properties influence and guide fracture mechanisms at larger length scales. To this end, a comprehensive structural, compositional, and mechanical assessment is performed using circularly polarized light microscopy, synchrotron nanocomputed tomography, focused ion beam/scanning electron microscopy, quantitative backscattered electron imaging, Fourier transform infrared spectroscopy, and nanoindentation testing. To predict how the mechanical behavior of osteons is affected by shifts in collagen fiber orientation, finite element models are generated. Fundamental disparities between both osteon types are observed: dark osteons are characterized by a higher degree of mineralization along with a higher ratio of inorganic to organic matrix components that lead to higher stiffness and the ability to resist plastic deformation under compression. On the contrary, bright osteons contain a higher fraction of collagen and provide enhanced ductility and energy dissipation due to lower stiffness and hardness.
Inactivating mutations in human ecto‐nucleotide pyrophosphatase/phosphodiesterase‐1 (ENPP1) may result in early‐onset osteoporosis (EOOP) in haploinsufficiency and autosomal recessive hypophosphatemic rickets (ARHR2) in homozygous deficiency. ARHR2 patients are frequently treated with phosphate supplementation to ameliorate the rachitic phenotype, but elevating plasma phosphorus concentrations in ARHR2 patients may increase the risk of ectopic calcification without increasing bone mass. To assess the risks and efficacy of conventional ARHR2 therapy, we performed comprehensive evaluations of ARHR2 patients at two academic medical centers and compared their skeletal and renal phenotypes with ENPP1‐deficient Enpp1asj/asj mice on an acceleration diet containing high phosphate treated with recombinant murine Enpp1‐Fc. ARHR2 patients treated with conventional therapy demonstrated improvements in rickets, but all adults and one adolescent analyzed continued to exhibit low bone mineral density (BMD). In addition, conventional therapy was associated with the development of medullary nephrocalcinosis in half of the treated patients. Similar to Enpp1asj/asj mice on normal chow and to patients with mono‐ and biallelic ENPP1 mutations, 5‐week‐old Enpp1asj/asj mice on the high‐phosphate diet exhibited lower trabecular bone mass, reduced cortical bone mass, and greater bone fragility. Treating the Enpp1asj/asj mice with recombinant Enpp1‐Fc protein between weeks 2 and 5 normalized trabecular bone mass, normalized or improved bone biomechanical properties, and prevented the development of nephrocalcinosis and renal failure. The data suggest that conventional ARHR2 therapy does not address low BMD inherent in ENPP1 deficiency, and that ENPP1 enzyme replacement may be effective for correcting low bone mass in ARHR2 patients without increasing the risk of nephrocalcinosis. © 2021 American Society for Bone and Mineral Research (ASBMR).
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