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PubMed1990

Chicken growth-associated protein GAP-43 is tightly bound to the actin-rich neuronal membrane skeleton.

We have identified the chicken equivalent of growth-associated protein GAP-43 in a detergent-resistant membrane skeleton from cultures of chick neurones and embryonic chick brain. Antisera to the membrane skeleton protein, the 3D5 antigen, precipitate the translation product of chick GAP-43 cDNA, and the 3D5 antigen is also detected by antisera against synthetic peptides from the known amino acid sequence of rat GAP-43. The chick protein and the rat GAP-43 are biochemically similar proteins that both serve as major targets of phosphorylation by endogenous protein kinase C. The detergent-resistant complex in which GAP-43 is found also contains actin (approximately 5% of the total protein) and a neurone-specific cell surface glycoprotein. We suggest that the membrane skeleton of neurones may be a primary site of action of GAP-43.

Actins↗

PubMed1987

Alterations in lipid fluidity induced by cholesterol and cholesterol hemisuccinate modulate the organization of microtubule skeletons in epithelial cells.

This study was designed to evaluate the role that cholesterol, and the more hydrophilic ester, cholesterol hemisuccinate (CHS) have on the ability of epithelial cells to attach, spread and reorganize microtubule skeletons on a defined substratum. A431 carcinoma cells were grown and incubated with cholesterol, or CHS in polyvinyl pyrrolidone. Subsequently the cells were plated either on plastic petri dishes or plasticware coated with collagen IV or laminin. The alteration in apparent membrane microviscosity was ascertained using fluorescence polarization measurements. Organization of microtubules was determined by immunofluorescence, and by transmission electron microscopy. Cholesterol and CHS inhibited attachment and spreading of epithelial cells. Cells previously attached and spread became spherical after treatment with cholesterol and CHS, but microtubules were unaffected. However, when the cells were pretreated in suspension with cholesterol or CHS the membrane microviscosities markedly increased, and upon subsequent plating those cells adhering neither spread nor organized microtubule skeletons. These results suggest that cholesterol-induced changes in lipid microviscosity modulate the membrane dynamics that control the ability of epithelial cells to attach, spread and organize microtubule skeletons.

Carcinoma↗

PubMed1993

Existence of a flat phase in red cell membrane skeletons.

Biomolecular membranes display rich statistical mechanical behavior. They are classified as liquid in the absence of shear elasticity in the plane of the membrane and tethered (solid) when the neighboring molecules or subunits are connected and the membranes exhibit solid-like elastic behavior in the plane of the membrane. The spectrin skeleton of red blood cells was studied as a model tethered membrane. The static structure factor of the skeletons, measured by small-angle x-ray and light scattering, was fitted with a structure factor predicted with a model calculation. The model describes tethered membrane sheets with free edges in a flat phase, which is a locally rough but globally flat membrane configuration. The fit was good for large scattering vectors. The membrane roughness exponent, zeta, defined through h alpha L zeta, where h is the average amplitude of out-of-plane fluctuations and L is the linear membrane dimension, was determined to be 0.65 +/- 0.10. Computer simulations of model red blood cell skeletons also showed this flat phase. The value for the roughness exponent, which was determined from the scaling properties of membranes of different sizes, was consistent with that from the experiments.

Chemical Phenomena↗

PubMed1991

The midline craniofacial skeleton in holoprosencephalic fetuses.

Craniofacial skeletal development in eight human holoprosencephalic fetuses from second trimester abortions were examined by radiography and histology. The whole spectrum of associated facial malformations from anophthalmia through cyclopia, ethmocephaly, cebocephaly, and median cleft lip to short philtrum was represented. Cases with the most severe facial malformations also had the most severely affected facial skeleton. In the facial skeleton, the premaxilla was most often affected; it was absent in seven cases and malformed in the one with only a short philtrum. This and other facial skeletal malformations can be explained as abnormal fusion of the facial bones because of defective development of the nasal cartilage. The occipital bones were normal, but the basicranial skeleton anterior to the spheno-occipital junction was affected in all cases. The findings support the hypothesis that the facial malformations in holoprosencephaly result from disturbance in embryonal life of the mesoderm at the rostral end of the notochord.

Facial Bones↗

PubMed1990

The oligomeric state of spectrin in the rat erythrocyte membrane skeleton.

The oligomeric state of spectrin in the erythrocyte membrane skeleton of the rat was investigated following extraction in a low ionic strength buffer for 24 and 96 h. All analyses were quantitatively compared with preparations from human erythrocyte membranes. After nondenaturing agarose-polyacrylamide gel electrophoresis, the human samples revealed their characteristic spectrin oligomer pattern; there were high molecular weight complexes near the origin of the gel, followed by several high order oligomers, tetramers, and dimers. The pattern in the rat membrane skeleton also included tetramers and a high molecular weight complex band, but had only one oligomer and no dimers. With time the high molecular weight complex diminished and oligomers accumulated in both the rat and human, while dimers accumulated only in the human and tetramers accumulated only in the rat. Tetramers decreased with time in the human. Extraction of spectrin increased with time and was greater from rat than the human red cell membrane at both time points. The percentage of spectrin and actin in the low ionic strength extract was similar between species, as analyzed by SDS-polyacrylamide electrophoresis, staining, and densitometry. Proteins 4.1 and 4.9 were present in greater percentages in the human. The only temporal effect on monomeric protein composition was an increase of protein A in the rat. There was no species difference in protein A percentage at 24 h, but at 96 h the rat was greater than the human. The results suggest that there are significant differences in the structural arrangement of the rat and human erythrocyte membrane skeleton.

Adult↗

PubMed1983

The spectrin membrane skeleton of normal and abnormal human erythrocytes: a review.

The erythrocyte membrane skeleton composed of spectrin, actin, and several other proteins is essential for the maintenance of the erythrocyte shape, reversible deformability, and membrane structural integrity in addition to controlling the lateral mobility of integral membrane proteins. In this review, we shall give an historical development of the current model of the erythrocyte membrane skeleton. We will then describe how the experimental technology developed to study the normal membrane skeleton has paved the way for the recent identification of alterations of skeletal protein interactions in hereditary spherocytosis, hereditary elliptocytosis, and hereditary pyropoikilocytosis. We will conclude with a discussion of some of the more exciting and promising directions for future research that are currently being initiated in this vanguard field of cell biology.

Actins↗

PubMed1996

The spectrin-based membrane skeleton as a membrane protein-sorting machine.

Normal cell function is dependent on the existence of membrane compartments that have unique populations of membrane proteins. Sorting of membrane proteins forms the basis for the biogenesis of distinct membrane compartments. There are many examples of membrane protein-sorting events in cells, but the molecular machinery involved is poorly understood. We discuss characteristics of a putative membrane protein-sorting machine and show that the spectrin-based membrane skeleton conforms to these characteristics. The spectrin-based membrane skeleton is a submembranous, spatially limited, two-dimensional lattice that binds a subset of membrane proteins. These properties allow the membrane skeleton to facilitate the formation of distinct membrane domains and thus reveal its potential as a membrane protein-sorting machine.

Animals↗

PubMed1981

Differential changes in bone mineral density of the appendicular and axial skeleton with aging: relationship to spinal osteoporosis.

Patterns of bone loss in the axial and the appendicular skeleton were studied in 185 normal volunteers (105 women and 82 men; age range, 20--89 yr) and in 76 women and 9 men with vertebral fractures due to osteoporosis. Bone mineral density was measured in vivo at the lumbar spine (predominantly trabecular bone) by dual photon absorptiometry and at the midradius (greater than 95% cortical bone) and distal radius (75% cortical and 25% trabecular bone) by single photon absorptiometry. In normal women, bone diminution from the vertebrae began in young adulthood and was linear. In the appendicular skeleton, bone diminution did not occur until age 50 yr, was accelerated from aged 51 to 65 yr, and then decelerated somewhat after age 65 yr. Overall bone diminution throughout life was 47% for the vertebrae, 30% for the midradius, and 39% for the distal radius. In normal men, vertebral and appendicular bone diminution with aging was minimal or insignificant. Mean bone mineral density was lower in patients with osteoporosis than in age- and sex-matched normal subjects at all three scanning sites, although spinal measurements discriminated best; however, there was considerable overlap. By age 65 yr, half of the normal women (and by age 85 yr, virtually all of them) had vertebral bone mineral density values below the 90th percentile of women with vertebral fractures and, thus, might be considered to have asymptomatic osteoporosis. For men, the degree of overlap was less. The data suggest that disproportionate loss of trabecular bone from the axial skeleton is a distinguishing characteristic of spinal osteoporosis.

Adult↗

PubMed1985

Molecular defect in the sickle erythrocyte skeleton. Abnormal spectrin binding to sickle inside-our vesicles.

Although functional abnormalities of the sickle erythrocyte membrane skeleton have been described, there is little quantitative data on the function of the proteins that compose the skeleton. We have examined the association of spectrin, the major skeletal protein, with ankyrin, its high-affinity membrane binding site, and found sickle erythrocytes to have markedly reduced binding. Binding is assayed by incubation of purified 125I-spectrin with spectrin-depleted inside-out vesicles (IOVs) and measurement of the label bound to IOVs. Sickle IOVs bind approximately 50% less ankyrin than do controls IOVs (P less than 0.001). Control experiments show that this reduced binding is not a function of faulty composition or orientation of sickle IOVs, or of reticulocytosis per se. Our least symptomatic patient has the highest binding capacity, suggesting that this abnormality may be related to clinical severity. This trend is supported by experiments showing that asymptomatic subjects with sickle trait, sickle cell anemia and high fetal hemoglobin, and sickle beta +-thalassemia have normal binding, whereas a symptomatic patient with sickle beta zero-thalassemia has abnormal binding. In contrast to what we see with ankyrin in situ on the IOV, when isolated and studied in solution, sickle ankyrin binds normally to spectrin. This discrepancy may be related to preferential purification of the normal ankyrin species or to an abnormal topography of the membrane near the spectrin attachment site. We hypothesize that sickle hemoglobin or perhaps the metabolic consequences of sickling damage the protein skeleton. This damage may alter the surface of the erythrocyte and result in abnormal cell-cell interactions which may be related to clinical severity.

Anemia, Sickle Cell↗

PubMed2002

Evidence that the red cell skeleton protein 4.2 interacts with the Rh membrane complex member CD47.

Rh(null) red cells are characteristically stomato-spherocytic. This and other evidence suggest that the Rh complex represents a major attachment site between the membrane lipid bilayer and the erythroid skeleton. As an attempt to identify the linking protein(s) between the red cell skeleton and the Rh complex, we analyzed the expression of Rh, RhAG, CD47, LW, and glycophorin B proteins in red cells from patients with hereditary spherocytosis associated with complete protein 4.2 deficiency but normal band 3 (4.2(-)HS). Flow cytometric and immunoblotting analysis revealed a severe reduction of CD47 (up to 80%) and a slower mobility of RhAG on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, possibly reflecting an overglycosylation state. Unexpectedly, 4.2(-/-) mice, which are anemic, displayed a normal red cell expression of CD47 and RhAG. These results suggest that human protein 4.2, through interaction with CD47, is involved in the skeleton linkage and/or membrane translocation of the Rh complex. However, these potential role(s) of protein 4.2 might be not conserved across species. Finally, the absence or low expression of red cell CD47 in CD47(-/-) mice and in some humans carrying RHCE gene variants (D--, D., and R(N)), respectively, had no detectable effect on protein 4.2 and RhAG expression. Since these cells are morphologically normal with no sign of hemolysis, it is assumed that CD47 deficiency per se is not responsible for the cell shape abnormalities and for the compensated hemolytic anemia typical of 4.2(-) and Rh(null) red cells.

Animals↗

PubMed1998

Differential effect of race on the axial and appendicular skeletons of children.

The prevalence of osteoporosis and the incidence of fractures are substantially lower in black than in white subjects, a finding generally attributed to racial differences in adult bone mass. Whether these racial differences are present in childhood is the subject of considerable interest, as the amount of bone gained during growth is a major determinant of future susceptibility to fractures. We measured the density and size of the vertebrae and femurs of 80 black and 80 white healthy children, 8-18 yr of age, matched for age, gender, height, weight, and stage of sexual development, using computed tomography. Race had a significant and differential effect on the bones in the axial and appendicular skeletons. In the axial skeleton, black children had greater cancellous bone density, but similar cross-sectional area of the vertebral bodies. In contrast, in the appendicular skeleton, black children had greater femoral cross-sectional area, but similar cortical bone area and cortical bone density. Compared to white children, vertebral bone density and femoral cross-sectional area at sexual maturity were, on the average, 10.75% and 5.7% higher, respectively, in black children. Such significant variations may contribute to the racial differences in the prevalence of osteoporosis between black and white adults.

Adolescent↗

PubMed2002

Clinical review 144: Estrogen and the male skeleton.

Because estrogen (E) and T are the major sex steroids in women and men, respectively, the traditional view had been that E primarily regulated bone turnover in women and T played the analogous role in men. The description of ER- deficient and aromatase-deficient males, however, initiated a major shift in our thinking on the relative roles of T and E in regulating the male skeleton, because these individuals all had unfused epiphyses, high bone turnover, and osteopenia. Similar, albeit less striking, findings were noted in mouse models with knock-out of either the ER-alpha or the aromatase genes. Although these human experiments of nature and mouse knock-out models clearly demonstrated an important role for E in the growth and maturation of the male skeleton, they did not define the role of E vs. T in regulating the adult male skeleton. The past several years have witnessed an accumulation of evidence from observational as well as direct interventional studies that now clearly indicates that E plays a major, and likely dominant, role in bone metabolism in men. These data also suggest that a threshold level of bioavailable (or non-SHBG bound) E is needed for skeletal E sufficiency in the male, and that with aging, an increasing percentage of elderly men begin to fall below this level. It is this subset of men who may be at greatest risk for the development of age-related bone loss and osteoporosis. Moreover, these men may also be the ones most likely to respond favorably to treatment with selective E receptor modulators, or perhaps even to T replacement, because the skeletal effects of the latter may be mediated largely via aromatization to E.

Animals↗

PubMed1994

Axial homeosis and appendicular skeleton defects in mice with a targeted disruption of hoxd-11.

Using gene targeting, we have created mice with a disruption in the homeobox-containing gene hoxd-11. Homozygous mutants are viable and the only outwardly apparent abnormality is male infertility. Skeletons of mutant mice show a homeotic transformation that repatterns the sacrum such that each vertebra adopts the structure of the next most anterior vertebra. Defects are also seen in the bones of the limb, including regional malformations at the distal end of the forelimb affecting the length and structure of phalanges and metacarpals, inappropriate fusions between wrist bones, and defects at the most distal end in the long bones of the radius and ulna. The phenotypes show both incomplete penetrance and variable expressivity. In contrast to the defects observed in the vertebral column, the phenotypes in the appendicular skeleton do not resemble homeotic transformations, but rather regional malformations in the shapes, length and segmentation of bones. Our results are discussed in the context of two other recent gene targeting studies involving the paralogous gene hoxa-11 and another member of the Hox D locus, hoxd-13. The position of these limb deformities reflects the temporal and structural colinearity of the Hox genes, such that inactivation of 3' genes has a more proximal phenotypic boundary (affecting both the zeugopod and autopod of the limb) than that of the more 5' genes (affecting only the autopod). Taken together, these observations suggest an important role for Hox genes in controlling localized growth of those cells that contribute to forming the appendicular skeleton.

Animals↗

PubMed1995

The membrane skeleton of acetylcholine receptor domains in rat myotubes contains antiparallel homodimers of beta-spectrin in filaments quantitatively resembling those of erythrocytes.

I used immunogold labeling and quick-freeze, deep-etch, rotary replication to characterize the membrane skeleton at regions with high concentrations of acetylcholine receptor domains in receptor clusters of cultured rat muscle cells. This membrane skeleton consists of a network of filaments closely applied to the cytoplasmic membrane surface. The filaments are specifically decorated by immunogold labeling with a monoclonal antibody, VIIF7, that recognizes an isoform of beta-spectrin colocalizing with acetylcholine receptors. The filaments are 32 +/- 11 nm in length and three to four filaments (average 3.1-3.3) join at each intersection to form the network. These parameters are nearly identical to those reported previously for the membrane skeleton of erythrocytes. Depending on the amount of platinum coating, filament diameters range from 9 to 11 nm in diameter, and are 1.4 nm larger on average than spectrin filaments of erythrocytes replicated at the same time. Filaments are decorated with gold particles close to one end, consistent with the location of the epitope recognized by the monoclonal antibody. Computer modeling shows that all filament intersections in the membrane skeletal network are equally capable of being labeled by the monoclonal antibody. This pattern of labeling is consistent with a network containing antiparallel homodimers of beta-spectrin.

Animals↗

PubMed1978

The early development of the human skeleton: a radiographic study of fetuses impregnated with silver nitrate.

The use of a silver nitrate impregnation technique and radiography for delineation of the bones of the developing skeleton is not widely known. Using this method, a study of skeleton development was undertaken over a three-year period and special attention was paid to 20 fetuses under the age of 16 weeks. The dates at which ossification in cartilage occurred and the sequence of bone development were noted. Although the technique may be used to delineate skeletal dysplasias in the stillborn, it is best suited to fetuses aged 9--20 weeks. It may become possible to show the earliest age at which bone dysplasias affect the skeleton though this is speculative at the moment.

Bone Development↗

PubMed1995

Alterations in estrogen levels during development affects the skeleton: use of an animal model.

Exposure to estrogens during various stages of development has been shown to irreversibly influence responsive target organs. The recent finding of the presence of estrogen receptor in both osteoblasts and osteoclasts has suggested a direct role of steroid hormones on bone tissue. Furthermore, estrogens have important effects on bone turnover in both humans and experimental animal models. Thus, this tissue is now regarded as a specific estrogen target tissue. To investigate whether a short-term developmental exposure to estrogens can influence bone tissue, we have injected female mice with diethylstilbestrol (DES) from day 1 through day 5 of life. Additionally, a group of pregnant female mice were injected with different doses of DES from day 9 through 16 of pregnancy. Mice were then weaned at 21 days of age, and effects on bone tissue of the female mice were evaluated in adulthood (7-12 months of age). These short-term treatments did not affect body weight of exposed mice. However, a dose-dependent increase in bone mass, both in the trabecular and compact compartments, was observed in the DES-exposed female offspring. Furthermore, femurs from DES-exposed females were shorter than femurs from controls. A normal skeletal mineralization accompanied these changes in the bone tissue. In fact, a parallel increase in total calcium content of the skeleton was found in concomitance with the increase in bone mass. Estrogen treatment induced an increase in the amount of mineralized skeleton when compared to untreated controls. In summary, this report shows that alterations of estrogen levels during development can influence the early phases of bone tissue development inducing permanent changes in the skeleton. These changes appear to be related to bone cell programming in early phases of life.

Animals↗

PubMed2003

Technical aspects of composite arterial grafting with double skeletonized internal thoracic arteries.

BACKGROUND: Complete myocardial revascularization with internal thoracic arteries (ITAs) improves long-term survival and decreases the rate of repeat operations, compared to vein grafts. Adequate length of the graft in coronary artery bypass graft (CABG) surgery is essential for providing complete arterial revascularization. Extra length can be obtained by skeletonization of both ITAs. In cases where the right ITA (RITA) is too short to bridge the distance to the target anastomotic site, it is used as a free graft in "composite" arterial grafting, a surgical technique in which free arterial conduits are proximally anastomosed end-to-side to an intact ITA. OBJECTIVES: To describe alternative surgical procedures adapted to accommodate special anatomic requirements. DESIGN: Retrospective study from April 1996 to April 1999. PATIENTS: One thousand fifty patients underwent CABG surgery using bilateral skeletonized ITAs: 650 patients (482 men and 168 women; mean +/- SD age, 69 +/- 7 years) underwent composite arterial grafting. Two hundred sixteen patients (33.2%) were diabetics, 87 patients (13.4%) had severe left ventricular dysfunction (ejection fraction < 35%), and 27 patients (4.2%) underwent emergency operations. INTERVENTIONS: The RITA was used as a free graft connected to the in situ left ITA (LITA) in 618 patients. A free LITA was attached to in situ RITA in 32 patients, and minicomposite grafts (free distal LITA on the LITA or free distal RITA on the RITA) were constructed in 38 patients. The average number of grafts was 3.2 per patient (range, 2 to 6 grafts per patient). MEASUREMENTS AND RESULTS: Operative mortality was 2.9% (n = 19), and there were 11 sternal wound infections (1.7%). Early recatheterization was performed in 41 symptomatic patients. The patency rate was 95%. The mean follow-up was 25 months (range, 14 to 36 months), and the 3-year survival was 92.5%, with 97% of the surviving patients being angina free. CONCLUSIONS: Planning CABG surgery using bilateral skeletonized ITAs as arterial conduits affords greater choice in grafting approaches, especially when a composite technique is feasible.

Aged↗

PubMed2005

[Comparative analysis of the flows of left internal thoracic artery grafts dissected in the pedicled versus skeletonized manner for myocardial revascularization surgery].

OBJECTIVE: To compare the free blood flow, caliber, and length of the left internal thoracic artery (LITA), dissected in the pedicled (P) and skeletonized (S) manners, during surgery before and after topical vasodilator (TV) application. METHODS: A randomized, blind, clinical trial was carried out with 50 patients undergoing elective myocardial revascularization to assess the use of the LITA in situ in its pedicled or skeletonized form. The 25 patients in the pedicled group (GP) had NYHA class II or III angina, ejection fraction (EF) of 50.8+/-9.2%, and 16 were of the male sex. The patients in the skeletonized group (SG) had NYHA class II angina, EF of 46.8+/-9.3%, and 19 were of the male sex. The measurements were performed before extracorporeal circulation and divided into 2 phases: phase 1 (before topical papaverine application) and phase 2 (15 min after topical application of papaverine, 2.5 mg/mL, at 37 degrees C). During the measurements, mean blood pressure, central venous pressure, and heart rate were monitored. RESULTS: The phase 1 and 2 results are as follows: 1) PG: blood flow, 46+/-16 and 77+/-28 mL/min; caliber, 1.4+/-0.1 and 1.7+/-0.1 mm, respectively; 2) SG: blood flow, 57+/-27 and 97+/-35 mL/min; and caliber, 1.4+/-0.1 and 1.8+/-0.2 mm, respectively. No significant differences were observed in length. CONCLUSION: The LITA in SG had a significant increase in blood flow and caliber after the use of TV compared with blood flow and caliber in PG (P=0.03 and P=0.01, respectively).

Adult↗