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PubMed2005

[The preliminary study on the characteristics of mandible and condyle in dentin matrix protein-1 gene knockout mice].

OBJECTIVE: To study the characteristics of mandible and condyle in Dmp1 gene knockout mice, and to investigate the role of Dmp1 in the osteogenesis and mineralization of bone and cartilage. METHODS: Dmp1-/-mice were executed at birth, 2 weeks, 2 months, 3 months and 5 months, and the mandible was taken out for physical, radiography, transmission electron microscopic, and histological examination. The difference between Dmp1 knockout mouse (ko) and wild type mouse (wt) in bone development, bone densitometry and histology were compared. RESULTS: There were obvious changes in the mandible and condyle of Dmp1-/-mouse, such as incomplete ossification, low density, decreased volume and condyle cartilage degeneration. CONCLUSIONS: Dmp1 is the key factor in the formation of growth plates and secondary ossification center, and plays an important role in the process of bone and cartilage formation and bone nodule remodeling. Dmp1 may be the candidate gene that controls the development of mandible and cartilage.

Animals↗
PubMed1995

Pattern of keratinocyte growth factor and keratinocyte growth factor receptor expression during mouse fetal development suggests a role in mediating morphogenetic mesenchymal-epithelial interactions.

Mesenchymal cells are required for the induction of epithelial development during mammalian organogenesis. Keratinocyte growth factor (KGF) is a mesenchymally derived mitogen with specific activity for epithelial cells, suggesting that it may play a role in mediating these interactions. To further evaluate this hypothesis, in situ hybridization was used to examine the spatial distribution of KGF and KGF receptor (KGFR) transcripts during organogenesis and limb formation in mouse embryos (days 14.5 through 16.5). To facilitate this aim, mouse KGF cDNA clones were isolated. There was extensive identity between the deduced mouse KGF protein sequence and that of its human and rat cognates, indicating that this gene has been highly conserved during mammalian evolution. In addition, mouse KGF protein was purified from fibroblasts and demonstrated to be structurally and functionally similar to human KGF protein. For organs within the integumental, respiratory, gastrointestinal, and urogenital systems, whose development is dependent upon mesenchymal-epithelial interactions, KGF mRNA was detected in mesenchymal cells, while epithelial cells expressed transcripts for the KGFR, KGF and KGFR mRNA was also expressed in certain other tissues such as perichondrium, cartilage of developing bones, developing skeletal muscle, and visceral smooth muscle whose development is not regulated by mesenchymal-epithelial interactions. KGF expression was also detected in tissues isolated from human embryos, suggesting similar functions for KGF in human development. Taken together, our results suggest that KGF plays an important role in mediating mesenchymal-epithelial interactions during organogenesis, but may also have other developmental functions in tissues not governed by such interactions.

Adult↗
PubMed2000

Chondromodulin-I as a novel cartilage-specific growth-modulating factor.

Cartilage is unique among mesenchymal tissues in that it is resistant to vascular invasion due to an intrinsic angiogenesis inhibitor. Chondromodulin-I (ChM-I), a 25-kilodalton glycoprotein purified from bovine epiphyseal cartilage on the basis of growth-promoting activity for chondrocytes, was recently identified as an angiogenesis inhibitor. Human ChM-I cDNA revealed that the mature protein consists of 120 amino acids and is coded as the C-terminal part of a larger transmembrane precursor. Expression of ChM-I cDNA in CHO cells indicated that mature ChM-I molecules were secreted from the cells after post-translational modifications and cleavage from the precursor protein at the predicted processing site. ChM-I stimulated growth and colony formation of cultured chondrocytes, but inhibited angiogenesis in vitro and in vivo. In situ hybridization and immunohistochemistry revealed that ChM-I is specifically expressed in the avascular zone of cartilage in developing bone, but not present in the late hypertrophic and calcified zones that allow vascular invasion. ChM-I actually inhibited vascular invasion into cartilage that was ectopically induced by demineralized bone matrix in nude mice, leading to the suppression of replacement of cartilage by bone in vivo. These results suggest that ChM-I participates in the angiogenic switching of cartilage, and that the withdrawal of its expression allows capillary in-growth, which triggers the replacement of cartilage by bone during endochondral bone development.

Amino Acid Sequence↗
PubMed2002

Transglutaminase factor XIIIA in the cartilage of developing avian long bones.

Previously, we showed that mRNA for transglutaminase factor XIIIA (FXIIIA) is up-regulated in the hypertrophic zone of the growth plate of the chicken tibiotarsus, a well-characterized model of long bone development. In the present study, we have studied the distribution of the FXIIIA protein and of transglutaminase enzymatic activity in this growth plate, as well as in the cartilage of the epiphysis, which includes that of the articular surface. By immunohistochemical analysis, the protein is detected in the zone of maturation, where it is mostly intracellular, and in the hypertrophic zone, where it is present both intracellularly and in the extracellular matrix. The intracellular enzyme is mostly a zymogen, as determined with an antibody specific for the activation peptide. Externalization of FXIIIA is accompanied by enzyme activation. To study the pattern of transglutaminase activity, a synthetic transglutaminase substrate, rhodamine-conjugated tetrapeptide (Pro-Val-Lys-Gly), was used for pulse labeling in organ cultures. Intensive incorporation of the fluorescent substrate was observed throughout the hypertrophic zone and in the cells surrounding the forming blood vessels. The patterns of FXIIIA immunostaining and substrate incorporation overlap almost completely. The cartilaginous factor XIIIA is different from the plasma form in that, both intracellularly and extracellularly, it exists as a monomer, as determined by Western analysis, whereas the plasma form of FXIII is a tetrameric complex composed of both A and B subunits. We also identified FXIIIA and transglutaminase activity within the articular and condylar regions of the tarsus, suggesting a possible involvement of mechanical pressure and/or stress in the production of the molecule and subsequent cross-linking of the cartilage matrix. Thus, transglutaminases, in particular FXIIIA, are involved in the formation of long bones through its activity both in the hypertrophic region of the growth plate and in the formation of articular/epiphyseal cartilages.

Animals↗
PubMed1996

Bone sialoprotein expression in primary human breast cancer is associated with bone metastases development.

Breast cancer metastasizes to bone more frequently than to any other organ, and over 80% of advanced breast cancer patients develop bone metastases. Our recent demonstration that human breast cancer cells express bone sialoprotein (BSP), a bone matrix protein, provides a possible clue for the selective affinity of breast cancer cells for bone. We tested the hypothesis that detection of BSP in primary human breast cancer could be a potential indicator of the ability of breast cancer cells to metastasize to bone. BSP expression was evaluated in the primary breast cancers of 39 patients using immunoperoxidase and two specific anti-BSP antibodies. None of these patients presented clinically or scintigraphically detectable bone metastases at the time of surgery. In the course of their disease, 22 patients developed clinically diagnosed bone metastases. Expression of BSP in breast cancer cells from patients who developed bone metastases was significantly higher (p = 0.008, according to the Mann-Whitney test) than in patients with no bone involvement. No association was found between BSP expression in the primary breast lesions and axillary lymph node metastases. BSP expression was significantly increased in infiltrating ductal carcinoma compared with infiltrating lobular carcinoma (p = 0.0023). No correlation was found between immunoreactivity to BSP antibodies and estrogen receptor (ER) status, progesterone receptor (PR) status, or age. Our data suggest that BSP could help to identity which women will develop bone metastases and provide new bases for the understanding of the molecular mechanism(s) responsible for breast cancer cells osteotropism.

Adult↗
PubMed2000

Osteopoiesis: the early development of bone cells.

An understanding of the disorders of bone formation clearly requires insights into the complex regulatory events occurring during the evolution of bone precursor cells into osteoblasts. Moreover, a rational approach to therapeutic interventions that might alter the clinical course of bone disorders must take into consideration the exact nature of the developmental control mechanism(s) being affected during the disease process. The process of osteopoiesis involves the proliferation and maturation of primitive precursor cells into functional osteoblasts. The bone cell lineage originates from mesenchymal stem cells that commit to the osteogenic cell lineage becoming osteoprogenitor cells, preosteoblasts, osteoblasts, and osteocytes. In order to understand how different regulatory signals coordinate bone cell development, it is important to study the responses of bone progenitor cells to different microenviromental signals. This requires that lineage markers be identified for the various populations of bone cells and their precursors, that cell separation techniques be established so that cells of the osteogenic lineage can be purified at different stages of differentiation, and that these isolated cells are studied under serum-free, chemically defined conditions. This review focuses on the current understanding of bone progenitor cell development, examining the various types of precursor cells, their responses to cytokines and other extracellular influences, and recent observations on the biochemical and molecular control of lineage-specific gene expression. Although the emphasis is on human cells, the importance of work using rodent cells goes without saying, and is addressed where relevant.

Bone Development↗
PubMed1983

Development of the frontal bone and cranial meninges in the embryonic chick: an experimental study of tissue interactions.

The frontal region of the embryonic chick was studied to determine whether epithelial influences are necessary for frontal bone development. The frontal bone is a membrane bone, of neural crest and head mesodermal origin, which develops within mesenchyme sandwiched between two epithelia, neural ectoderm and epidermis. Rudiments were treated enzymatically to separate epithelial and mesenchymal tissues. Frontal mesenchyme then was grown as chorioallantoic membrane grafts either in the presence or absence of neural ectoderm and/or epidermis. The results indicate that neural ectoderm, though required during early stages of development to induce frontal bone development (Schowing, 1968), is not required during later stages (HH 22-30, the stages tested in this study) for osteogenesis. Epidermis, however, was shown to be required for frontal bone development during the stages tested. Frontal mesenchyme formed bone when epidermis was present on the outer aspect of the mesenchyme, and did not form bone when the epidermis had been removed prior to grafting, whether or not neural ectoderm was present. This dependence upon epidermis continues beyond the onset of meningeal differentiation. Once the outer ectomeninx-dermis is distinguishable from the inner endomeninx, osteogenic capabilities are confined to the ectomeninx-dermis layer. Furthermore, the ectomeninx-dermis layer attached to epidermis is able to form membrane bone in the absence of the endomeninx and neural ectoderm. The endomeninx, though normally nonchondrogenic, was shown to be capable of forming cartilage when the neural ectoderm is removed. Neural ectoderm, therefore, may have an inhibitory effect on chondrogenesis in the endomeninx.

Animals↗
PubMed2003

Organisation of bone morphogenetic proteins in renal development.

Bone morphogenetic proteins (BMPs) comprise the largest subfamily of the transforming growth factor-beta (TGF-beta) superfamily of secreted proteins. Evidence for the involvement of BMPs in metanephric development emerged recently when renal phenotypes were observed in BMP7 null mutant mice. Since then, several other BMPs, BMP receptor serine/threonine kinases and BMP signal transduction molecules (Smads) have been implicated in mammalian metanephric development. It appears that particular BMPs have pivotal roles in specific aspects of metanephric development. Current knowledge and evidence of specific roles of particular BMPs are presented in this review.

Animals↗
PubMed2001

[Leptin: factor in the central nervous system regulation of bone mass. Development of a new understanding of bone remodeling, skeletal reconstruction, skeletal preservation and skeletal repair].

Bone remodeling is the physiologic process used by vertebrates to maintain a constant bone mass between the end of puberty and gonadal failure. Besides the well-characterized and critical local regulation of bone remodeling, recent genetic studies have shown that there is a central control of bone formation, one aspect of bone remodeling. This central regulation involves leptin, an adipocyte-secreted hormone that controls body weight, reproduction, and bone remodeling following binding to its receptor located on the hypothalamic nuclei. This genetic result in rodents is in line with clinical observations in humans and offers a whole new direction for research in bone physiology.

Adolescent↗
PubMed1999

Biochemical markers of bone turnover and the volume and the density of bone in children at different stages of sexual development.

Bone mass and biochemical markers of bone turnover increase significantly during puberty. We studied the possible relationships between markers of bone formation and bone resorption and increases in skeletal size, bone volume, and bone density in healthy children at different stages of sexual development. Serum concentrations of bone specific alkaline phosphatase (BALP) and osteocalcin (bone Gla protein, BGP), urinary levels of pyridinoline (Pyr) and deoxypyridinoline (Dpyr) and computed tomography (CT) measurements of the cross-sectional areas of the vertebrae and the femurs, the apparent density of cancellous bone in the vertebrae, and the volume and the material density of cortical bone in the femurs were determined in 126 boys and 143 girls, ages 7-18 years. Serum levels of BALP and BGP and urinary concentrations of Pyr and Dpyr peaked in early puberty and were lowest in the later stages of puberty. CT measurements for the cross-sectional areas of the vertebrae and the femurs, the femoral cortical bone areas, and the apparent density of cancellous bone increased in all children during puberty, while values for material bone density did not change significantly with the stage of sexual development. BALP and BGP showed significant inverse correlations with the material density of bone (r = -0.23 and -0.24, respectively), but no association with bone volume in the appendicular or axial skeleton. In contrast, Pyr and Dpyr correlated with femoral cross-sectional area (r = -0.24 and -0.33, respectively) and cortical bone area (r = -0.29 and -0.33, respectively), and with the apparent density of vertebral cancellous bone (r = -0.26 and -0.19, respectively), but not with the material density of bone. We conclude that, during puberty, there is a differential association between the two components of bone mass and the markers of bone formation and bone resorption; while markers of bone formation are related to the material density of bone, markers of bone resorption are related to the volume of bone.

Adolescent↗
PubMed2000

Bone morphogenetic protein excipients: comparative observations on poloxamer.

Clinicians await the availability of synthetic bioimplants that will replace the need for autogeneic bone grafts in bone reconstructive surgery. For more than a decade, researchers have evaluated delivery vehicles for the tissue morphogen bone morphogenetic protein. The object of this investigation was to measure induced bone development when bone morphogenetic protein was delivered by human tendon collagen, human demineralized bone matrix, hydroxyapatite, a composite of human tendon collagen and human demineralized bone matrix (tendon collagen + demineralized bone matrix), Poloxamer 407, and a composite of human demineralized bone matrix and Poloxamer 407. Sixty-three adult male Swiss Webster mice (Harlan Sprague-Dawley, Indianapolis, Ind.) received 126 implants. The animals were divided into seven groups of nine animals, depending on carrier (six carriers plus the positive control group) used. Each animal received a bone morphogenetic protein-enhanced carrier in one hindquarter muscle mass, with the contralateral leg being implanted with the carrier alone. Implants were evaluated by quantitative radiomorphometry validated by histologic methods. Radiographically, no significant differences were identified among any of the implants evaluated (p > 0.05). Histomorphometric analysis demonstrated that Poloxamer 407 was significantly (p < 0.05) better at delivering bone morphogenetic protein than the other carriers involved in this investigation. The new bone developed in a tubular or spherical shape. Interaction of endogenous and exogenous delivery systems seems to be essential for optimal transmission of bone morphogenetic protein. The importance of the excipient to deliver bone morphogenetic protein and develop a bone morphogenetic protein concentration gradient has been emphasized by other investigators and confirmed by our research on poloxamer. With further research on the physicochemical mechanisms of localization and transmission of bone morphogenetic protein, it may be possible to avoid hazardous operations with autogeneic bone.

Animals↗
PubMed1983

The development of embryonic bone and cartilage in tissue culture.

Embryonic chick long bone develops in a series of temporally controlled, cellular events and involves the integration of at least three distinctly different sets of cells: collar osteoblasts, core osteoblasts, and resorptive or osteoclastic cells. The morphology of the long bones is established by the developing cartilage rudiment or model. All of these events seem to be influenced by positional cues. The cultivation of all of these cells and their presumptive progenitor cells potentially allows a detailed analysis of their individual and collective phenotypic traits. Future studies can include how long bones form, how bone-forming and bone-resorbing cells interact, and how osteogenic cells influence each other throughout each stage of their respective developmental lineages.

Animals↗
PubMed2003

Function of bone morphogenetic protein signaling during mouse development.

Bone morphogenetic proteins (BMPs) play pleiotropic roles during development and after birth in many different organisms. BMPs are members of TGF-beta superfamily. There are more than 20 members with three type II receptors and three type I receptors. Genetic approaches using the mouse as a model system revealed many of the functions of BMPs. Particularly, results obtained through loss-of-function analyses of BMP ligands and their receptors are reviewed in this article.

Animals↗
PubMed1994

Possible involvement of vitamin D3-deficiency and relatively enhanced bone resorption in the development of bone loss in streptozotocin-induced diabetic rats.

To explore the pathogenesis of diabetes associated osteopenia, we characterized the osteopenia in streptozotocin (STZ)-diabetic rats pharmacologically and biochemically. The femur metaphyseal bone mineral density measured by single photon absorptiometry decreased time-dependently in the STZ rats compared with that in control, and the difference reached statistical significance from 2 weeks after treatment with STZ. Closely similar bone loss was obtained in ovariectomized (Ovx) and vitamin D deficient(D(-)) rats. Daily oral treatment with a bone resorption inhibitor, FR78844 (a bisphosphonate compound, 100 mg/kg), for 4 weeks significantly attenuated the osteopenia in the STZ and Ovx rats, but not in the D(-) rats, while 1 alpha-hydroxyvitamin D3 (1 alpha-(OH)D3) significantly attenuated the osteopenia in the STZ and D(-) rats in a dose of 0.1 microgram/kg/day, and that in the Ovx rats in 1 microgram/kg/day. The latter dose of 1 alpha-(OH)D3 significantly increased the metaphyseal bone mineral density of the femur in normal rats. Serum levels of 1 alpha, 25-dihydroxyvitamin D (1 alpha, 25-(OH)2D), the most active metabolite of vitamin D, hardly changed in the Ovx rats compared with that in control, but decreased to 24 and 76% that of control in the STZ and D(-) rats, respectively. Serum PTH levels in the STZ, Ovx and D(-) rats were comparable with those in controls, but serum calcitonin levels were reduced to 60 and 66% of control in the STZ and Ovx rats, respectively. Serum osteocalcin levels also decreased in the STZ rats compared to control. It is thus speculated that the predominance of bone resorption over bone formation and the reduction of 1 alpha, 25-(OH)2D are involved in the pathogenesis of diabetes associated osteopenia.

Animals↗
PubMed1979

The effect of protein-energy malnutrition on the development of bones in newborn rats.

Collagen synthesis, 45Ca uptake, and the half-life of 45Ca in mandibles and long bones of rat pups suckled on dams fed 25 or 6% protein diets were determined. Collagen synthesis in both mandibles and long bones was impaired in the malnourished group at an early age. Protein-energy malnutrition appears to affect different developmental processes in these two bones. The principal interference with collagen synthesis in the mandible occurs when bone proline is converted into hydroxyproline. In contrast, proline uptake from the blood for deposit in bone matrix is the step of collagen synthesis mainly affected in long bone. In addition, the critical growth period of mandible was different from that of long bone. The calcium complex fraction (calcium bound to protein plus that in inorganic salts) was the main compartment affected in the malnourished group. However, the efficiency of calcification per milligram of matrix in the calcium complex fraction of the mandible and long bone was approximately the same in the control and malnourished groups, thus suggesting that accumulation of calcium occurs in parallel with the formation of bone matrix regardless of the nutritional conditions. The half-life of 45Ca in the various calcium fractions of both types of bone was 72 hours in both the control and malnourished groups except the calcium complex portion of the long bone of the control group, which was about 100 hours.

Aging↗