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Calcified Tissue International Feb 2012Notch signaling mediates cell-to-cell interactions that are critical for embryonic development and tissue renewal. In the canonical signaling pathway, the Notch receptor... (Review)
Review
Notch signaling mediates cell-to-cell interactions that are critical for embryonic development and tissue renewal. In the canonical signaling pathway, the Notch receptor is cleaved following ligand binding, resulting in the release and nuclear translocation of the Notch intracellular domain (NICD). NICD induces gene expression by forming a ternary complex with the DNA binding protein CBF1/Rbp-Jk, Suppressor of Hairless, Lag1, and Mastermind-Like (Maml). Hairy Enhancer of Split (Hes) and Hes related with YRPW motif (Hey) are classic Notch targets. Notch canonical signaling plays a central role in skeletal development and bone remodeling by suppressing the differentiation of skeletal cells. The skeletal phenotype of mice misexpressing Hes1 phenocopies partially the effects of Notch misexpression, suggesting that Hey proteins mediate most of the skeletal effects of Notch. Dysregulation of Notch signaling is associated with diseases affecting human skeletal development, such as Alagille syndrome, brachydactyly and spondylocostal dysostosis. Somatic mutations in Notch receptors and ligands are found in tumors of the skeletal system. Overexpression of NOTCH1 is associated with osteosarcoma, and overexpression of NOTCH3 or JAGGED1 in breast cancer cells favors the formation of osteolytic bone metastasis. Activating mutations in NOTCH2 cause Hajdu-Cheney syndrome, which is characterized by skeletal defects and fractures, and JAG1 polymorphisms, are associated with variations in bone mineral density. In conclusion, Notch is a regulator of skeletal development and bone remodeling, and abnormal Notch signaling is associated with developmental and postnatal skeletal disorders.
Topics: Animals; Bone Development; Bone Diseases; Bone Remodeling; Humans; Receptors, Notch; Signal Transduction
PubMed: 22002679
DOI: 10.1007/s00223-011-9541-x -
The Proceedings of the Nutrition Society Nov 2006The growth and development of the human skeleton requires an adequate supply of many different nutritional factors. Classical nutrient deficiencies are associated with... (Review)
Review
The growth and development of the human skeleton requires an adequate supply of many different nutritional factors. Classical nutrient deficiencies are associated with stunting (e.g. energy, protein, Zn), rickets (e.g. vitamin D) and other bone abnormalities (e.g. Cu, Zn, vitamin C). In recent years there has been interest in the role nutrition may play in bone growth at intakes above those required to prevent classical deficiencies, particularly in relation to optimising peak bone mass and minimising osteoporosis risk. There is evidence to suggest that peak bone mass and later fracture risk are influenced by the pattern of growth in childhood and by nutritional exposures in utero, in infancy and during childhood and adolescence. Of the individual nutrients, particular attention has been paid to Ca, vitamin D, protein and P. There has also been interest in several food groups, particularly dairy products, fruit and vegetables and foods contributing to acid-base balance. However, it is not possible at the present time to define dietary reference values using bone health as a criterion, and the question of what type of diet constitutes the best support for optimal bone growth and development remains open. Prudent recommendations (Department of Health, 1998; World Health Organization/Food and Agriculture Organization, 2003) are the same as those for adults, i.e. to consume a Ca intake close to the reference nutrient intake, optimise vitamin D status through adequate summer sunshine exposure (and diet supplementation where appropriate), be physically active, have a body weight in the healthy range, restrict salt intake and consume plenty of fruit and vegetables.
Topics: Adolescent; Adult; Aged; Bone Development; Child; Child, Preschool; Female; Growth; Humans; Infant; Infant, Newborn; Male; Middle Aged; Nutritional Physiological Phenomena; Nutritional Requirements; Osteoporosis; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 17181901
DOI: 10.1017/s0029665106005192 -
Frontiers in Immunology 2019
Topics: Animals; Biomarkers; Bone Development; Bone and Bones; Disease Susceptibility; Humans; Osteocytes; Signal Transduction
PubMed: 31798574
DOI: 10.3389/fimmu.2019.02595 -
Poultry Science May 2019The present study was carried out to investigate the tibia phosphorus (P) retention and development as well as their correlations and possible mechanisms of broilers at...
The present study was carried out to investigate the tibia phosphorus (P) retention and development as well as their correlations and possible mechanisms of broilers at different ages. A total of 320 1-day-old Arbor Acres male broilers were raised in 8 replicate cages of 40 birds per cage, and fed the same corn-soybean diets for 42 d. Plasma and tibia samples of broilers were collected on day 0, 7, 14, 21, 28, 35, or 42. The results showed that the tibia ash P content increased linearly (P = 0.017), and the total P accumulation in tibia ash increased linearly and quadratically (P < 0.001) with age. The traits of bone development including the tibia bone mineral content (BMC), the tibia bone mineral density (BMD), and the tibia ash content increased linearly and quadratically (P < 0.001), while the tibia breaking strength increased linearly (P < 0.001) with age. The tibia bone gal protein (BGP) content decreased linearly (P = 0.011), but neither a linear nor quadratic (P > 0.15) response was observed for the tibia alkaline phosphatase (ALP) with age. The tibia ash P content was positively correlated with the tibia BMD (r = 0.325, P = 0.014), ash (r = 0.325, P = 0.001), and ALP (r = 0.377, P = 0.004). The total P accumulation in tibia ash also was positively correlated with all of the above traits of bone development (r = 0.437 to 0.976, P < 0.001); however, it was negatively correlated with the tibia BGP (r = -0.426, P = 0.0014). Additionally, the tibia ALP was positively correlated with the tibia ash (r = 0.369, P < 0.001), and the tibia BGP was negatively correlated with the tibia BMC (r = -0.453, P < 0.001), breaking strength (r = -0.384, P < 0.001), and ash content (r = -0.361, P < 0.001). The above results indicated that the bone P retention was involved in the bone development of broilers from 1 to 42 d of age possibly via the regulation of the bone ALP and BGP.
Topics: Animal Feed; Animals; Bone Development; Chickens; Diet; Male; Phosphorus, Dietary; Tibia
PubMed: 30608596
DOI: 10.3382/ps/pey565 -
Tissue Engineering. Part B, Reviews Aug 2021Bone is a highly vascularized organ, providing structural support to the body, and its development, regeneration, and remodeling depend on the microvascular homeostasis.... (Review)
Review
Bone is a highly vascularized organ, providing structural support to the body, and its development, regeneration, and remodeling depend on the microvascular homeostasis. Loss or impairment of vascular function can develop diseases, such as large bone defects, avascular necrosis, osteoporosis, osteoarthritis, and osteopetrosis. In this review, we summarize how vasculature controls bone development and homeostasis in normal and disease cases. A better understanding of this process will facilitate the development of novel disease treatments that promote bone regeneration and remodeling. Specifically, approaches based on tissue engineering components, such as stem cells and growth factors, have demonstrated the capacity to induce bone microvasculature regeneration and mineralization. This knowledge will have relevant clinical implications for the treatment of bone disorders by developing novel pharmaceutical approaches and bone grafts. Finally, the tissue engineering approaches incorporating vascular components may widely be applied to treat other organ diseases by enhancing their regeneration capacity. Impact statement Bone vasculature is imperative in the process of bone development, regeneration, and remodeling. Alterations or disruption of the bone vasculature leads to loss of bone homeostasis and the development of bone diseases. In this study, we review the role of vasculature on bone diseases and how vascular tissue engineering strategies, with a detailed emphasis on the role of stem cells and growth factors, will contribute to bone therapeutics.
Topics: Bone Regeneration; Bone and Bones; Microvessels; Neovascularization, Physiologic; Osteogenesis
PubMed: 32940150
DOI: 10.1089/ten.TEB.2020.0154 -
International Journal of Molecular... Jul 2021Interaction between endothelial cells and osteoblasts is essential for bone development and homeostasis. This process is mediated in large part by osteoblast... (Review)
Review
Interaction between endothelial cells and osteoblasts is essential for bone development and homeostasis. This process is mediated in large part by osteoblast angiotropism, the migration of osteoblasts alongside blood vessels, which is crucial for the homing of osteoblasts to sites of bone formation during embryogenesis and in mature bones during remodeling and repair. Specialized bone endothelial cells that form "type H" capillaries have emerged as key interaction partners of osteoblasts, regulating osteoblast differentiation and maturation and ensuring their migration towards newly forming trabecular bone areas. Recent revolutions in high-resolution imaging methodologies for bone as well as single cell and RNA sequencing technologies have enabled the identification of some of the signaling pathways and molecular interactions that underpin this regulatory relationship. Similarly, the intercellular cross talk between endothelial cells and entombed osteocytes that is essential for bone formation, repair, and maintenance are beginning to be uncovered. This is a relatively new area of research that has, until recently, been hampered by a lack of appropriate analysis tools. Now that these tools are available, greater understanding of the molecular relationships between these key cell types is expected to facilitate identification of new drug targets for diseases of bone formation and remodeling.
Topics: Animals; Bone Development; Bone Remodeling; Bone and Bones; Endothelial Cells; Homeostasis; Humans; Osteoblasts; Osteogenesis; Signal Transduction
PubMed: 34298886
DOI: 10.3390/ijms22147253 -
ELife Oct 2021Osteoblast differentiation is sequentially characterized by high rates of proliferation followed by increased protein and matrix synthesis, processes that require...
Osteoblast differentiation is sequentially characterized by high rates of proliferation followed by increased protein and matrix synthesis, processes that require substantial amino acid acquisition and production. How osteoblasts obtain or maintain intracellular amino acid production is poorly understood. Here, we identify SLC1A5 as a critical amino acid transporter during bone development. Using a genetic and metabolomic approach, we show SLC1A5 acts cell autonomously to regulate protein synthesis and osteoblast differentiation. SLC1A5 provides both glutamine and asparagine which are essential for osteoblast differentiation. Mechanistically, glutamine and to a lesser extent asparagine support amino acid biosynthesis. Thus, osteoblasts depend on to provide glutamine and asparagine, which are subsequently used to produce non-essential amino acids and support osteoblast differentiation and bone development.
Topics: Amino Acid Transport System ASC; Animals; Asparagine; Bone Development; Female; Glutamine; Mice; Minor Histocompatibility Antigens; Osteoblasts; Osteogenesis
PubMed: 34647520
DOI: 10.7554/eLife.71595 -
Birth Defects Research Sep 2018Evaluation of the skeleton in laboratory animals is a standard component of developmental toxicology testing. Standard methods of performing the evaluation have been... (Review)
Review
Evaluation of the skeleton in laboratory animals is a standard component of developmental toxicology testing. Standard methods of performing the evaluation have been established, and modification of the evaluation using imaging technologies is under development. The embryology of the rodent, rabbit, and primate skeleton has been characterized in detail and summarized herein. The rich literature on variations and malformations in skeletal development that can occur in the offspring of normal animals and animals exposed to test articles in toxicology studies is reviewed. These perturbations of skeletal development include ossification delays, alterations in number, shape, and size of ossification centers, and alterations in numbers of ribs and vertebrae. Because the skeleton is undergoing developmental changes at the time fetuses are evaluated in most study designs, transient delays in development can produce apparent findings of abnormal skeletal structure. The determination of whether a finding represents a permanent change in embryo development with adverse consequences for the organism is important in study interpretation. Knowledge of embryological processes and schedules can assist in interpretation of skeletal findings.
Topics: Animals; Bone Development; Bone and Bones; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions; Embryology; Embryonic Development; Fetus; Humans; Mammals; Organogenesis; Primates; Rabbits; Rodentia; Skeleton
PubMed: 29921029
DOI: 10.1002/bdr2.1350 -
Calcified Tissue International May 2017A complex interplay of genetic, environmental, hormonal, and behavioral factors affect skeletal development, several of which are associated with childhood fractures.... (Review)
Review
A complex interplay of genetic, environmental, hormonal, and behavioral factors affect skeletal development, several of which are associated with childhood fractures. Given the rise in obesity worldwide, it is of particular concern that excess fat accumulation during childhood appears to be a risk factor for fractures. Plausible explanations for this higher fracture risk include a greater propensity for falls, greater force generation upon fall impact, unhealthy lifestyle habits, and excessive adipose tissue that may have direct or indirect detrimental effects on skeletal development. To date, there remains little resolution or agreement about the impact of obesity and adiposity on skeletal development as well as the mechanisms underpinning these changes. Limitations of imaging modalities, short duration of follow-up in longitudinal studies, and differences among cohorts examined may all contribute to conflicting results. Nonetheless, a linear relationship between increasing adiposity and skeletal development seems unlikely. Fat mass may confer advantages to the developing cortical and trabecular bone compartments, provided that gains in fat mass are not excessive. However, when fat mass accumulation reaches excessive levels, unfavorable metabolic changes may impede skeletal development. Mechanisms underpinning these changes may relate to changes in the hormonal milieu, with adipokines potentially playing a central role, but again findings have been confounding. Changes in the relationship between fat and bone also appear to be age and sex dependent. Clearly, more work is needed to better understand the controversial impact of fat and obesity on skeletal development and fracture risk during childhood.
Topics: Adiposity; Bone Development; Bone and Bones; Child; Female; Humans; Male; Obesity
PubMed: 28013362
DOI: 10.1007/s00223-016-0218-3 -
Molecules and Cells Feb 2020Runx2 is an essential transcription factor for skeletal development. It is expressed in multipotent mesenchymal cells, osteoblast-lineage cells, and chondrocytes. Runx2... (Review)
Review
Runx2 is an essential transcription factor for skeletal development. It is expressed in multipotent mesenchymal cells, osteoblast-lineage cells, and chondrocytes. Runx2 plays a major role in chondrocyte maturation, and Runx3 is partly involved. Runx2 regulates chondrocyte proliferation by directly regulating expression. It also determines whether chondrocytes become those that form transient cartilage or permanent cartilage, and functions in the pathogenesis of osteoarthritis. Runx2 is essential for osteoblast differentiation and is required for the proliferation of osteoprogenitors. Ihh is required for Runx2 expression in osteoprogenitors, and hedgehog signaling and Runx2 induce the differentiation of osteoprogenitors to preosteoblasts in endochondral bone. Runx2 induces Sp7 expression, and Runx2, Sp7, and canonical Wnt signaling are required for the differentiation of preosteoblasts to immature osteoblasts. It also induces the proliferation of osteoprogenitors by directly regulating the expression of and . Furthermore, Runx2 induces the proliferation of mesenchymal cells and their commitment into osteoblast-lineage cells through the induction of hedgehog (, , ), Fgf (, ), Wnt (, ), and Pthlh () signaling pathway gene expression in calvaria, and more than a half-dosage of is required for their expression. This is a major cause of cleidocranial dysplasia, which is caused by heterozygous mutation of . Cbfb, which is a co-transcription factor that forms a heterodimer with Runx2, enhances DNA binding of Runx2 and stabilizes Runx2 protein by inhibiting its ubiquitination. Thus, Runx2/Cbfb regulates the proliferation and differentiation of chondrocytes and osteoblast-lineage cells by activating multiple signaling pathways and via their reciprocal regulation.
Topics: Bone Development; Core Binding Factor Alpha 1 Subunit; Humans
PubMed: 31896233
DOI: 10.14348/molcells.2019.0244