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At least 649 records · Page 36Linked to original sources
PubMed1995

Fumonisin B1 is fetotoxic in rats.

Groups of 5-6 pregnant F344/N rats were dosed (po) from d 8 to 12 of gestation with 30 or 60 mg purified fumonisin B1 (FB1)/kg body weight, or with a fat-soluble extract of Fusarium proliferatum/corn culture derived from an amount of corn culture that would provide approximately 60 mg FB1/kg. Control rats were dosed with water or corn oil. Food intake was monitored daily during dosing. Fetal bone development was examined after staining with alizarin red, whereas internal organ development was examined in hematoxylin and eosin-stained tissue sections. Although group differences in maternal body weight were not statistically significant, weight was 6% less in dams dosed with 60 mg FB1/kg compared with the control group (p < 0.12). Relative litter weight was significantly suppressed by 60 mg FB1/kg. Ossification of the sternebrae and vertebral bodies was significantly impaired by FB1 treatment. Litters from mothers treated with a fat-soluble extract of F proliferatum/corn culture did not have suppression of weight or impairment of bone development. Fumonisin B1 is fetotoxic to rats by suppressing growth and fetal bone development.

Animals↗
PubMed2006

Networks and hubs for the transcriptional control of osteoblastogenesis.

We present an overview of the concepts of tissue-specific transcriptional control mechanisms essential for development of the bone cell phenotype. BMP2 induced transcription factors constitute a network of activities and molecular switches for bone development and osteoblast differentiation. Among these regulators are Runx2 (Cbfa1/AML3), the principal osteogenic master gene for bone formation, as well as homeodomain proteins and osterix. Runx2 has multiple regulatory activities, including activation or repression of gene expression, and integration of biological signals from developmental cues, such as BMP/TGFbeta, Wnt and Src signaling pathways. Runx2 provides a new paradigm for transcriptional control by functioning as a principal scaffolding protein in nuclear microenvironments to control gene expression in response to physiologic signals (growth factors, cytokines and hormones). The protein serves as a hub for the coordination of activities essential for the expansion and differentiation of osteogenic lineage cells through the formation of co-regulatory protein complexes organized in subnuclear domains. Mechanisms by which Runx2 supports commitment to osteogenesis and determines cell fate involve its retention on mitotic chromosomes. Disruption of a unique protein module, the subnuclear targeting signal of Runx2, has profound effects on osteoblast differentiation and metastasis of cancer cells in the bone microenvironment. Runx2 target genes include regulators of cell growth control, components of the bone extracellular matrix, angiogenesis, and signaling proteins for development of the osteoblast phenotype and bone turnover. The specificity of Runx2 regulatory activities provides a basis for novel therapeutic strategies to correct bone disorders.

Animals↗
PubMed1983

[Dysplastic changes in the development of bone tissue in congenital pseudarthrosis].

Angiographic examinations of shin blood vessels were carried out in 11 patients of 2 1/2 to 16 years with congenital false joints, and in 3 of these patients also pathomorphological and ultrastructural studies of the bone and cartilage tissue from the false joint area were performed. The deepest disorders of the blood supply were found at the level of the false joint. Dysplastic changes in the bone consisted in disorders of normal osteogenesis and atypical development of the cartilage, thinning of the bone structures, ultrastructural invalidity of osteocytes and insufficient mineral saturation of the organic matrix. Dystrophy of chondrocytes and deficient ultrastructure of collagen fibrills were noted.

Adolescent↗
PubMed2000

Dietary 4-HPR suppresses the development of bone metastasis in vivo in a mouse model of prostate cancer progression.

The effects of the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) on prostate cancer metastasis in vivo were evaluated in the mouse prostate reconstitution (MPR) model. MPRs were produced by infection of either heterozygous (+/-) or nullizygous (-/-) p53-mutant fetal prostatic epithelial cells with the recombinant retrovirus Zipras/myc 9. Previous studies have documented that loss of p53 function potentiates metastasis in this model system. MPRs were grafted into homozygous (+/+) p53 male mice, fed a 4-HPR containing diet or a control diet and maintained until the status of tumor progression dictated sacrifice. Under these experimental conditions, treatment with 4-HPR did not have a significant effect on primary tumor wet weight for either p53 +/- or p53 -/- MPRs. For, p53 +/- MPRs the animals fed the 4-HPR diet had a slight improvement in survival and a significant reduction in the number of mesenteric metastases (P = 0.0477, t-test). Notably, in p53 +/- MPRs the incidence of metastasis to lumbar spine and sternum was 92% in the control animals compared to 54% in the 4-HPR treated animals (P = 0.035, chi2-test). In p53 -/- MPRs there was a trend toward a reduction in the number of soft tissue metastases to lung and liver in the 4-HPR group relative to the control diet group and a statistically significant reduction in the incidence of metastasis to bone was demonstrated in that 50% of control animals versus 30% of 4-HPR treated p53 -/- animals harbored bone metastases (P = 0 < 0.05, chi2-test). Cell lines were established from portions of the primary tumor and from selected metastatic deposits in each experimental group. Clonal analysis, by retroviral integration pattern, indicated increased clonal diversity in both the primary tumors and metastasis-derived cell lines from 4-HPR treated animals relative to the control animals. In vitro treatment with 4-HPR did not reveal discriminating differences between cell lines derived from primary tumors and bone metastases or control and treatment groups in regard to growth arrest or apoptotic responses. Overall these studies indicate limited anti-tumor and anti-metastatic activity in this highly aggressive in vivo mouse model of prostate cancer, yet 4-HPR treatment significantly suppressed the development of bone metastases in p53 +/- and p53 -/- MPRs revealing a novel and potentially clinically useful activity of this retinoid.

Animals↗
PubMed1978

Premature fusion of facial sutures with free periosteal grafts. An experimental study with special reference to bone formation with free periosteal grafts from the tibia, the scapula and the calvarium.

The present study was undertaken to obtain more information on the bone forming mechanisms with free periosteal grafts and to study premature synostosis of facial sutures achieved with free periosteal grafts. The results are based on a material of 196 rabbits operated on at the age of two weeks. It was found that the bone forming mechanism with free periosteal grafts from the tibia, the scapula and the calvarium is essentially the same. When implanted in the tibialis anterior muscle of the leg of the same animal they all produced bone. The mechanism of bone formation is reminiscent of the enchondral bone formation seen in fracture healing. There is no difference in the bone forming mechanism with the periosteum from an enchondrally ossifying bone when compared with the periosteum of an intramembranously ossifying bone. In all the three different periosteal grafts studied, there was a cartilage stage before bone formation. In the muscle, all these three periosteal grafts, in spite of their tubular or membranous bone origin, produced bones tubular in shape. When the transplants were overlying the membranaceous facial bones, membrane shaped bone developed via intramembraneceous type of ossification in the recipient area. It can be concluded from these experiments that the shape and type of bone developed with free periosteal grafts depends mainly on the environmental conditions in the recipient area. Fusion of the premaxillo-maxillary and fronto-nasal sutures was achieved with free periosteal grafts from the tibia. Free periosteal grafts from the scapula and the calvarium failed to develop premature fusion of the sutures. The fusion developed due to increased bone formation in the suture area. The fusion of the premaxillo-maxillary suture stopped the growth in this area and caused a severe growth disturbance of the whole snout. The fusion of the fronto-nasal suture by the bone bridge retarded the growth of the nasal bone on the fused side and led to deviation of the snout to the operated side. Compensatory changes developed in other sites of the cranio-facial skeleton in order to minimize the effects of the growth disturbance. The fused fronto-nasal suture was used as a model to study the treatment of premature synostosis of facial bones. Resection of the fused area led to correction of the developed growth disturbance and to subsequent normal growth of the snout.

Animals↗
PubMed1987

[Two cases of heterotopic bone formation in the kidney and clinico-pathological study of 36 cases reported in Japan].

We report two cases of heterotopic bone formation in the kidney. One patient was a 54-year-old man who consulted his family physician with the complaint of fever-up and nocturia. X-ray examination revealed a calcification in the left kidney and location of the pelvis for outside. Therefore, abdominal CT scan and selective renal angiography were performed. As a malignant renal tumor with hypovascularity could not be neglected, left nephrectomy was performed on August 18, 1980. Grossly, the resected kidney was 230 g in weight and had a 8 X 3 cm mass with a white cut surface and bone-like tendency. Histopathologically, a well-developed bone with erythropoietic bone marrow was found outside of the renal capsule. The other patient was a 52-year-old man with the complaint of painful swelling of left scrotum and lumbago. X-ray examination revealed bilateral renal stones and left ureteral stone. Bilateral nephrolithotomy and left ureterolithotomy were performed, and some stones and a part of bilateral renal pelvis which was bony hard and white in color were resected. Histopathologically, there were well-developed bone formation and infiltration of inflammatory cells in renal pelvic membrane. Among 36 reported cases in Japan, 16 cases were in male and 20 cases in female patients. Our second case was the first cases of bilateral renal heterotopic bone formation complicated with bilateral renal stones in 5 reported cases with renal stones. Including our first case, 5 cases which had heterotopic bone formation in renal capsule have been reported.

Humans↗
PubMed2005

[Functions of BMPs, Runx2, and osterix in the development of bone and cartilage].

BMP signaling plays important roles in craniofacial development, limb development, and joint formation. BMPs enhance chondrocyte differentiation and proliferation but inhibit the terminal differentiation of chondrocytes. Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 and Osterix are essential for osteoblast differentiation. Runx2 and Runx3 induce Ihh, which enhances chondrocyte proliferation and inhibits chondrocyte maturation, in prehypertrophic chondrocytes, and Ihh induces Runx2 in the perichondrial cells leading to their differentiation into osteoblasts.

Animals↗
PubMed2003

In vitro and in vivo endochondral bone formation models allow identification of anti-angiogenic compounds.

A major obstacle in the study of angiogenesis and the testing of new agents with anti-angiogenic potential has been the lack of experimental models with predictive in vivo value. We describe here the combined use of in vitro and in vivo angiogenesis models that are based on endochondral bone development. This approach led to the identification of a new inhibitor of matrix metalloprotease (MMP) activity that inhibits neovascularization in vitro and in vivo while osteoclast invasion, which occurs simultaneously during bone development, remained unaffected. In contrast, the broad-spectrum MMP-inhibitor marimastat inhibited both in vitro angiogenesis and osteoclastogenesis dose-dependently but displayed severe toxic side effects in vivo. The combined use of these experimental models may, therefore, facilitate the discovery of mechanisms underlying angiogenesis and lead to identification of new pharmacological compounds with clinical efficacy and appropriate selectivity in the treatment of angiogenesis-dependent disorders like arthritis and cancer.

Angiogenesis Inhibitors↗
PubMed1998

Immortalization and characterization of bone marrow stromal fibroblasts from a patient with a loss of function mutation in the estrogen receptor-alpha gene.

A male patient with abnormal postpubertal bone elongation was shown earlier to have a mutation in both alleles of the estrogen receptor, resulting in a nonfunctional gene. Marrow stromal fibroblasts (MSFs) derived from this patient were called HERKOs (human estrogen receptor knock outs), and in order to obtain continuous HERKO cell lines, they were immortalized using a recombinant adenovirus-origin-minus SV40 virus. MSFs are unique cells because they support hematopoesis and contain a mixed population of precursor cells for bone, cartilage, and fat. Three established cell lines (HERKO2, HERKO4, and HERKO7) were characterized and compared with the heterogeneous population of nonimmortalized HERKOs for their osteogenic potential. We performed Northern analysis of matrix genes implicated in bone development and metabolism and an in vivo bone formation assay by transplanting the cells subcutaneously into immunodeficient mice. All three HERKO lines expressed high amounts of collagen 1A1, osteopontin, osteonectin, fibronectin, decorin, biglycan, and alkaline phosphatase. Except for osteopontin, expression of these genes was slightly lower compared with nonimmortalized HERKOs. In the in vivo bone formation assay, the heterogeneous population of nonimmortalized HERKOs formed bone with high efficiency, while the HERKO lines induced a high-density, bone-like matrix. Finally, all HERKO cell types secreted high levels of insulin-like growth factor I and interleukin-6 into the culture medium relative to cells of normal human subjects. In summary, these lines of HERKO cells retain several of the phenotypic traits of MSFs after immortalization, including matrix and cytokine production, and provide a valuable source of a unique human material for future studies involving estrogen action in bone and bone marrow metabolism.

Adult↗
PubMed2003

SU6668 in idiopathic myelofibrosis--a rational therapeutic approach targeting several tyrosine kinases of importance for the myeloproliferation and the development of bone marrow fibrosis and angiogenesis.

Idiopathic myelofibrosis is a chronic myeloproliferative disorder being featured by progressive accumulation of connective tissue in concert with marked neovascularization (angiogenesis) of the bone marrow. Both fibrogenesis and angiogenesis are considered to develop consequent to the intramedullary release of various growth-promoting factors from rapidly proliferating and dysplastic megakaryocytes. Among these growth factors are platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), transforming growth factor beta (TGF-beta) and vascular endothelial growth factor (VEGF). The protein kinase inhibitor SU6668 is a potent antiangiogenic inhibitor of receptor tyrosine kinases, including those of VEGFR, PDGFR, bFGFR, and c-kit. The hypothesis is that SU6668 may be an effective agent in the treatment of idiopathic myelofibrosis. This compound has an inhibitory target profile on several tyrosine kinases involved in the myeloproliferation, the development of myeloid metaplasia (bFGFR, PDGFR, VEGFR, and c-kit) and the development of the major stromal changes in the bone marrow - fibrosis and angiogenesis (bFGFR, PDGFR, and VEGFR).

Bone Marrow↗
PubMed2004

Collagen, type V, alpha1 (COL5A1) is regulated by TGF-beta in osteoblasts.

Bone matrix contains high concentrations of growth factors that are known to play important regulatory roles during osteogenesis, particularly transforming growth factor-beta (TGF-beta). Divergent effects of TGF-beta on bone formation have been reported both in vitro and in vivo depending upon experimental conditions, cells employed and their stage of maturation. In this study, we have used a clonal osteoblastic cell line MC3T3-E1, derived from newborn mouse calvaria, as an in vitro model of bone development. These cells undergo an ordered, time-dependent developmental sequence characterized by three stages (proliferation, differentiation and mineralization), over a 30-35-day period. In this study, cDNA microarray technology was used to study the expression profile of 8470 genes, in the presence of TGF-beta1 during osteoblast development. Microarray analysis revealed 120 cDNAs to be differentially expressed in MC3T3-E1 osteoblasts that had been treated with TGF-beta1. From the 120 differentially expressed genes, we selected Collagen, type V, alpha1 (COL5A1) {differential expression=+4.9} for further studies since it represents a previously uncharacterized component of the bone matrix. Using Northern blotting, we found that, when MC3T3-E1 cells were treated with TGF-beta1, COL5A1 was up-regulated during the proliferation and differentiation phases of osteogenesis. Furthermore, by a combination of RNA in situ hybridization and Northern blotting, we found COL5A1 mRNA to be expressed in the calvaria and developing bone of the E17.5 mouse embryos. Lastly, significant COL5A1 protein expression was observed by immunohistochemistry in the developing bone of the E17.5 mouse embryos. In conclusion, by the use of in vitro and in vivo approaches, we have discovered that the COL5A1 gene is a target of TGF-beta during osteogenesis.

Alkaline Phosphatase↗
PubMed2001

Protein intake and bone growth.

Among osteotrophic nutrients, proteins play an important role in bone development, thereby influencing peak bone mass. Consequently, protein malnutrition during development can increase the risk of osteoporosis and of fragility fracture later in life. Both animal and human studies indicate that low protein intake can be detrimental for both the acquisition of bone mass during growth and its conservation during adulthood. Low protein intake impairs both the production and action of IGF-I (Insulin-like growth factor-I). IGF-I is an essential factor for bone longitudinal growth, as it stimulates proliferation and differentiation of chondrocytes in the epiphyseal plate, and also for bone formation. It can be considered as a key factor in the adjustments of calcium-phosphate metabolism required for normal skeletal development and bone mineralization during growth. In healthy children and adolescents, a positive association between the amount of ingested proteins and bone mass gain was observed in both sexes at the level of the lumbar spine, the proximal femur and the midfemoral shaft. This association appears to be particularly significant in prepubertal children. This suggests that, like for the bone response to either the intake of calcium or weight-bearing exercise, the skeleton would be particularly responsive to the protein intake during the years preceding the onset of pubertal maturation.

Animals↗
PubMed1996

Prognostic value of contrast enhanced Gd-DTPA MRI for development of bone erosive changes in rheumatoid arthritis.

Conventional radiograms have been used to quantitate the progression of rheumatoid arthritis, mainly through the assessment of bone erosions, but this approach has many limitations. It has been suggested that an advantage of contrast-enhanced Gd-DTPA MRI over radiography may be its prognostic value due to its ability to show the natural history of active destructive to inactive fibrous pannus. The aim of this study was to evaluate the possible prognostic value of MRI for future development of bone erosive changes in small hand joints in patients with RA. The results of the study confirm that in joints in which inflammatory active pannus is shown by contrast-enhanced MRI, progression of bone-destructive changes can be expected.

Arthritis, Rheumatoid↗
PubMed2006

Contributions of matrix metalloproteinases toward Meckel's cartilage resorption in mice: immunohistochemical studies, including comparisons with developing endochondral bones.

The middle portion of Meckel's cartilage (one of four portions that disappear with unique fate) degrades via hypertrophy and the cell death of chondrocytes and via the resorption of cartilage by chondroclasts. We have examined the immunolocalization of matrix metalloproteinase-2 (MMP-2), MMP-9, MMP-13, and MMP-14 (members of the MMP activation cascade) and galectin-3 (an endogenous substrate for MMP-9 and an anti-apoptotic factor) during resorption of Meckel's cartilage in embryonic mice and have compared the results with those of developing endochondral bones in hind limbs. MMP immunoreactivity, except for MMP-2, is present in nearly all chondrocytes in the middle portion of Meckel's cartilage. On embryonic day 15 (E15), faint MMP-2-immunoreactive and intense MMP-13-immunoreactive signals occur in the periosteal bone matrix deposited by periosteal osteoblasts on the lateral surface, whereas MMP-9 and MMP-14 are immunolocalized in the peripheral chondrocytes of Meckel's cartilage. The activation cascade of MMPs by face-to-face cross-talk between cells may thus contribute to the initiation of Meckel's cartilage degradation. On E16, immunopositive signaling for MMP-13 is detectable in the ruffled border of chondroclasts at the resorption front, whereas immunostaining for galectin-3 is present at all stages of chondrocyte differentiation, especially in hypertrophic chondrocytes adjacent to chondroclasts. Galectin-3-positive hypertrophic chondrocytes may therefore coordinate the resorption of calcified cartilage through cell-to-cell contact with chondroclasts. In metatarsal specimens from E16, MMPs are detected in osteoblasts, young osteocytes, and the bone matrix of the periosteal envelope, whereas galectin-3 immunoreactivity is intense in young periosteal osteocytes. In addition, intense MMP-9 and MMP-14 immunostaining has been preferentially found in pre-hypertrophic chondrocytes, although galectin-3 immunoreactivity markedly decreases in hypertrophic chondrocytes. These results indicate that the degradation of Meckel's cartilage involves an activation cascade of MMPs that differs from that in endochondral bone formation.

Acid Phosphatase↗
PubMed2003

The role of dietary calcium in bone health.

Approximately 99% of body Ca is found in bone, where it serves a key structural role as a component of hydroxyapatite. Dietary requirements for Ca are determined by the needs for bone development and maintenance, which vary throughout the life stage, with greater needs during the periods of rapid growth in childhood and adolescence, during pregnancy and lactation, and in later life. There is considerable disagreement between expert groups on the daily Ca intake levels that should be recommended, reflecting the uncertainty in the data for establishing Ca requirements. Inadequate dietary Ca in early life impairs bone development, and Ca supplementation of the usual diet for periods of < or = 3 years has been shown to enhance bone mineral status in children and adolescents. However, it is unclear whether this benefit is long term, leading to the optimisation of peak bone mass in early adulthood. In later years inadequate dietary Ca accelerates bone loss and may contribute to osteoporosis. Ca supplementation of the usual diet in post-menopausal women and older men has been shown to reduce the rate of loss of bone mineral density at a number of sites over periods of 1-2 years. However, the extent to which this outcome reduces fracture risk needs to be determined. Even allowing for disagreements on recommended intakes, evidence indicates that dietary Ca intake is inadequate for maintenance of bone health in a substantial proportion of some population groups, particularly adolescent girls and older women.

Adolescent↗
PubMed1988

Development of bone-like substance in cartilaginous rat nasal septum under experimental conditions.

The anterior part of the mammalian nasal septum (NS) persists throughout the life span as hyaline cartilage, in contrast to cartilage in most parts of the body, which is gradually replaced by bone during development. In this study, we have cultured differentiating rat NS under various experimental conditions in an attempt to gain some insight into the osteogenic potential, if any, of the NS and its surrounding connective tissue. Differentiating NS from E15 and E19 rat embryos were dissected and grown under the following conditions: 1) organ cultured in Waymouth's medium or modified Eagle's medium, with or without serum; 2) cultured on chick chorioallantoic membrane (CAM); 3) implanted under rat kidney capsule (KC). Bone-like substance (BLS) never developed in organ cultures, but was observed in CAM cultures and KC implants after 7 days. The BLS was located external to the perichondrium of the NS and was stained red by the van Gieson's technique, indicating the presence of mature collagen. Further evidence of its bone-like characteristics was demonstrated by the presence of alkaline phosphatase and type I collagen. The CAM and KC represent two experimental conditions under which progenitor cells in the nasal septum area may be induced to synthesize BLS.

Allantois↗