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At least 199 records · Page 11Linked to original sources
PubMed2000

Transcription factor ERG variants and functional diversification of chondrocytes during limb long bone development.

During limb development, chondrocytes located at the epiphyseal tip of long bone models give rise to articular tissue, whereas the more numerous chondrocytes in the shaft undergo maturation, hypertrophy, and mineralization and are replaced by bone cells. It is not understood how chondrocytes follow these alternative pathways to distinct fates and functions. In this study we describe the cloning of C-1-1, a novel variant of the ets transcription factor ch-ERG. C-1-1 lacks a short 27-amino acid segment located approximately 80 amino acids upstream of the ets DNA binding domain. We found that in chick embryo long bone anlagen, C-1-1 expression characterizes developing articular chondrocytes, whereas ch-ERG expression is particularly prominent in prehypertrophic chondrocytes in the growth plate. To analyze the function of C-1-1 and ch-ERG, viral vectors were used to constitutively express each factor in developing chick leg buds and cultured chondrocytes. We found that virally driven expression of C-1-1 maintained chondrocytes in a stable and immature phenotype, blocked their maturation into hypertrophic cells, and prevented the replacement of cartilage with bone. It also induced synthesis of tenascin-C, an extracellular matrix protein that is a unique product of developing articular chondrocytes. In contrast, virally driven expression of ch-ERG significantly stimulated chondrocyte maturation in culture, as indicated by increases in alkaline phosphatase activity and deposition of a mineralized matrix; however, it had modest effects in vivo. The data show that C-1-1 and ch-ERG have diverse biological properties and distinct expression patterns during skeletogenesis, and are part of molecular mechanisms by which limb chondrocytes follow alternative developmental pathways. C-1-1 is the first transcription factor identified to date that appears to be instrumental in the genesis and function of epiphyseal articular chondrocytes.

Alkaline Phosphatase↗
PubMed2001

Characterization of a novel KRAB/C2H2 zinc finger transcription factor involved in bone development.

Osteogenic differentiation involves a cascade of coordinated gene expression that regulates cell proliferation and matrix protein formation in a defined temporo-spatial manner. Here we have used differential display to identify a novel zinc finger transcription factor (AJ18) that is induced during differentiation of bone cells in vitro and in vivo. The 64-kDa protein, encoded by a 7- kilobase mRNA, contains a Krüppel-associated box (KRAB) domain followed by 11 successive C(2)H(2) zinc finger motifs. AJ18 mRNA, which is also expressed in kidney and brain, is developmentally regulated in embryonic tibiae and calvariae, with little expression in neonate and adult animals. During osteogenic differentiation in vitro AJ18 mRNA is expressed as cells approach confluence and declines as bone formation occurs. Using bacterially expressed, His-tagged AJ18 in a target detection assay, we identified a consensus binding sequence of 5'-CCACA-3', which forms part of the consensus element for Runx2, a master gene for osteogenic differentiation. Overexpression of AJ18 suppressed Runx2-mediated transactivation of an osteocalcin promoter construct in transient transfection assays and reduced alkaline phosphatase activity in bone morphogenetic protein-induced C3H10T1/2 cells. These studies, therefore, have identified a novel zinc finger transcription factor in bone that can modulate Runx2 activity and osteogenic differentiation.

Amino Acid Sequence↗
PubMed2001

Expression of the novel transcription factor OASIS, which belongs to the CREB/ATF family, in mouse embryo with special reference to bone development.

The OASIS gene, which encodes a novel CREB/ATF family member, was isolated from long-term cultured astrocytes that were employed as an in vitro gliosis model. In the present study, we examined the expression pattern of the OASIS gene in the developing mouse embryo by in situ hybridization histochemistry and compared it with the expression of osteogenesis markers. OASIS mRNA expression was most strongly detected in preosteoblasts of the outer bony cortex of the ribs. Alveolar bone also showed strong signals for OASIS gene expression. OASIS mRNA was also localized to the preodontoblast of tooth buds. Expression began at embryonic day 12 (D12.5), peaked around D14.5-16.5, and continued to D18.5. The pattern of expression was very similar to that of hXBP-1 mRNA, which encodes another CREB/ATF family member. Spatiotemporal patterns of OASIS partly overlapped that of osteopontin, osteonectin, and alpha1 type I procollagen genes. Among these, the time course of OASIS mRNA expression was most similar to that of osteopontin mRNA expression, suggesting that the OASIS protein is involved in the late phase of osteoblast differentiation, as compared to the Cbfa1 that regulates early phases of osteoblast differentiation.

Animals↗
PubMed1992

Morphological changes in long bone development in fetal akinesia deformation sequence: an experimental study in curarized rat fetuses.

In order to investigate the transverse growth of the long bones during intrauterine development in the fetal akinesia deformation sequence (FADS), we studied curarized rat fetuses. Curarization was performed by daily subcutaneous administration of D-Tubocurarine from day 17 of gestation until term. Experimental fetuses were compared with a sham-operated control group. The total area and perimeter, the absolute and relative amount of periosteum and bone trabeculae, the major and minor axes, and the elongation factor were measured from histological cross-sections of the femoral metaphysis and diaphysis using an IBAS 1 image analysis system. Curarized rat fetuses showed growth retardation, a short umbilical cord, and multiple articular contractures, a phenotype consistent with FADS. Alterations in femoral shape and transverse growth that affected the diaphysis were noted in these fetuses. These included a decrease of total cross-section area and reduction of the absolute and relative amounts of bone trabeculae with marked thinning of the periosteum. Femoral cross-sections was rounder than controls. These results evidenced an impairment of the membraneous (periosteal) ossification of long bones produced by immobilization and/or decrease of muscular strength, and support our previous clinical findings of bone hypoplasia and osteopenia in FADS.

Animals↗
PubMed2000

Bone development.

Early development of the vertebrate skeleton depends on genes that pattern the distribution and proliferation of cells from cranial neural crest, sclerotomes, and lateral plate mesoderm into mesenchymal condensations at sites of future skeletal elements. Within these condensations, cells differentiate to chondrocytes or osteoblasts and form cartilages and bones under the control of various transcription factors. In most of the skeleton, organogenesis results in cartilage models of future bones; in these models cartilage is replaced by bone by the process of endochondral ossification. Lastly, through a controlled process of bone growth and remodeling the final skeleton is shaped and molded. Significant and exciting insights into all aspects of vertebrate skeletal development have been obtained through molecular and genetic studies of animal models and humans with inherited disorders of skeletal morphogenesis, organogenesis, and growth.

Animals↗
PubMed1983

Effect of low salt, sodium, and chloride levels in poult rations on growth, bone development, and related factors.

Two 4-week trials were conducted to determine the role of sodium chloride (salt) on field rickets in poults. A comparison of added dietary salt at 0, .075, .10, .25, and .45% to a corn-soy basal with .103% salt showed significant differences (P less than .05) in body weight gains, blood calcium, magnesium and sodium, feed conversion, and adrenal gland weights among the treatments. Mortality and abnormal bone scores decreased with increasing salt. When sodium was added to the basal diet as a single element for the poults at either 0, .09, .10, .11, and .12%, or chloride at 0, .009, .01, .02, and .03% in comparison to a control group with .20% sodium and .30% chloride, significant differences were found in weekly gain, bone ash, bone breaking strength, tibia weight/body weight, and serum alkaline phosphatase levels between the sodium, chloride, and the combined element groups. Bone abnormality scores decreased with increasing levels of both sodium and chloride in diets.

Animals↗
PubMed1995

Species differences in uroepithelium-induced bone development: observations on transplants of human uroepithelium in cortisone-treated mice.

Specimens (2-3 x 3-5 mm) of human urinary tract mucosa from bladder (67 cases), ureter and renal pelvis (35 cases) were implanted intramuscularly into cortisone-treated mice in order to elucidate whether human urothelium has the potency to induce osteogenesis. Although xenogeneic epithelium survived up to 14 days after implantation, in none of the 300 implants performed was a bone or cartilage induction observed. Implantation of urinary bladder mucosa from guinea pig and dog resulted in a heterotopic bone and cartilage formation in the graft's vicinity in 28 of 39 cases. The survival of animal transitional epithelium was similar to that of human. It is concluded that human transitional epithelium does not possess osteoinductive potency. Some clinical data pointing to a link between heterotopic osteogenesis and surgical intervention on urinary tract have been reconsidered and explained by the authors' own hypothesis. In addition, data presented in this paper indicate that one should be very careful when attempting to transmit results performed on dog urinary tract to humans.

Adult↗
PubMed1988

The influence of supplemental feed on growth and bone development of nursing foals.

Thirty foals of mixed breeding, from two consecutive years, were used in two 120-d experiments to evaluate the effects of supplemental feeding (creep feed) on growth in nursing foals. At 10 d postpartum, foals were randomly assigned either to a creep-fed group (CF) or an unsupplemented group (NCF). Initial measurements of body weight (BW), height at the withers (WH), third metatarsal length (MtIII) and third metacarpal length (McIII) were made at 10 d of age and at 30-d intervals thereafter. Medial and lateral cortical peak values for radiographic bone density, cortical width and cortical area at the midpoint of the third metacarpal were used to assess bone quality. Creep feed containing National Research Council (NRC, 1978) recommended levels for all nutrients was offered at 1.5% of BW per day. When compared with unsupplemented foals, supplemented foals had greater gains in BW (P less than .05), in WH (P less than .10) and in MtIII (P less than .05). Mean gains during the trial in BW, WH, MtIII and McIII for the CF foals were 133.3 kg, 22.8 cm, 2.1 cm and 1.9 cm and for the NCF foals were 117.6 kg, 21.2 cm, 1.5 cm and 1.9 cm, respectively. The mean value for the lateral cortical peak was slightly lower (P less than .10) for the CF foals. No differences (P greater than .10) were observed for the medial cortical peak, cortical width or cortical area of the third metacarpal. The results of this study indicate that a creep feeding program that supplies NRC-recommended nutrient levels can increase the rate of skeletal growth with little decrease in quality of bone.

Animal Feed↗
PubMed1991

Tooth and bone development in a Danish medieval mandible with unilateral absence of the mandibular canal.

A Danish anthropological collection of medieval human skeletons excavated in 1986 involves a mandible (No. 212) from an adult female born without the lower alveolar nerve and mandibular canal. It is believed that the defect has resulted in lack of tooth development on the affected side and that the mylohyoid nerve has partially compensated for this defect by development of teeth in localized areas. The defective mandibular dentition has caused a compensatory development of the alveolar process in the maxilla. The missing occlusal support has altered muscular traction on the mandible. This has caused an alteration in mandibular shape. Whether the asymmetric development of the mandible is caused by muscular dysfunction, by failure in angular growth apposition, or by a combination of these factors is discussed. The case presents valuable data in the ongoing discussion about the interaction between nerve tissue and tooth formation and about the interaction between occlusion, jaw morphology, and muscular traction. The study shows how archeological material in an interdisciplinary cooperation between archeological, embryological and orthodontic research can contribute to the clarification of current biological problems.

Alveolar Process↗
PubMed2002

Functions of AP1 (Fos/Jun) in bone development.

Genetically modified mice and cells have provided important insights into the biological functions of the dimeric transcription factor complex AP1, in particular into its role in skeletal development. Data obtained from knockout mice revealed that some components, such as c-Fos are key regulators of bone cell differentiation, whereas others, like c-Jun, JunB and Fra-1 are essential in embryonic and/or postnatal development. Apart from identifying the specific roles of AP1 proteins in developmental processes, researchers are beginning to obtain a better molecular understanding of their cell-context dependent functions, their downstream target genes and how they regulate bone cell proliferation, differentiation, and apoptosis.

Animals↗
PubMed1983

Effect of dietary sodium fluoride on growth and bone development in growing turkeys.

Large White male turkeys were fed rations containing 0, 12.5, 25, 50, 100, 200, 400, and 800 ppm added fluoride (F) from sodium fluoride in a corn-soybean assay diet containing tricalcium phosphate and 3 to 5 ppm F. The 800 ppm treatment was discontinued at 8 weeks because of low weight gains and a high incidence of leg disorders. Turkeys receiving defluorinated phosphate (32% calcium, 18% phosphorus) had significantly higher 4-week body weights than turkeys receiving tricalcium phosphate. Turkeys fed 0, 400, and 800 ppm F had significantly lower body weights at 8 weeks than turkeys fed 50 ppm F. A similar weight pattern was seen at 18 weeks, although the differences were not statistically significant. Based on growth response in this study, a requirement of 20 ppm F is proposed. Increasing levels of dietary F resulted in large increases in tibia F. Removal of high dietary F in certain groups at 8 weeks resulted in growth recovery and reduction in tibia F by 18 weeks. Elevated plasma alkaline phosphatase activity was observed with added dietary F of 400 and 800 ppm. At 4 weeks, tibiae from turkeys receiving high F had a trend (not statistically significant) toward lower percentage ash and a significantly lower breaking strength than controls. Compared to controls, tibiotarsi from turkeys on high F rations were significantly shorter, had thinner cortices, and had a narrower proliferative zone of proximal growth plates. A high incidence of tibial dyschondroplasia was observed, but it was not correlated with dietary treatment.

Alkaline Phosphatase↗
PubMed1994

1,25-Dihydroxyvitamin D3 and 22-oxa-1,25-dihydroxyvitamin D3 in vivo nuclear receptor binding in developing bone during endochondral and intramembranous ossification.

Target cells for 3H-labeled 1 alpha, 25(OH)2 vitamin D3 [1,25(OH)2D3, vitamin D] and its analog 3H-labeled 22-oxa-1 alpha, 25(OH)2 vitamin D3 (OCT) have been identified during endochondral and intramembranous ossification in developing, undecalcified, unembedded bone, using thaw-mount autoradiography. Two-day-old neonatal rats were injected with [3H]1,25(OH)2D3 or [3H]OCT; after 2 h leg, spine, and head were frozen and sectioned. In the epiphyseal-metaphyseal region specific nuclear concentrations of [3H]1,25(OH)2D3 and [3H]OCT were observed in identical cell populations, being low in cells of the articular and resting zone, intermediate in the proliferating zone, and highest in hypertrophic chondrocytes and in osteoblasts and precursor cells. In the primary spongiosa intertrabecular spaces there were a large number of cells with nuclear labeling--probably osteoblasts and precursor cells. In contrast, in the secondary spongiosa intertrabecular spaces, apparent blood-forming cells were mostly unlabeled. Osteoblasts along bone spicules and compact bone in long bones, vertebrae, and head also showed strong nuclear labeling, as did cells of the periosteum. These data suggest that 1,25(OH)2D3 and OCT regulate development, differentiation, and activities of chondrocytes and osteoblasts, including differentiation of resting chondrocytes into proliferating and hypertrophic chondrocytes that involve "chondroclastic" enlargement of lacunae and "trans-differentiation" of surviving hypertrophic chondrocytes; differentiation of stroma cells into osteoblasts; and in periosteum and other regions of intramembranous ossification differentiation of precursor cells and osteoblasts. Nuclear receptor binding and their selective and hierarchical distribution during cell differentiation appear to correspond to multiple genomic effects toward growth, regeneration and repair. The findings indicate a physiological significance and therapeutic potential of 1,25(OH)2D3 and in particular of its less hypercalcemic analog OCT.

Animals↗
PubMed1982

Bone development following transplants of urinary bladder wall: a quantitative histological and ultrastructural study.

Bone formation occurred ten days after transplantation of guinea-pig urinary bladder wall to the anterior abdominal wall. A quantitative analysis showed that the bone which formed in the tissues of the transplant site grew rapidly during the following week. Thereafter, bone growth slowed and remodelling became evident histologically. The bone continued to enlarge for up to six months but growth was mainly confined to an increase in thickness. Matrix vesicles were observed in the early bone formation, but later, when bone growth slowed, these structures could not be observed on the bone surfaces.

Abdominal Muscles↗
PubMed1999

Restoration of normal bone development by human homologue of collagen type II (COL2A1) gene in Col2a1 null mice.

Development of the vertebrate skeleton is a highly complex process in which collagen type II plays a vital role in the formation of long bones via endochondral ossification. Collagen type II, which is encoded by a single COL2A1/ Col2a1 gene, is the most abundant structural protein in the cartilage matrix, where it undergoes complex interactions with several other proteins. The sequence of mature collagen type II chains, each with about 1,100 amino acids, is conserved between different mammalian species. There are 37 amino acid positions that are different between mouse and human collagen type II. Previously, we have demonstrated that transgenic mice, in which Col2a1 gene is knocked out, exhibit a lethal phenotype due to the absence of endochondral bone formation. To investigate whether the biological role of collagen type II is conserved between the species, human COL2A1 gene was expressed in Col2a1 null mice by crossing with transgenic mice in which human COL2A1 gene was integrated. The collagen type II from human gene rescued the lethal phenotype in null mice, indicating that the biological function of collagen type II is conserved between human and mouse. The animals exhibited normal endochondral bone formation and a normal growth plate in tibio-tarsal joint. Chondrocytes isolated from the cartilage of these mice secreted human protein, suggesting that the animals incorporated heterologous protein to form cartilage which is essentially "humanized." The animals reached puberty and produced normal progeny. A completely normal phenotype in newborns indicates that human COL2A1 gene is expressed properly both temporally and spatially. These animals may be useful to generate models to study the effect of COL2A1 mutations on skeletal development in humans by introducing mutated gene constructs either into embryos or by crossing with transgenic animals with COL2A1 mutations.

Animals↗
PubMed2000

Matrix metalloproteinase 9 and vascular endothelial growth factor are essential for osteoclast recruitment into developing long bones.

Bone development requires the recruitment of osteoclast precursors from surrounding mesenchyme, thereby allowing the key events of bone growth such as marrow cavity formation, capillary invasion, and matrix remodeling. We demonstrate that mice deficient in gelatinase B/matrix metalloproteinase (MMP)-9 exhibit a delay in osteoclast recruitment. Histological analysis and specialized invasion and bone resorption models show that MMP-9 is specifically required for the invasion of osteoclasts and endothelial cells into the discontinuously mineralized hypertrophic cartilage that fills the core of the diaphysis. However, MMPs other than MMP-9 are required for the passage of the cells through unmineralized type I collagen of the nascent bone collar, and play a role in resorption of mineralized matrix. MMP-9 stimulates the solubilization of unmineralized cartilage by MMP-13, a collagenase highly expressed in hypertrophic cartilage before osteoclast invasion. Hypertrophic cartilage also expresses vascular endothelial growth factor (VEGF), which binds to extracellular matrix and is made bioavailable by MMP-9 (Bergers, G., R. Brekken, G. McMahon, T.H. Vu, T. Itoh, K. Tamaki, K. Tanzawa, P. Thorpe, S. Itohara, Z. Werb, and D. Hanahan. 2000. Nat. Cell Biol. 2:737-744). We show that VEGF is a chemoattractant for osteoclasts. Moreover, invasion of osteoclasts into the hypertrophic cartilage requires VEGF because it is inhibited by blocking VEGF function. These observations identify specific actions of MMP-9 and VEGF that are critical for early bone development.

Animals↗