A biochemical comparison of development of various facial bones in neonatal rats.
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Animals↗
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Results for “Bone Development”
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[Effects of strontium in drinking water on the growth of school-age children].
An epidemiological study on the effect of strontium in drinking water on body shape development, bone age, prevalence of caries and dental fluorosis was carried out. The results show: there is a certain promotion on the development of bone age of school-age children, especially of girls, and there is no obvious impact on body shape developing when the concentration of strontium in drinking water is only 10 mg/L. The correlation between strontium in drinking water and the prevalence of caries in children could not get a conclusive evidence in this paper. A further epidemiological investigation is necessary if the role of strontium against caries should be proved.
Adolescent↗
Ectopic expression of bone sialoprotein in human thyroid cancer.
Bone sialoprotein (BSP) is a small, highly posttranslationally modified integrin binding protein found in the mineral compartment of developing bone. The recent discovery that BSP can be detected in a variety of human cancers, particularly those that metastasize preferentially to the skeleton, shed light on potential new biological functions for this protein. The demonstration of a positive association between BSP expression in primary breast tumors and the development of bone metastases suggests that this glycoprotein could play a role in the selective implantation of breast cancer cells in bone. BSP is also expressed in most lung and prostate cancers as well as in multiple myeloma, three other osteotropic malignancies. Because thyroid carcinoma also metastasizes preferentially to the skeleton, we decided to look at the expression of BSP in a collection of 145 thyroid malignant lesions including 24 follicular thyroid carcinomas (FTCs), 55 papillary thyroid carcinomas (PTCs), 19 medullary thyroid carcinomas (MTCs), 23 anaplastic carcinomas (ACs), and 24 poorly differentiated carcinomas (PDCs). BSP expression was evaluated by immunoperoxidase technique using two specific polyclonal antibodies. Most of the thyroid carcinomas (72%) examined expressed high levels of BSP. Expression of BSP was significantly lower in FTCs and MTCs compared with PDCs, which are more aggressive (p = 0.0009 and 0.0003, respectively). Our study demonstrates for the first time that ectopic BSP expression is a common feature of thyroid cancer. The prognostic value of BSP detection in thyroid adenocarcinoma and the potential role of BSP in the propension of this type of cancer to metastasize to bone are currently under investigation.
Adenocarcinoma, Follicular↗
Alcohol consumption inhibits bone growth and development in young actively growing rats.
Adolescence is an age of widespread alcohol abuse, but the effect of alcohol consumption on bone formation has not been studied in the young population. This study addresses the effect of alcohol on the early phases of bone growth and development in an animal model. Four-week-old, female Sprague-Dawley rats were divided into three groups. Alcohol-treated animals were fed a modified Lieber-DeCarli diet ad libitum containing 35% ethanol-derived calories, whereas the pair-fed animals (weight-matched to ethanol rats) received an isocaloric liquid diet in which maltose-dextrin substituted calories supplied by ethanol. Chow animals were fed a standard rat chow ad libitum. Proximal tibiae (primarily cancellous bone) and femora (primarily cortical bone) were removed for analysis after 2, 4, 6, or 8 weeks on the diets. Serum was collected for analysis of calcium levels, osteocalcin, corticosterone, growth hormone, parathyroid hormone, and 25-hydroxyvitamin D. The most rapid weight gain occurred between 6 and 8 weeks of age, it was significantly delayed in alcohol and pair-fed animals. Almost all morphological parameters of bone were lower in the alcohol groups. No significant difference in serum calcium levels, osteocalcin, or growth hormone levels were found, and small difference in calciotropic hormone levels was found between groups. The results indicated that chronic alcohol consumption during the age of bone development reduces bone density and peak bone mass in both cortical and cancellous bone. The mechanism whereby this effect occurs is not fully understood, but, our results suggest that the negative impact of alcohol on growing bone is not due to the secondary effects of altered bone mineral regulating hormones.
Age Factors↗
Apoptosis in murine calvarial bone and suture development.
To study the possible role of apoptosis in calvarial bone and suture development, terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) was performed on whole mount and sectioned calvariae from mice aged between E14 and P6. We also analyzed by in situ hybridization the expression of Msx2, Bmp4 and Bmp7 genes, which are known to act in conserved signaling pathways leading to apoptosis. We found TUNEL-positive cells from E16 onwards in the calvarial bones, intervening sutures and fontanelles. TUNEL-positive osteoblasts and preosteoblasts were identified at or close to the osteogenic fronts, areas of intense osteogenic activity, with TUNEL-positive mesenchymal cells located in the midsutural mesenchyme. TUNEL-positive osteoclasts and osteocytes were also observed in a sporadic fashion, as well as TUNEL-positive dural cells. Msx2 was expressed in the sutural mesenchyme and the dura mater. Bmp4 was expressed in the developing bone, underlying dura mater, the osteogenic fronts, and also weakly in the sutural mesenchyme. Bmp7 was detected at the same locations as Bmp4 but with noticeably stronger intensity in the meninges and overlying epidermis. We propose that this apoptosis is part of normal suture development, and is integral to the balance between bone formation and resorption, so that abnormal apoptosis may lead to premature (Craniosynostosis) or delayed (Cleidocranial dysplasia) suture closure.
Animals↗
Relationships between trabecular bone remodeling and bone vascularization: a quantitative study.
Beside its well-known role in bone development, vascularization plays a major role in bone cell migration for bone remodeling and metastatic tumor invasion. However, the various techniques used to identify vessels in bone have never been tested for trabecular bone vessel quantification, whereas bone remodeling quantitative parameters are commonly assessed. In this context, we developed and compared various histological techniques used to visualize blood vessels in rat bone in order to quantify them. First, several products were tested by intracardiac infusion to opacify the bone vascular network. The best results were obtained using either an India ink-1% agarose solution or an India ink-saturated barium sulfate solution followed by X-ray microradiography. Second, to identify the types of vessels, we also performed histoenzymology and immunohistochemistry stainings. Neither alkaline phosphatase (for endothelial cells) nor adenosine triphosphatase (ATPase) stainings (for smooth muscle cells) provided a low enough background to allow for vessel identification and quantification. For immunohistochemistry, various specific vessel constituents were analyzed: laminin, smooth muscle cell alpha-actin, factor VIII, and lectin Griffonia simplifolia. Anti-laminin and anti-smooth muscle cell alpha-actin antibodies gave the best results for quantification. Third, after optimization of these techniques, we performed quantitative bone and vessel histomorphometry on two groups of 12 rats each, for which bone remodeling and vessel number and area parameters were measured. No statistical differences were observed between the two groups, confirming the reproducibility of our measurements. A significant relationship was found between vessel number and histodynamic parameters; that is, bone formation rate correlated positively with India ink-positive vessel area (p < 0.009, r2 = 0.54) and alpha-actin-positive vessel number (p < 0.05, r2 = 0.66). Furthermore, we report reproducible techniques for visualization and quantification of vessels in bone that also allowed for simultaneous conventional bone histomorphometry. This methodology should help researchers to better understand the functional and anatomical relationship between trabecular bone and its vascularization during normal or pathological processes.
Adenosine Triphosphatases↗
The cartilage specific microRNA-140 targets histone deacetylase 4 in mouse cells.
MicroRNAs (miRNA) are short RNA molecules regulating the expression of specific mRNAs. We investigated the expression pattern and potential targets of mouse miR-140 and found that miR-140 is specifically expressed in cartilage tissues of mouse embryos during both long and flat bone development. MiR-140 expression was detected in the limbs of E11.5 embryos in the primorida of future bones both in the fore and hindlimb and across autopod, zeugopod and stylopod. All digits of E14.5 fore- and hindlimbs showed accumulation of miR-140, except the first digit of the hindlimb. MiR-140 expression was also detected in the cartilagenous base of E17.5 skulls and in the sternum, the proximal rib heads and the developing vertebral column of E15.5 embryos. A potential target of miR-140, histone deacetylase 4, was validated experimentally and the possible role of miR-140 in long bone development is discussed.
Animals↗
The T-box transcription factor Tbx15 is required for skeletal development.
During early limb development several signaling centers coordinate limb bud outgrowth as well as patterning. Members of the T-box gene family of transcriptional regulators are crucial players in these processes by activating and interpreting these signaling pathways. Here, we show that Tbx15, a member of this gene family, is expressed during limb development, first in the mesenchyme of the early limb bud, then during early endochondral bone development in prehypertrophic chondrocytes of cartilaginous templates. Expression is also found in mesenchymal precursor cells and prehypertrophic chondrocytes, respectively, during development of skeletal elements of the vertebral column and the head. Analysis of Tbx15 null mutant mice indicates a role of Tbx15 in the development of skeletal elements throughout the body. Mutants display a general reduction of bone size and changes of bone shape. In the forelimb skeleton, the scapula lacks the central region of the blade. Cartilaginous templates are already reduced in size and show a transient delay in ossification in mutant embryos. Mutants show a significantly reduced proliferation of prehypertrophic chondrocytes as well as of mesenchymal precursor cells. These data suggest that Tbx15 plays an important role in the development of the skeleton of the limb, vertebral column and head by controlling the number of mesenchymal precursor cells and chondrocytes.
Alleles↗
Genetic loci influencing natural variations in femoral bone morphometry in mice.
This study identifies genetic loci affecting femoral bone length and width measures in mature mice. Sixteen month old female F2 progeny of a C57BL/6J and DBA/2J intercross were examined for femur length and width of the femoral head, intertrochanteric region and three locations of the diaphysis using digitized images of femur radiographs obtained in the anterior-posterior and lateral projections. A genome wide linkage map was constructed using microsatellite markers at an average density of 20 cM, and quantitative trait locus analysis used to identify regions of the genome showing linkage with the traits measured. Femur length showed significant linkage with loci on proximal chromosome 3 (lod 6.1), and suggestive linkage with a locus on chromosome 14. A major locus on mid-chromosome 7 controlled width of the diaphysis (lod 6.8). Other loci were identified on chromosomes 2 and 4. Width at the intertrochanteric region had suggestive linkage with loci on chromosomes 6 and 19. No loci were found with linkage for width of the femoral head. Candidate genes related to bone development or metabolism are present at most of these loci. These findings show that genetic regulation of femoral bone morphology is complex, and are consistent with the distinct biologic processes that control longitudinal and lateral growth of the femur.
Animals↗
Impact of estrogen replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 gene.
Recent reports of the impact of estrogen receptor alpha and aromatase deficiency have shed new light on the importance of estrogen for bone formation in man. We describe a novel mutation of the CYP19 gene in a 27-yr-old homozygous male of consanguinous parents. A C to A substitution in intron V, at position -3 of the splicing acceptor site before exon VI of the CYP19 gene, is the likely cause of loss of aromatase activity. The mRNA of the patient leads to a frameshift and a premature stop codon 8 nucleotides downstream the end of exon V. Both parents were shown to be heterozygous for the same mutation. Apart from genua valga, kyphoscoliosis, and pectus carniatus, the physical examination was normal including secondary male characteristics with normal testicular size. To substitute for the deficiency, the patient was treated with 50 micro g transdermal estradiol twice weekly for 3 months, followed by 25 micro g twice weekly. After 6 months estrogen levels (<20 at baseline and 45 pg/ml at 6 months; normal range, 10-50) and estrone levels (17 and 34 ng/ml; normal range, 30-85) had normalized. Bone maturation progressed and the initially unfused carpal and phalangeal epiphyses began to close within 3 months and were almost completely closed after 6 months. The bone age, assessed by roentgenographic standards for bone development by Gruelich and Pyle, was 16.5 at baseline and 18-18.5 yr after 6 months of treatment. Bone density of the distal radius (left), assessed by quantitative computed tomography, increased from 52 to 83 mg/cm(3) (normal range, 120-160) and bone mineral density of the lumbar spine, assessed by dual-energy x-ray-absorptiometry, increased from 0.971 to 1.043 g/cm(2) (normal range, >1.150). Osteocalcin as a bone formation parameter increased from 13 to 52 micro g/l (normal range, 24-70) and aminoterminal collagen type I telopeptide as a bone resorption parameter increased from 62.9 to 92.4 nmol/mmol creatinine (normal range, 5-54). Semen analysis revealed oligoazoospermia (17.4 million/ml; normal >20) at baseline. After 3 months of treatment, the sperm count increased (23.1 million/ml) and decreased rapidly (1.1 million/ml) during the following 3 months. The sperm motility was reduced at baseline and decreased further during treatment. Area under the curve of insulin, C-peptide, and blood glucose levels during oral glucose tolerance test decreased after 6 months (insulin: 277 vs. 139 micro U/ml.h; C-peptide 52 vs. 15 ng/m.h; area under the curve glucose: 17316 vs. 12780 mg/d.min). Triglycerides (268 vs. 261 mmol/liter) and total cholesterol levels (176 vs. 198 mmol/liter) did not change significantly, but the low-density lipoprotein/high-density lipoprotein ratio decreased from 5.37 to 3.56 and lipoprotein (a) increased from 19.9 to 60.0 mg/dl (normal range, <30). In this rare incidence of estrogen deficiency, estrogen replacement demonstrated its importance for bone mineralization and maturation and glucose metabolism in a male carrying a novel mutation in the CYP19 gene.
Adult↗
Extramedullary leukemic relapses following hematopoietic stem cell transplantation with nonmyeloablative conditioning.
Of a group of 149 patients who underwent allogeneic stem cell transplantation using the "Mexican approach", a nonablative preparative regimen, 49 individuals developed bone marrow relapse, and 8 patients developed extramedullary relapse (EMR). All EMR cases presented in patients who received allografts for myeloid malignancies. In contrast, bone marrow relapses presented in patients with myeloid or lymphoid malignancies. EMR presented 60 to 1010 days after the allograft and appeared in 3 cases as subcutaneous nodules in different parts of the body, in the vertebrae in 3 cases, and in the kidney and the breast in 1 case each. One patient had both subcutaneous nodules and epididymis EMR. When EMR was noted, acute graft-versus-host disease (GVHD) had presented in 4 patients, and limited forms of chronic GVHD were present in 3 patients. All but 1 of the patients were full chimeras when the EMR ensued, and the EMR preceded an overt hematologic relapse in all but 1 of the patients. Patients who experienced an overt hematologic relapse died 20 to 180 days (median, 40 days) after the EMR. The only individual alive 240 days after relapse shows no evidence of a full-blown hematologic relapse. An EMR after allogeneic hematopoietic stem cell transplantation usually has a bad prognosis and presents mainly in individuals with high-risk malignancies.
Adult↗
Role of Wnts in prostate cancer bone metastases.
Prostate cancer (CaP) is unique among all cancers in that when it metastasizes to bone, it typically forms osteoblastic lesions (characterized by increased bone production). CaP cells produce many factors, including Wnts that are implicated in tumor-induced osteoblastic activity. In this prospectus, we describe our research on Wnt and the CaP bone phenotype. Wnts are cysteine-rich glycoproteins that mediate bone development in the embryo and promote bone production in the adult. Wnts have been shown to have autocrine tumor effects, such as enhancing proliferation and protecting against apoptosis. In addition, we have recently identified that CaP-produced Wnts act in a paracrine fashion to induce osteoblastic activity in CaP bone metastases. In addition to Wnts, CaP cells express the soluble Wnt inhibitor dickkopf-1 (DKK-1). It appears that DKK-1 production occurs early in the development of skeletal metastases, which results in masking of osteogenic Wnts, thus favoring osteolysis at the metastatic site. As metastases progress, DKK-1 expression decreases allowing for unmasking of Wnt's osteoblastic activity and ultimately resulting in osteosclerosis at the metastatic site. We believe that DKK-1 is one of the switches that transitions the CaP bone metastasis activity from osteolytic to osteoblastic. Wnt/DKK-1 activity fits a model of CaP-induced bone remodeling occurring in a continuum composed of an osteolytic phase, mediated by receptor activator of NFkB ligand (RANKL), parathyroid hormone-related protein (PTHRP) and DKK-1; a transitional phase, where environmental alterations promote expression of osteoblastic factors (Wnts) and decreases osteolytic factors (i.e., DKK-1); and an osteoblastic phase, in which tumor growth-associated hypoxia results in production of vascular endothelial growth factor and endothelin-1, which have osteoblastic activity. This model suggests that targeting both osteolytic activity and osteoblastic activity will provide efficacy for therapy of CaP bone metastases.
Adult↗
Hypoxia and HIF-1alpha in chondrogenesis.
In endochondral bone development chondrocytes undergo proliferation, hypertrophic differentiation, mineralization of the surrounding matrix, death, blood vessel invasion, and finally replacement of cartilage with bone. The chondrocytic growth plate is a unique mesenchymal tissue, as it is avascular but it requires blood vessel invasion in order to be replaced by bone. We have recently provided evidence that the growth plate is hypoxic during fetal development. Adaptation to hypoxia is a critical event in numerous pathological settings, such as tumor progression and survival of tissues in which blood flow has been suddenly interrupted. One of the hallmarks of the response to hypoxia is activation of the transcription factor HIF-1alpha. The von Hippel-Lindau (VHL) tumor suppressor protein is a component of a ubiquitin ligase promoting proteolysis of HIF-1alpha. By using a genetic approach, we have demonstrated that VHL and HIF-1alpha are critical regulators of endochondral bone development.
Animals↗
Skeletons in the p53 tumor suppressor closet: genetic evidence that p53 blocks bone differentiation and development.
A series of in vitro tissue culture studies indicated that the p53 tumor suppressor promotes cellular differentiation, which could explain its role in preventing cancer. Quite surprisingly, however, two new in vivo studies provide genetic evidence that p53 blocks osteoblast differentiation and bone development. These interesting results and their biological and clinical implications are the focus of this comment.
Animals↗
Interplay between bone morphogenetic proteins and cognate binding proteins in bone and cartilage development: noggin, chordin and DAN.
This commentary is a concise discussion of the interactions between bone morphogenetic proteins (BMPs) and their binding proteins in bone and cartilage morphogenesis. BMPs are a family of growth and differentiation factors, and they act on mesenchymal cells to induce cartilage and bone differentiation in concentration-dependent thresholds. The BMP-BMP receptor binding leads to a cascade of signaling and transcription of BMP response genes. BMP binding proteins, noggin, chordin and DAN, act as antagonists and determine the bioavailability of BMPs for binding to cognate receptors to elicit the biological response. Noggin null mice with unrestricted action of BMPs exhibit defects in joint morphogenesis. BMPs and their binding proteins may reciprocally regulate the dynamic topography of joints, muscle, tendons and ligaments during morphogenesis of the skeleton. In addition, BMP actions may be potentiated by twisted gastrulation. BMPs and their binding proteins may play a critical role in regeneration of cartilage in osteoarthritis.
Animals↗
Menin and its interacting proteins: elucidation of menin function.
The multiple endocrine neoplasia type 1 (MEN1) gene is a tumor suppressor gene encoding a 610 amino acid nuclear protein, menin. Although mutations of the MEN1 gene are responsible for MEN 1 syndrome, the intracellular functions of menin have not been fully elucidated. Recent data suggest that interactions between menin and menin-interacting proteins have a role in physiological regulation of cell growth, control of the cell cycle and genome stability, and are potentially important in bone development and multipotent mesenchymal stem cell differentiation. Loss of these interactions might also contribute to the development of MEN 1 syndrome.
Bone Development↗
Enhanced expression of TGF-beta and c-fos mRNAs in the growth plates of developing human long bones.
The expression of mRNAs for type I and type II procollagens, transforming growth factor-beta (TGF-beta) and c-fos was studied in developing human long bones by Northern blotting and in situ hybridization. The cells producing bone and cartilage matrix were identified by hybridizations using cDNA probes for types I and II collagen, respectively. Northern blotting revealed that the highest levels of TGF-beta mRNA were associated with the growth plates. By in situ hybridization, this mRNA was localized predominantly in the osteoblasts and osteoclasts of the developing bone, in periosteal fibroblasts and in individual bone marrow cells. These findings are consistent with the view that TGF-beta may have a role in stimulation of type I collagen production and bone formation. Only a low level of TGF-beta mRNA was detected in cartilage where type II collagen mRNA is abundant. In Northern hybridization, the highest levels of c-fos mRNA were detected in epiphyseal cartilage. In situ hybridization revealed two cell types with high levels of c-fos expression: the chondrocytes bordering the joint space and the osteoclasts of developing bone. These differential expression patterns suggest specific roles for TGF-beta and c-fos in osseochondral development.
Bone Development↗
Morphological and histochemical events during first bone formation in embryonic chick limbs.
Staged embryos from White Leghorn chicken eggs were used to assemble a detailed morphological, cellular and molecular picture of the complex events of first-bone formation. To provide these details, light and electron microscopic, histochemical and immunocytochemical techniques were used to establish a temporal sequence for long bone development in chick wing and leg from Hamburger-Hamilton stage 29 through stage 35. Three distinctive cell regions can be morphologically identified by stage 28 (leg) or 29 (wing) at the mid-diaphysis. These regions are: 1. an outer grouping of loose mesenchymal and myogenic cells, 2. an osteoprogenitor layer which will later divide to maintain this progenitor layer in a brickwork or stacked configuration and to produce round, tightly packed osteoblasts, and 3. a core (rod) of cartilage. First bone is laid down just outside the cartilage core, initially as a layer of Type I collagen-rich osteoid which later becomes mineralized. Vascular elements then come to reside above this mineral layer, and osteoid is laid down between vascular elements and eventually above them to form a second layer of trabecular bone. As this radial formation of layers of bone is progressing, so too is the proximal and distal expansion of the first bone forming process. A model is presented which considers that chondrogenic and osteogenic cell commitment occur simultaneously in early limb development and that it is the expression of the osteogenic phenotype which governs the boundaries of cartilage development. Importantly, the vasculature plays a key role in the patterning of bone formation well before it enters the cartilaginous core at stage 35 and participates in the erosion of the core. While this report is restricted to events occurring through stage 35, it relies on data presented in a companion report detailing later bone development and remodeling (Pechak et al; Bone 1986) and emphasizes that the cartilage model does not provide the scaffolding for bone but rather defines the marrow space.
Animals↗