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At least 469 records · Page 26Linked to original sources

PubMed2000

Bone tissue specific transcriptional control: options for targeting gene therapy to the skeleton.

BACKGROUND: The transplantation of multipotential bone marrow cells containing bone tissue specific promoter-controlled transgenes provides an efficacious approach to deliver therapeutic gene expression to osteoblasts for the treatment of patients with bone disorders or tumor metastasis to the skeleton. The specificity of tissue-restricted gene therapy can be refined by utilization of a 31-amino-acid segment of the hematopoietic and osteogenic AML/CBF transcription factors that direct the regulatory proteins to subnuclear sites that support gene expression. METHODS: Unfractionated adherent bone marrow cells from transgenic mice constructed with the proximal 1.7 kb of the osteocalcin gene promoter fused to a CAT reporter were transplanted by intravenous infusion. Engraftment and expression at the single-cell level within the context of tissue organization was established by immunohistochemistry using an anti-CAT antibody. Sequences that support the intranuclear trafficking of AML/CBF transcription factors to subnuclear sites that support transcription were determined by the expression and visualization of mutated and epitope tagged AML/CBF proteins. RESULTS: Immunohistochemical staining of an extensive series of tissue sections from mice posttransplantation using an anti-CAT antibody indicated that CAT-positive osteoblasts and osteocytes were present in bone sections. These findings indicate that donor bone marrow-derived cells engraft in bone tissue in an environment that supports maturation to the developmental stage at which a bone specific osteocalcin promoter is transcriptionally active. Characterization of functional domains in AML/CBF transcription factors has established that there are at least two regulated events that are required for targeting the factors to transcriptionally active nuclear domains: A nuclear localization signal in the amino terminal region controls nuclear import and retention, and a nuclear matrix targeting signal in the carboxyl region controls association with nuclear matrix-linked sites where transcription occurs. CONCLUSIONS: The specificity of hematopoietic and bone phenotypic promoters, together with the additional level of specificity inherent in the AML/CBF family of hematopoietic and osteogenic intranuclear targeting signals, offers viable options for constructing gene therapy regimens that are targeted to the skeleton for the control of metastatic disease. It is realistic to anticipate that, as additional parameters of gene regulatory mechanisms are defined, particularly components of transcriptional control that are operative within a three-dimensional context of nuclear architecture, opportunities for enhancing the effectiveness of treating patients with tumors that metastasize to bone will be extended.

Animals↗

PubMed2000

Bisphosphonates in the management of prostate carcinoma metastatic to the skeleton.

BACKGROUND: Prostate carcinoma metastasizes frequently to the skeleton, causing significant morbidity, particularly severe bone pain. Metastatic lesions typically are osteosclerotic, but there is experimental, histologic, and biochemical evidence of increased bone resorption. Furthermore, bone resorption rates appear to correlate with bone pain. These observations provide the rationale for the use of bisphosphonates in the management of patients with prostate carcinoma and skeletal metastases. METHODS: The authors reviewed the literature and current findings on the use of biphosphonates in the management of patients with prostate carcinoma metastatic to the skeleton. RESULTS: Compared with the large number of studies with bisphosphonates in predominantly osteolytic bone disease, there have been relatively few (mostly uncontrolled) studies in patients with prostate carcinoma. Apart from the lack of appropriate experimental models, the osteoblastic nature of the metastases and the low incidence of objectively assessed endpoints of treatment (e.g., hypercalcemia, pathologic fractures) have delayed developments. Available data, however, strongly suggest that potent bisphosphonates are efficacious in reducing skeletal morbidity in patients with prostate carcinoma. CONCLUSIONS: For the optimal management of patients with skeletal metastases from prostate carcinoma with bisphosphonates their mode of administration, the dose and duration of treatment need to be evaluated. Better understanding of the cellular and molecular mechanisms underlying bone metastases can lead to the design of improved treatment protocols with potent bisphosphonates.

Bone Neoplasms↗

PubMed2000

Mass spectrometric studies of the pterocarpan skeleton.

The mass spectrometric characteristics of the pterocarpan skeleton have been studied with the aid of metastable decomposition (CAD-MIKES), high resolution mass measurements and specific deuterium labeling. New structural rotations have been postulated for the [M - H](+) ions which can explain the fragmentation routes for the pterocarpan skeleton.

Antifungal Agents↗

PubMed1988

Bone cell biology: the regulation of development, structure, and function in the skeleton.

Bone cells compose a population of cells of heterogeneous origin but restricted function with respect to matrix formation, mineralization, and resorption. The local, mesenchymal origin of the cells which form the skeleton contrasts with their extraskeletal, hemopoietic relatives under which bone resorption takes place. However, the functions of these two diverse populations are remarkably related and interdependent. Bone cell regulation, presently in its infancy, is a complicated cascade involving a plethora of local and systemic factors, including some components of the skeletal matrices and other organ systems. Thus, any understanding of bone cell regulation is a key ingredient in understanding not only the development, maintenance, and repair of the skeleton but also the prevention and treatment of skeletal disorders.

Animals↗

PubMed1992

Localization of type II collagen, long form alpha 1(IX) collagen, and short form alpha 1(IX) collagen transcripts in the developing chick notochord and axial skeleton.

In this study we compare, by in situ hybridization, the spatial and temporal expression patterns of transcripts of avian type II collagen and the long and short forms of the (alpha 1) chain of type IX collagen during the development of the notochord and axial skeleton. We observed type II collagen and short form type IX collagen transcripts in the developing (stage 25-28) nonchondrogenic notochord. Conversely, long form type IX transcripts were not detectable in the notochord or perinotochordal sheath. Interestingly, all three transcripts colocalized in the developing chondrogenic vertebrae of the axial skeleton as well as in the chondrocranium and Meckel's cartilage. The expression of the short form of type IX collagen in these regions was more restricted than that of the long form. This report provides additional support for a complex regulatory pathway of cartilage marker gene expression in chondrogenic vs. nonchondrogenic tissues during avian embryogenesis.

Animals↗

PubMed1986

Marrow mass and distribution in murine skeletons cleaned by beetles as compared to cut up carcasses and a further simplification of the latter technique.

Distribution of 59Fe into various bone groups of the complete murine skeleton was studied using two methods of dividing up the bones: 1) our previously reported technique of simply cutting up a skinned, eviscerated carcass and 2) separating bones from skeletons cleaned of overlying tissue by beetles, Dermestes species. The total percentage of injected 59Fe recovered in the sum of all skeletal parts, the percentage of total skeletal 59Fe found in each bone group, and the overall accuracy of determining these values were quite similar for the two techniques. The only statistically significant difference shown was a modest decrease in the percentage of total skeletal iron found in ribs plus sternum plus cervical and thoracic spine in beetle-cleaned as compared to cut up groups and we would not consider this to be of biological significance. Cutting up carcasses is the simpler of the two techniques but there are circumstances in which beetle digestion would be advantageous. In addition, we collected data on the reproducibility and precision of determining the percentage of 59Fe injected which is found in a "pulled off" foreleg plus scapula and of the distribution of 59Fe within three cut up pieces from the leg and within the scapula. These data can be used as a measure of overall changes in marrow mass and/or distribution, or at least they can be used as a screening procedure to detect such. This simple procedure adds potentially useful values for fully interpreting hematopoietic changes in the mouse.

Anatomy↗

PubMed2001

Subspecific genetic differences in the saddle-back tamarin (Saguinus fuscicollis) postcranial skeleton.

Saddle-back tamarins (Saguinus fuscicollis) have been differentiated into subspecies based on coat color and facial morphology. Morphology of first-generation genetic hybrids can provide an understanding of population differences and evolution that may otherwise be difficult to obtain. This study compares postcranial morphology in two hybrids of saddle-back tamarins (S. f. illigeri x S. f. lagonotus and S. f. illigeri x S. f. leucogenys) to the purebred subspecies. We examine whether postcranial morphology differs between the purebred subspecies and their hybrids, and whether hybrids exhibit heterosis indicative of genetic differences between the parental subspecies. Fifty postcranial dimensions, or traits, were measured on 287 S. fuscicollis skeletons. Measurements were corrected for sex differences and environmental differences (wild-derived or laboratory-born). Females were larger than males for most postcranial dimensions, especially in the pelvis. Significant environmental differences were found throughout the postcranial skeleton, with wild-derived animals generally larger than animals born in the laboratory. Significant heterosis was found for six postcranial traits in the S. f. illigeri x S. f. leucogenys cross, and heterosis was found for 15 postcranial traits in the S. f. illigeri x S. f. lagonotus cross. These results suggest that subspecies differences in skeletal morphology are generally due to genetic rather than environmental differences. The subspecies appear to represent geographic isolates that differ in gene frequencies and directional dominance for skeletal traits.

Animals↗

PubMed2004

Sagittal clefting of the body and other vertebral developmental errors in Canadian Inuit skeletons.

The objective of this study was to determine the expression, distribution in the column, and overall frequency of sagittal clefting of the vertebral body in the skeletons of two Canadian Inuit groups. One group, referred to as Thule-Historic, lived along the coast northwest of Hudson Bay, while the other, known as the Sadlermiut, were limited to Southampton Island and Coats Island north of Hudson Bay. The Thule-Historic people are thought to be the ancestors of the present-day Inuit of this region, whereas the much smaller, relatively isolated Sadlermiut became extinct during the winter of 1902-1903. The sagittal clefting results were also compared with those obtained for two other vertebral developmental problems, segmentation error and spina bifida. Sagittal clefting was found to occur with high frequency in the two Inuit series, especially in the region T6-T10. Segmentation errors were found to occur in approximately the same region of the column, while spina bifida produced a completely different pattern, occurring primarily at T11 and S1. The T11 involvement is limited to females, while S1 involvement occurs primarily in males. Sagittal clefting and spina bifida occur in the same individual more frequently than sagittal clefting and segmentation error. Possibly reflecting the smaller population size and isolated location of the Sadlermiut, sagittal clefting was found with greater frequency and intensity in the skeletons of this group than in those of the Thule-Historic Inuit. Am J Phys Anthropol, 2003.

Adult↗

PubMed1995

Ohalo II H2: a 19,000-year-old skeleton from a water-logged site at the Sea of Galilee, Israel.

The discovery of well-preserved human remains at the site of Ohalo II in the northern Jordan Valley substantially augments the meager fossil record of the Levantine late Upper Pleistocene. The Ohalo II H2 specimen, dated to ca. 19,000 B.P., is the most complete early Epipaleolithic hominid discovered in Israel and promises to contribute to the clarification of a number of problematic issues in the local evolution of anatomically modern humans. In addition to a description of the burial and its Kebaran context, a detailed anatomical description of the skeleton is offered and morphometric comparisons are made to other Upper Paleolithic hominids. Ohalo II H2 is shown to demonstrate affinities in the craniofacial skeleton to fossils from the early Upper Paleolithic and late Epi-Paleolithic of the Levant.

Adult↗

PubMed1995

Comparison of radiologic and gross examination for detection of cancer in defleshed skeletons.

The reliability of visual examination of defleshed bones was assessed for detection of postcranial metastatic disease in individuals known to have had cancer. This was compared with standard clinical radiologic techniques. The skeletons of 128 diagnosed cancer patients from an early 20th century autopsied skeletal collection (Hamann-Todd Collection) were examined. Radiologic examination detected evidence of metastatic disease in 33 individuals, compared to 11 by visual examination of the postcranial skeletons. Four of these cases were detected by both techniques. Blastic lesions were most commonly overlooked on visual examination, because they were localized to trabecular (internal bone) structures. The ilium was the most commonly affected bone, with lytic or blastic lesions detected in 30 of 33 individuals. While the proximal femur was affected in only nine individuals, x-ray of the proximal femur and ilium detected all individuals with postcranial evidence of metastatic disease. Skeletal distribution of metastases provides no clue to the location of origin or histologic subtype of the cancer. Survey of archeological human remains for metastatic cancer requires radiologic examination. Such skeletal surveys should x-ray at least the ilia and femora.

Anthropology, Physical↗

PubMed2006

Effect of ethnicity and sex on the growth of the axial and appendicular skeleton of children living in a developing country.

Bones in the axial and appendicular skeletons exhibit heterogeneous growth patterns between different ethnic and sex groups. However, the influence of this differential growth on the expression of bone mineral content is not yet established. The aims of the present study were to investigate: 1) whether there are ethnic and sex differences in axial and appendicular dimensions of South African children; and 2) whether regional segment length is a better predictor of bone mass than stature. Anthropometric measurements of stature, weight, sitting height, and limb lengths were taken on 368 black and white, male and female 9-year-old children. DXA (dual-energy x-ray absorptiometry) scans of the distal ulna, distal radius, and hip and lumbar spine were also obtained. Analyses of covariance were performed to assess differences in limb lengths, adjusted for differences in stature. Multiple regression analyses were used to assess significant predictors of site-specific bone mass. Stature-adjusted means of limb lengths show that black boys have longer legs and humeri but shorter trunks than white boys. In addition, black children have longer forearms than white children, and girls have longer thighs than boys. The regression analysis demonstrated that site-specific bone mass was more strongly associated with regional segment length than stature, but this had little effect on the overall pattern of ethnic and sex differences. In conclusion, there is a differential effect of ethnicity and sex on the growth of the axial and appendicular skeletons, and regional segment length is a better predictor of site-specific bone mass than stature.

Anthropometry↗

PubMed1994

Neutrophil chemoattractant receptors and the membrane skeleton.

Signal transduction via receptors for N-formylmethionyl peptide chemoattractants (FPR) on human neutrophils is a highly regulated process which involves participation of cytoskeletal-elements. Evidence exists suggesting that the cytoskeleton and/or the membrane skeleton controls the distribution of FPR in the plane of the plasma membrane, thus controlling the accessibility of FPR to different proteins in functionally distinct domains. In desensitized cells, FPR are restricted to domains which are depleted of G proteins but enriched in cytoskeletal proteins such as actin and fodrin. Thus, the G protein signal transduction partners of FPR become inaccessible to the agonist-occupied receptor, preventing cell activation. The mechanism of interaction of FPR with the membrane skeleton is poorly understood but evidence is accumulating that suggests a direct binding of FPR (and other receptors) to cytoskeletal proteins such as actin.

Animals↗

PubMed1994

Angiographic changes in the hepatic artery after skeletonization resection for biliary tract cancer.

Using preoperative and postoperative arteriography, angiographic changes in the hepatic artery were studied after skeletonization of the hepatoduodenal ligament and hepatic resection for biliary tract carcinoma. Of 52 patients evaluated (32 with carcinoma of the bile duct, 20 with gallbladder cancer), no angiographic changes were apparent after operation in 30 (58 per cent) and there were pathological findings in 22 (42 per cent; smooth stenosis in five patients, irregular stenosis in seven, a beaded appearance in four, dilatation in two, obstruction in four). Based on angiographic findings, patients were classified into three subgroups (no change, 30 patients; irregular form, 18; obstructed, four). Postoperative liver function was also evaluated. No definite correlation was evident between angiographic findings and the incidence of hepatic failure or liver dysfunction in the first month after operation. Given that connective tissue and lymph node dissection in the hepatoduodenal ligament is essential for curative resection of biliary tract carcinoma, these findings suggest that skeletonization is an acceptable operative procedure.

Adolescent↗

PubMed2003

Asymmetric carbon-carbon bond-forming reaction at the 2-position of a piperidine skeleton.

An asymmetric carbon-carbon bond-forming reaction at the 2-position of a piperidine skeleton was exploited. This method consisted of a reaction between 1-(4-methoxybenzoyl)-3,4-didehydro-2-methoxypiperidines and dimethyl malonate catalyzed by Cu(II)-chiral 2,2'-isopropylidenebis(4-phenyl-2-oxazoline) to afford a 2-substituted piperidine skeleton with moderate enantioselectivity.

Indicators and Reagents↗

PubMed1988

The organization and regulation of the macrophage actin skeleton.

To move, leukocytes extend portions of their cortical cytoplasm as pseudopods. These pseudopods are filled with a three-dimensional actin filament skeleton, the reversible assembly of which in response to receptor stimulation is thought to play a major role in providing the mechanical force for these protrusive movements. The organization of this actin skeleton occurs at different levels within the cell, and a number of macrophage proteins have been isolated and shown to affect the architecture, assembly, stability, and length of actin filaments in vitro. The architecture of cytoplasmic actin is regulated by proteins that cross-link filaments in higher-order structures. Actin-binding protein plays a major role in defining network structure by cross-linking actin filaments into orthogonal networks. Gelsolin may have a central role in regulating network structure. It binds to the sides of actin filaments and severs them, and binds the "barbed" filament end, thereby blocking monomer addition at this end. Gelsolin is activated to bind actin filaments by microM calcium. Dissociation of gelsolin bound on filament ends occurs in the presence of the polyphosphoinositides, PIP and PIP2. Calcium and PIP2 have been shown to be intracellular messengers of cell stimulation.

Actins↗

PubMed2001

Postnatal Msx1 expression pattern in craniofacial, axial, and appendicular skeleton of transgenic mice from the first week until the second year.

Phenotypes associated with Msx1 mutations have established the prominent role of this divergent homeogene in skeletal patterning. Previous studies have been achieved during antenatal development in relation with the early death of null mutant mice. Therefore, the present study is devoted to Msx1 homeogene in the postnatal craniofacial, axial, and appendicular skeleton. A knock-in transgenic mouse line was studied from the first postnatal week until 15 months. Whole-mount beta-galactosidase enzymology identified Msx1 protein expression pattern. Maintained expression of Msx1 was observed in growing and adult mice, specifically in the sites where Msx1 plays an early morphogenetic role during initial skeletal patterning. These included the craniofacial sutures, autopodium, mandible, and alveolar bone. Furthermore, active membranous and endochondral bone formation involved Msx1 in the entire skeleton. Histologic sections showed that progenitor as well as differentiating and differentiated cells of all the bone cell lineages could express the Msx1 protein (chondrocytes, osteoblasts, tartrate-resistant acid phosphatase positive osteoclasts and chondroclasts). Recent developments in the genetic and developmental biology of skeletal morphogenesis demonstrate that genes critical for development are jointly expressed in discrete embryonic signalling and growth centers, the enamel knot in teeth, the cranial suture in skull morphogenesis, and the progress zone in the limb buds. The present study suggests that these signalling pathways are jointly important throughout the entire lifetime with an exquisite site-specificity spatially related to early patterning.

Animals↗

PubMed2006

Expression of the dlx gene family during formation of the cranial bones in the zebrafish (Danio rerio): differential involvement in the visceral skeleton and braincase.

We have used dlx genes to test the hypothesis of a separate developmental program for dermal and cartilage bones within the neuro- and splanchnocranium by comparing expression patterns of all eight dlx genes during cranial bone formation in zebrafish from 1 day postfertilization (dPF) to 15 dPF. dlx genes are expressed in the visceral skeleton but not during the formation of dermal or cartilage bones of the braincase. The spatiotemporal expression pattern of all the members of the dlx gene family, support the view that dlx genes impart cellular identity to the different arches, required to make arch-specific dermal bones. Expression patterns seemingly associated with cartilage (perichondral) bones of the arches, in contrast, are probably related to ongoing differentiation of the underlying cartilage rather than with differentiation of perichondral bones themselves. Whether dlx genes originally functioned in the visceral skeleton only, and whether their involvement in the formation of neurocranial bones (as in mammals) is secondary, awaits clarification.

Animals↗

PubMed1997

Isoelectric properties of the soluble matrices in relation to the chemical composition of some Scleractinian skeletons.

Soluble matrices of four Scleractinian skeletons (Madrepora, Favia, Leptastrea and Fungia), were extracted and studied by isoelectric focusing (IEF). The main part of the extracted matrices is acidic. IEF gels are poorly stained or unstained by Coomassie Blue and silver. The positive Alcian Blue staining is indicative of a sulfated and acidic nature of the glycoproteins. Chemical analysis shows high S contents in Scleractinian skeletons. These results are supported by the comparison with IEF and chemical contents of Molluscan shells.

Animals↗