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Using a novel marker of C-type natriuretic peptide (CNP) synthesis [amino-terminal pro-CNP (NT-proCNP)], we have recently shown that plasma NT-proCNP is strongly correlated with skeletal growth and markers of bone formation and is reversibly reduced by glucocorticoids. The effects on CNP of other catabolic or anabolic factors, known to affect skeletal growth, are unknown. Accordingly, we have studied the response of plasma CNP forms to acute catabolic (caloric restriction) and anabolic [growth hormone (GH) stimulation] interventions in lambs and related the findings to circulating IGF-I levels, growth velocity, and markers of bone formation. Lambs fed a reduced caloric intake (25% of normal) for 6 days exhibited reduced live weight, plasma urea, and IGF-I (P < 0.001 for all) compared with control lambs. Basal levels of NT-proCNP (40.1 [+ or -] 0.9 pmol/l) fell promptly to a nadir (28.1 [+ or -] 0.8 pmol/l, P < 0.001) on day 6, returning rapidly to basal levels upon refeeding. Although plasma alkaline phosphatase (ALP) fell (P < 0.001), reductions in metacarpal growth velocity were not significant within the 12-day period of study. In contrast to caloric restriction, long-acting bovine recombinant GH (2.5 mg/kg on days 0 and 6), as expected, increased plasma IGF-I more than twofold above control for 12 days (P < 0.001). Growth velocity did not differ during the 30 days of observation, and, consistent with unchanged growth velocity, plasma NT-proCNP and ALP were also unaffected. In conclusion, CNP synthesis and markers of bone formation are acutely sensitive to catabolism but unaffected by doses of GH that fail to stimulate skeletal growth. skeleton; bone growth; malnutrition; growth hormone; insulin-like growth factor I; amino-terminal pro-C-type natriuretic peptide doi:10.1152/ajpendo.00469.2006

High-density single-nucleotide polymorphism arrays are used to perform homozygosity mapping in five Sardinian and three Turkish families with Crisponi syndrome and a critical region on chromosome 19p12-13.1 is identified. It is found that neither type nor the location of the CRLF1 mutations points to a phenotype/genotype correlation that accounts for the most severe phenotype in Crisponi syndrome.

Mechanistic interpretations of bone cross-sectional shapes are based on the paradigm of shape optimization such that bone offers maximum mechanical resistance with a minimum of material. Recent in vivo strain studies (Demes et al., Am J Phys Anthropol 106 (1998) 87-100, Am J Phys Anthropol 116 (2001) 257-265; Lieberman et al., Am J Phys Anthropol 123 (2004) 156-171) have questioned these interpretations by demonstrating that long bones diaphyses are not necessarily bent in planes in which they offer maximum resistance to bending. Potential limitations of these in vivo studies have been pointed out by Ruff et al. (Am J Phys Anthropol 129 (2006) 484-498). It is demonstrated here that two loading scenarios, asymmetric bending and buckling, would indeed not lead to correct predictions of loads from strain. It is also shown that buckling is of limited relevance for many primate long bones. This challenges a widely held view that circular bone cross sections make loading directions unpredictable for bones which is based on a buckling load model. Asymmetric bending is a potentially confounding factor for bones with directional differences in principal area moments ([I.sub.max] > [I.sub.min]). Mathematical corrections are available and should be applied to determine the bending axis in such cases. It is concluded that loads can be reliably extra-polated from strains. More strain studies are needed to improve our understanding of the relationships between activities, bone loading regimes associated with them, and the cross-sectional geometry of bones. KEY WORDS cross-sectional geometry; asymmetric bending; buckling; second moment of area

Mutations in filamin B (FLNB), a gene encoding a cytoplasmic actin-binding protein, have been found in human skeletal disorders, including boomerang dysplasia, spondylocarpotarsal syndrome, Larsen syndrome, and atelosteogenesis phenotypes I and III. To examine the role of FLNB in vivo, we generated mice with a targeted disruption of Flnb. Fewer than 3% of homozygous embryos reached term, indicating that Flnb is important in embryonic development. Heterozygous mutant mice were indistinguishable from their wild-type siblings. Flnb was ubiquitously expressed; strong expression was found in endothelial cells and chondrocytes. Flnb-deficient fibroblasts exhibited more disorganized formation of actin filaments and reduced ability to migrate compared with wild-type controls. Flnb-deficient embryos exhibited impaired development of the microvasculature and skeletal system. The few Flnb-deficient mice that were born were very small and had severe skeletal malformations, including scoliotic and kyphotic spines, lack of intervertebral discs, fusion of vertebral bodies, and reduced hyaline matrix in extremities, thorax, and vertebrae. These mice died or had to be euthanized before 4 weeks of age. Thus, the phenotypes of Flnb-deficient mice closely resemble those of human skeletal disorders with mutations in FLNB. chondrocytes | endothelial cell | gene targeting

Several studies in animals and humans have shown positive effects of nondigestible oligosaccharides (NDO) on mineral absorption and metabolism and bone composition and architecture. These include inulin, oligofructose, fructooligosac-charides, galactooligosaccharides, soybean oligosaccharide, and also resistant starches, sugar alcohols, and difructose anhydride. A positive outcome of dietary prebiotics is promoted by a high dietary calcium content up to a threshold level and an optimum amount and composition of supplemented prebiotics. There might be an optimum composition of fructooligosaccharides with different chain lengths (synergy products). The efficacy of dietary prebiotics depends on chronological age, physiological age, menopausal status, and calcium absorption capacity. There is evidence for an independent probiotic effect on facilitating mineral absorption. Synbiotics, i.e., a combination of probiotics and prebiotics, can induce additional effects. Whether a low content of habitual NDO would augment the effect of dietary prebiotics or synbiotics remains to be studied. The underlying mechanisms are manifold: increased solubility of minerals because of increased bacterial production of short-chain fatty acids, which is promoted by the greater supply of substrate; an enlargement of the absorption surface by promoting proliferation of enterocytes mediated by bacterial fermentation products, predominantly lactate and butyrate; increased expression of calcium-binding proteins; improvement of gut health; degradation of mineral complexing phytic acid; release of bone-modulating factors such as phytoestrogens from foods; stabilization of the intestinal flora and ecology, also in the presence of antibiotics; stabilization of the intestinal mucus; and impact of modulating growth factors such as polyamines. In conclusion, prebiotics are the most promising but also best investigated substances with respect to a bone-health-promoting potential, compared with probiotics and synbiotics. The results are more prominent in animal models, where more studies have been performed, than in human studies, where experimental conditions are more difficult to control.

Computed tomography and a 3-point bending test were performed on the metacarpal bones of adult production pigs to test the hypothesis that bone strength is strongly correlated with areal bone mineral density (BMD) in this population. The aim of the study was to subject material from adult production pigs grouped by BMD to 3-point bending, to test this hypothesis and determine any correlations. In all, 168 individual computed tomography scans and mechanical tests were performed on the collected material. For evaluation purposes, the material was divided into the categories low, medium, and high BMD (1.4 g/[cm.sup.2], respectively). The results showed a difference in the maximum load, in the stress at maximum load, and stiffness among each BMD group (P [less than or equal to] 0.001) and in elastic modulus between the low BMD group and the 2 other groups (P [less than or equal to] 0.001). A correlation between both intrinsic and extrinsic measures of bone strength and BMD was thus demonstrated. The projected change in each of the variables reported, for a 0.1 g/[cm.sup.2] alteration in BMD (within the BMD range evaluated in this study), is as follows: maximum load, 708 N; stress at maximum load, 50 N/[mm.sup.2]; stiffness, 391.6 N/mm; and elastic modulus, 108 N/[mm.sup.2] (P [less than or equal to] 0.001). The results confirm the relationship between BMD and bone strength and indicate that BMD screening can be used in fracture risk assessments in production pigs. Key words: bone mineral density, pig, 3-point bending test

Bone formation is carried out by the osteoblast, a mesenchymal cell whose lifespan and activity are regulated by growth factor signaling networks. Growth factors activate phosphatidylinositol 3-kinase (PI3K), which enhances cell survival and antagonizes apoptosis through activation of Akt/PKB. This process is negatively regulated by the Pten phosphatase, which inhibits the activity of PI3K. In this study, we investigated the effects of Akt activation in bone in vivo by conditionally disrupting the Pten gene in osteoblasts by using Cre-mediated recombination. Mice deficient in Pten in osteoblasts were of normal size but demonstrated a dramatic and progressively increasing bone mineral density throughout life. In vitro osteoblasts lacking Pten differentiated more rapidly than controls and exhibited greatly reduced apoptosis in association with markedly increased levels of phosphorylated Akt and activation of signaling pathways downstream of activated Akt. These findings support a critical role for this tumor-suppressor gene in regulating osteoblast lifespan and likely explain the skeletal abnormalities in patients carrying germ-line mutations of PTEN. Akt | bone acquisition | osteoblast survival | high bone mass

Acute nutrient ingestion leads to a rapid inhibition of bone resorption while effects on makers of bone formation are less marked or absent, suggesting that there is a transient shift toward skeletal accretion in the immediate postprandial period. The cellular bases for these effects are not clear. Glucose-dependent insulinotropic peptide (GIP), a known modulator of glucose-induced insulin secretion, is secreted from intestinal endocrine cells in response to nutrient ingestion. In addition to the effect of GIP on pancreatic [beta]-cells, GIP receptors are expressed by osteoblastic cells in bone, suggesting a role for this incretin hormone in bone formation. To determine whether GIP also plays a role in the anti-resorptive effect of nutrient ingestion, osteoclasts were analyzed for the presence of GIP receptors by PCR, immunohistochemical and immunocytochemical analyses of bone tissue, and freshly isolated mature osteoclasts and osteoclast-like cells cultured in vitro. Osteoclast function was assessed by fetal long bone resorption assay and by use of the Osteologic disc assay. Our results demonstrate that GIP receptor transcripts and protein are present in osteoclasts. In addition, with the use of an in vitro organ culture system and mature osteoclasts, GIP was found to inhibit bone resorption in the organ culture system and the resorptive activity of mature osteoclasts. These data are consistent with the hypothesis that GIP inhibits bone breakdown through a direct effect on osteoclast-resorptive activity and suggest one mechanism for the postprandial reduction in markers of bone breakdown. nutrition; bone breakdown; incretin

To restore skeleton function in the field of orthopaedic and oral-maxillofacial surgery, bone tissue regeneration remains an important challenge. Spinal fusion, augmentation of fracture healing, and reconstruction of bone defects [...]

Despite the enormous potential of analyses of ancient DNA for phylogeographic studies of past populations, the impact these analyses, most of which are performed with fossil samples from natural history museum collections, has been limited to some extent by the inefficient recovery of ancient genetic material. Here we show that the standard storage conditions and/or treatments of fossil bones in these collections can be detrimental to DNA survival. Using a quantitative paleogenetic analysis of 247 herbivore fossil bones up to 50,000 years old and originating from 60 different archeological and paleontological contexts, we demonstrate that freshly excavated and nontreated unwashed bones contain six times more DNA and yield twice as many authentic DNA sequences as bones treated with standard procedures. This effect was even more pronounced with bones from one Neolithic site, where only freshly excavated bones yielded results. Finally, we compared the DNA content in the fossil bones of one animal, a [approximately equal to] 3,200-year-old aurochs, excavated in two separate seasons 57 years apart. Whereas the washed museum-stored fossil bones did not permit any DNA amplification, all recently excavated bones yielded authentic aurochs sequences. We established that during the 57 years when the aurochs bones were stored in a collection, at least as much amplifiable DNA was lost as during the previous 3,200 years of burial. This result calls for a revision of the postexcavation treatment of fossil bones to better preserve the genetic heritage of past life forms. ancient DNA | bone diagenesis | conservation | DNA preservation

For methodological or other reasons, a variety of skeletal elements are analyzed and subsequently used as a basis for describing general bone loss and mass. However, bone loss and mass may not be uniform within and among skeletal elements of the same individual because of biomechanical factors. We test the hypothesis that a homogeneity in bone mass exists among skeletal elements of the same individual. Measures indicative of bone mass were calculated from the midshafts of six skeletal elements from the same individuals (N = 41). The extent of intraskeletal variability in bone mass (relative cortical area) was then examined for the entire sample, according to age, sex, and pathological status. The results of the analysis showed that all measures reflect a heterogeneity in bone mass (P [less than or equal to] 0.001). Specifically, differences were observed between the bones of the upper limb and those of the lower limb. Both sexes showed intraskeletal variability in bone mass, but the difference between the sexes is not significant (P = 0.509). When the sample is subdivided according to age, all groups show intraskeletal variability in bone mass, but the difference did not differ significantly among the groups (P = 0.217). However, significant differences in intraskeletal variability are observed between individuals below and above the age of 50. Pathological individuals show intraskeletal variability in bone mass, but the difference between the pathological and non-pathological groups is not significant (P = 0.095). These results indicate that the bone mass of any particular skeletal element is intricately tethered to its specific mechanical loading environment. KEY WORDS mechanical loading; bone loss; aging; cortical bone; skeletal biology

Menatetrenone (vitamin [K.sub.2]) reduces the incidence of vertebral fractures but has only modest effects on bone mineral density (BMD) in postmenopausal women with osteoporosis. Combined treatment with bisphosphonates and menatetrenone may be more effective than treatment with bisphosphonates alone in preventing vertebral fractures, despite the lack of an additive effect of menatetrenone on the BMD increase by bisphosphonates. Menatetrenone improves bone architecture in ovariectomized rats, and the mineral/ matrix ratio of the bone in terms of matrix volume and bone strength (without increasing bone mass) in rats with magnesium deficiency. Thus, available evidence supports an effect of menatetrenone on bone quality during osteoporosis treatment. Key words: bone formation, bone quality, postmenopausal osteoporosis, undercarboxylated osteocalcin, vitamin [K.sub.2] doi: 10.1301/nr.2006.dec.509-517

A study on border region between perichondrium and periosteum cells during vascularization is presented.

Major depression is associated with low bone mass and increased incidence of osteoporotic fractures. However, causality between depression and bone loss has not been established. Here, we show that mice subjected to chronic mild stress (CMS), an established model of depression in rodents, display behavioral depression accompanied by impaired bone mass and structure, as portrayed by decreases in trabecular bone volume density, trabecular number, and trabecular connectivity density assessed in the distal femoral metaphysis and L3 vertebral body. Bone remodeling analysis revealed that the CMS-induced skeletal deficiency is accompanied by restrained bone formation resulting from reduced osteoblast number. Antidepressant therapy, which prevents the behavioral responses to CMS, completely inhibits the decrease in bone formation and markedly attenuates the CMS-induced bone loss. The depression-triggered bone loss is associated with a substantial increase in bone norepinephrine levels and can be blocked by the [beta]-adrenergic antagonist propranolol, suggesting that the sympathetic nervous system mediates the skeletal effects of stress-induced depression. These results define a linkage among depression, excessive adrenergic activity, and reduced bone formation, thus demonstrating an interaction among behavioral responses, the brain, and the skeleton, which leads to impaired bone structure. Together with the common occurrence of depression and bone loss in the aging population, the present data implicate depression as a potential major risk factor for osteoporosis and the associated increase in fracture incidence. antidepressant | chronic depression | osteoporosis | bone formation | adrenergic signaling

The aim of this paper is to analyze how the uncertainties in modelling the geometry and the material properties of a human bone affect the predictions of a finite-element model derived from computed tomography (CT) data. A sensitivity analysis, based on a Monte Carlo method, was performed using three femur models generated from in vivo CT datasets, each subjected to two different loading conditions. The geometry, the density and the mechanical properties of the bone tissue were considered as random input variables. Finite-element results typically used in biomechanics research were considered as statistical output variables, and their sensitivity to the inputs variability assessed. The results showed that it is not possible to define a priori the influence of the errors related to the geometry definition process and to the material assignment process on the finite-element analysis results. The errors in the geometric representation of the bone are always the dominant variables for the stresses, as was expected. However, for all the variables, the results seemed to be dependent on the loading condition and to vary from subject to subject. The most interesting result is, however, that using the proposed method to build a finite-element model of a femur from a CT dataset of the quality typically achievable in the clinical practice, the coefficients of variation of the output variables never exceed the 9%. The presented method is hence robust enough to be used for investigating the mechanical behavior of bones with subject-specific finite-element models derived from CT data taken in vivo. Index Terms--Computed tomography, finite-element methods, Monte Carlo methods, sensitivity analysis.

Traditional measures of structural stiffness in the primate skeleton do not consider the heterogeneous material stiffness distribution of bone. This assumption of homogeneity introduces an unknown degree of error in estimating stiffness in skeletal elements. Measures of weighted stiffness can be developed by including heterogeneous grayscale variations evident in computed tomographic (CT) images. Since gray scale correlates with material stiffness, the distribution of bone quality and quantity can be simultaneously considered. We developed weighted measures of bending resistance and applied these to CT images at three locations along the mandibular corpus in the hominoids Gorilla, Pongo, and Pan. We calculated the traditional (unweighted) moment of inertia for comparison to our weighted measure, which weighs each pixel by its gray-scale value. This weighing results in assignment of reduced moment of inertia values to sections of reduced density. Our weighted and unweighted moments differ by up to 22%. These differences are not consistent among sections, however, such that they cannot be calculated by simple correction of unweighted moments. The effect of this result is that the rank ordering of individual sections within species changes if weighted moments are considered. These results suggest that the use of weighted moments may spur different interpretations of comparative data sets that rely on stiffness measures as estimates of biomechanical competence. KEY WORDS biomechanics; bone density; computed tomography; image analysis; moment of inertia

Neural crest cells are a migratory cell population that give rise to the majority of the cartilage, bone, connective tissue, and sensory ganglia in the head. Abnormalities in the formation, proliferation, migration, and differentiation phases of the neural crest cell life cycle can lead to craniofacial malformations, which constitute one-third of all congenital birth defects. Treacher Collins syndrome (TCS) is characterized by hypoplasia of the facial bones, cleft palate, and middle and external ear defects. Although TCS results from autosomal dominant mutations of the gene TCOF1, the mechanistic origins of the abnormalities observed in this condition are unknown, and the function of Treacle, the protein encoded by TCOF1, remains poorly understood. To investigate the developmental basis of TCS we generated a mouse model through germ-line mutation of Tcof1. Haploinsufficiency of Tcof1 leads to a deficiency in migrating neural crest cells, which results in severe craniofacial malformations. We demonstrate that Tcof1/Treacle is required cell-autonomously for the formation and proliferation of neural crest cells. Tcof1/Treade regulates proliferation by controlling the production of mature ribosomes. Therefore, Tcof1/Treacle is a unique spatiotemporal regulator of ribosome biogenesis, a deficiency that disrupts neural crest cell formation and proliferation, causing the hypoplasia characteristic of TCS craniofacial anomalies. craniofacial development | embryo | mouse | Treacher Collins syndrome

The role of mediator of RNA polymerase II transcription subunit 12 homolog in the activation of Sox9 transcription factor, which is essential for neural crest, cartilage, and ears formation in zebrafish, is analyzed.

Using a study on mice, the roles of transcription factors, Runx2 and Cbfbeta, in embryonic skeletal development are analyzed.

Introduction: Weight-bearing exercise during growth enhances peak bone mass. However, the window of opportunity for optimizing positive effects of exercise on peak bone mass remains to be fully defined. Ballet dancing provides a model of mechanical loading patterns required to site-specifically modulate bone. Methods: We assessed the effects of ballet dancing on bone mineral accrual in female non-elite dancers and normally active controls for 3 years across puberty. We recruited 82 ballet dancers and 61 controls age 8-11 years at baseline. Participants were measured over 3 consecutive years; however, the overlap in ages allowed analysis of the groups across 8-14 years of age. We annually assessed bone mineral content (BMC) at the total body (TB), including upper and lower limb regions, and biannually assessed BMC at the proximal femur and lumbar spine (LS) using dual x-ray absorptiometry (DXA). We derived TB lean mass and fat mass from DXA TB scans. Anthropometry, exercise levels, and calcium intake were also measured biannually. Maturational age was determined by age at peak height velocity (PHV). A multilevel regression model was used to determine the independent effects of body size, body composition, maturation, exercise levels, and calcium intake at each measurement occasion. Results: When adjusted for growth and maturation, dancers had significantly greater BMC at the TB, lower limbs, femoral neck (FN), and LS than controls. Excepting the FN region, these differences became apparent at 1 year post-PHV, or the peripubertal years, and by 2 years post-PHV the differences represented a cumulative advantage in dancers of 0.6-1.3% (p Keywords Bone mineral accrual * Exercise * Girls * Growth * Longitudinal

Introduction: Statins are drugs that inhibit HMG Co-A reductase and have been shown to enhance bone formation in vitro and in vivo in rodents. However, the statins currently used for cholesterol-lowering have been selected for their capacity to target the liver where their effects on cholesterol synthesis are mediated and they undergo first pass metabolism. When given in lipid-lowering doses, these agents do not likely reach sufficient blood concentrations to reliably cause substantial increases in bone formation in humans. Moreover, statins are inactivated by cytochrome P450 enzymes, resulting in even less peripheral distribution of the biologically active moieties beyond the liver. Method: To investigate whether an alternate method of administration might produce beneficial effects on bone formation, we administered lovastatin by dermal application to rats to circumvent the first-pass effects of the gut wall and liver. Results: We found that the statin blood levels measured by HMG Co-A reductase activity were higher, maintained longer and less variable following transdermal application than those following oral administration. Also the increased circulating statin levels were associated with significantly enhanced biological effects on bone. After only 5 days of administration of transdermal lovastatin to rats, there was a 30-60% increase in trabecular bone volume, and 4 weeks later, we observed more than a 150% increase in bone formation rates. There was also a significant increase in serum osteocalcin, a marker of bone formation. We also found that lovastatin administered transdermally produces these profound effects at doses in the range of 1% of the oral dose, without any evidence of the hepatotoxicity or myotoxicity that can occur following oral statin administration. Several doses (0.01-5 mg [kg.sup.-1] [day.sup.-1]) and dosage schedules were examined, and collectively the data strongly suggest a powerful anabolic effect but with an unusually flat dose-response curve. Conclusion: These results show transdermal application of statins produces greater beneficial effects on bone formation than oral administration does. Keywords BMP2 * Bone formation * HMG CoA reductase inhibitors * Postmenopausal osteoporosis * Statins . Transdermal delivery

Introduction: The objective of this study was to determine the effect of a moderate reduction of dietary magnesium [50% of nutrient requirement (50% NR)] on bone and mineral metabolism in the rat, and to explore possible mechanisms for the resultant reduced bone mass. Methods: Female rats were 6 weeks of age at the start of study. Serum magnesium (Mg), calcium (Ca), parathyroid hormone (PTH), 1,25[(OH).sub.2]-vitamin D, alkaline phosphatase, osteocalcin, and pyridinoline were measured during the study at 3- and 6-month time points in control (dietary Mg of 100% NR) and Mg-deficient animals (dietary Mg at 50% NR). Femurs and tibias were also collected for mineral content analyses, micro-computerized tomography, histomorphometry, and immunohistochemical localization of substance P, TNF[alpha], and IL-1[beta] at 3 and 6 months. Results: Although no significant change in serum Mg was observed, Mg deficiency developed, as assessed by the reduction in bone Mg content at the 3- and 6-month time points (0.69 [+ or -] 0.05 and 0.62 [+ or -] 0.04% ash, respectively, in the Mg depletion group compared to 0.74 [+ or -] 0.04 and 0.67 [+ or -] 0.04% ash, respectively, in the control group; p=0.0009). Hypercalcemia did not develop. Although serum Ca level remained in the normal range, it fell significantly with Mg depletion at 3 and 6 months (10.4 [+ or -] 0.3 and 9.6 [+ or -] 0.3 mg/dl, respectively, compared to 10.5 [+ or -] 0.4 and 10.1 [+ or -] 0.6 mg/dl, respectively, in the control group; p=0.0076). The fall in serum Ca in the Mg-depleted animals was associated with a fall in serum PTH concentration between 3 and 6 months (603 [+ or -] 286 and 505 [+ or -] 302 pg/ml, respectively, although it was still higher than the control). The serum 1,25[(OH).sub.2]-vitamin D level was significantly lower in the Mg depletion group at 6 months (10.6 [+ or -] 7.1 pg/ml) than in the control (23.5 [+ or -] 12.7 pg/ml) (p Keywords Inflammatory cytokines * Magnesium * Osteoporosis * PTH * Substance P * 1,25[(OH).sub.2]-Vitamin D

Study of cardiovascular development in chicken through treatment of proepicardium with bone morphogenic protein for deternination of fibroblast growth factor is presented.

Study of endochondral bone formation, through differentiation of osteoblasts by inducing enzymatic activity on osteoprotegerin is presented.

Background. Results of cross-sectional analyses of the association of kidney function with bone mineral density (BMD) have been conflicting. We examined the association of cystatin-C, a new marker of kidney function that is unrelated to lean mass, with initial and follow-up BMD, in an ancillary study of the Cardiovascular Health Study, a population-based cohort of individuals >65 years old. Methods. Two years after measurement of cystatin-C and other covariates, the first BMD was measured in Pittsburgh, Pennsylvania and Davis, California, by using dual energy x-ray absorptiometry. Follow-up BMD was measured in Pittsburgh 4 years later. Associations of cystatin-C with initial BMD and the change in BMD (%/y) at the hip were examined with linear regression. Analyses were conducted separately for men and women. Results. In 1519 participants who had cystatin-C and initial BMD assessed, 614 had follow-up BMD. The percent annual change in BMD at the total hip by cystatin-C quartiles was -0.24, 4.13, -0.40, and -0.66%/y (first to fourth quartile) in women and -0.02, -0.30, -0.18, and -0.94%/y in men. After adjusting for potential confounders, cystatin-C was marginally associated with initial BMD in men but not women. Cystatin-C was associated with bone loss in men; after adjustment for weight loss, cystatin-C was not associated with bone loss in women. Conclusion. Kidney dysfunction, as assessed by cystatin-C, is associated with a more rapid loss of BMD at the hip, especially in men. Further studies are needed to confirm these findings and to determine whether this loss leads to an elevated risk of fracture.

Growth hormone (GH) is important in the development and maintenance of bone; however, the IGF-dependent and -independent molecular pathways involved remain to be established. We used microarray analysis to evaluate GH signaling pathways in 4-wk-old GH-deficient mice following a single injection of GH (4 mg/kg body wt) or PBS (n = 6/group) at 6 or 24 h after treatment. Six thousand one hundred sixty genes were differentially expressed at P [less than or equal to] 0.05, and 17% of these genes were identified at both time points. Several of the genes differentially expressed were expressed sequence tags, and the remaining genes fell into 49 Gene Ontology categories. For subsequent studies, we focused on T-box (Tbx)3, a novel transcription factor, which increased more than twofold at both time points. Real-time RT-PCR analysis determined that pretreatment with IGF-binding protein-4 did not block GH-induced Tbx3 expression in vitro. Pretreatment with TNF-[alpha] blocked GH-induced Tbx3 expression. Tbx3 expression increased during osteoblast differentiation and following BMP-7 and Wnt3a treatment (P [less than or equal to] 0.05). Blocking Tbx3 expression by small interfering RNA decreased cell number and [[sup.3.H]]Thymidine incorporation (P < 0.01). In conclusion, 1) GH caused acute changes in several novel genes, suggesting that many GH-induced signaling pathways and target genes remain to be discovered; 2) because Tbx3 expression is regulated in osteoblasts and blockage of Tbx3 expression decreased cell number and DNA synthesis, we propose that Tbx3 is an important determinant of osteoblast cell number. insulin-like growth factor I; lit/lit mouse; signaling pathways

Relationships among bone mineral density (BMD), bone turnover markers, cortisol, calcium and vitamin D intakes, and cognitive eating restraint score were examined. Sixty-five healthy women, ages 18 to 25 years, had total body, spine, hip, and forearm BMD measured by dual-energy x-ray absorptiometry. Serum osteocalcin, urinary cross-linked N-telopeptide of type I collagen NTx, and salivary cortisol were measured, and intakes of calcium and vitamin D were estimated from questionnaires. Cognitive eating restraint scores were determined from the Eating Inventory. Associations between measures were analyzed by Pearson correlations; predictors of BMD and bone turnover markers were tested using stepwise regression. Serum osteocalcin (P<0.01) and urinary NTx (P<0.05) were negatively related to cognitive eating restraint score. Intakes of calcium (P<0.05) and vitamin D (P<0.05) were associated with forearm BMD. Regression analyses indicated that vitamin D intake predicted total body (P<0.08) and forearm (P<0.01) BMD. Negative associations between cognitive eating restraint score and bone biomarkers suggest a reduction in bone remodeling, not reflected in current BMD.

Introduction: The purpose of this study was to evaluate the effects of alendronate (ALN) on bone mineral density (BMD) and bone turnover markers in patients with orthotopic liver transplantation (OLT). Methods: In the prospective, controlled, open study with 24 months of follow-up, 98 patients with OLT were randomised to receive ALN 70 mg weekly or no ALN; calcium (Ca) 1,000 mg daily and 0.5 mcg calcitriol daily were provided to all patients. Lumbar spine (LS) and hip BMDs were measured at 6-month intervals by dual-energy X-ray absorptiometry (DEXA). Spinal radiographs were obtained to assess vertebral fractures. Additionally, bone turnover markers, serum parathyroid hormone (PTH) and biochemical parameters were determined every 3 months. Results: Compared with the control group, the ALN group showed significant increases in BMD of the LS (5.1 [+ or -] 3.9% vs 0.4 [+ or -] 4.2%, p Keywords Alendronate * Bone fractures * Bone turnover * Liver transplantation * Osteoporosis

There is conflicting information on the physiological role of growth hormone (GH) in the control of aging. This study reports dual-energy x-ray absorptiometry (DXA) measurements of body composition and bone characteristics in young, adult, and aged long-lived GH receptor knockout (GHR-KO) and normal mice to determine the effects of GH resistance during aging. Compared to controls, GHR-KO mice showed an increased percentage of body fat. GHR-KO mice have reduced total-body bone mineral density (BMD), bone mineral content, and bone area, but these parameters increased with age. In addition, GHR-KO mice have decreased femur length, femur BMD, and lower lumbar BMD compared to controls in all age groups. These parameters also continued to increase with age. Our results indicate that GH resistance alters body composition, bone growth, and bone maintenance during aging in GHR-KO mice.

Mechanical cues present in the ECM have been hypothesized to provide instructive signals that dictate cell behavior. We probed this hypothesis in osteoblastic cells by culturing MC3T3-E1 cells on the surface of type I collagen-modified hydrogels with tunable mechanical properties and assessed their proliferation, migration, and differentiation. On gels functionalized with a low type I collagen density, MC3T3-E1 cells cultured on polystyrene proliferated twice as fast as those cultured on the softest substrate. Quantitative time-lapse video microscopic analysis revealed random motility speeds were significantly retarded on the softest substrate (0.25 [+ or -] 0.01 [micro]m/min), in contrast to maximum speeds on polystyrene substrates (0.42 [+ or -] 0.04 [micro]m/min). On gels functionalized with a high type I collagen density, migration speed exhibited a biphasic dependence on ECM compliance, with maximum speeds (0.34 [+ or -] 0.02 [micro]m/min) observed on gels of intermediate stiffness, whereas minimum speeds (0.24 [+ or -] 0.03 [micro]m/min) occurred on both the softest and most rigid (i.e., polystyrene) substrates. Immature focal contacts and a poorly organized actin cytoskeleton were observed in cells cultured on the softest substrates, whereas those on more rigid substrates assembled mature focal adhesions and robust actin stress fibers. In parallel, focal adhesion kinase (FAK) activity (assessed by detecting pY397-FAK) was influenced by compliance, with maximal activity occurring in cells cultured on polystyrene. Finally, mineral deposition by the MC3T3-E1 cells was also affected by ECM compliance, leading to the conclusion that altering ECM mechanical properties may influence a variety of MC3T3-E1 cell functions, and perhaps ultimately, their differentiated phenotype. bone; focal adhesion kinase; mechanotransduction: cytoskeleton; integrins

The femoral head deteriorates in osteonecrosis. As a consequence of that, the cortical shell of the femoral head can buckle into the cancellous bone supporting it. In order to examine the buckling scenario we performed numerical analysis of a realistic femoral head model. The analysis included a solution of the hip contact problem, which provided the contact pressure distribution, and subsequent buckling simulation based on the given contact pressure. The contact problem was solved iteratively by approximating the cartilage by a discrete set of unilateral linear springs. The buckling calculations were based on a finite element mesh with brick elements for the cancellous bone and shell elements for the cortical shell. Results of 144 simulations for a variety of geometrical, material, and loading parameters strengthen the buckling scenario. They, particularly, show that the normal cancellous bone serves as a strong supporting foundation for the cortical shell and prevents it from buckling. However, under the development of osteonecrosis the deteriorating cancellous bone is unable to prevent the cortical shell from buckling and the critical pressure decreases with the decreasing Young modulus of the cancellous bone. The local buckling of the cortical shell seems to be the driving force of the progressive fracturing of the femoral head leading to its entire collapse. The buckling analysis provides an additional criterion of the femoral head collapse, the critical contact pressure. The buckling scenario also suggests a new argument in speculating on the femoral head reinforcement. If the entire collapse of the femoral head starts with the buckling of the cortical shell then it is reasonable to place the reinforcement as close to the cortical shell as possible. [DOI: 10.1115/1.2187050] Keywords: femoral head, collapse, osteonecrosis, cortical shell, buckling, finite element method, discrete element analysis

Background. The vibrational characteristics of any object are directly dependent on the physical properties of that object. Therefore, changing the physical properties of an object will cause the object to adopt changed natural frequencies. A fracture in a bone results in the loss of mechanical stability of the bone. This change in mechanical properties of a bone should result in a change of the resonant frequencies of that bone. A vibrational method for bone evaluation has been introduced. Method of approach. This method uses the radiation force of focused amplitude-modulated ultrasound to exert a vibrating force directly, and remotely, on a bone. The vibration frequency is varied in the range of interest to induce resonances in the bone. The resulting bone motion is recorded and the resonance frequencies are determined. Experiments are conducted on excised rat femurs and resonance frequencies of intact, fractured, and bonded (simulating healed) bones are measured. Results. The experiments demonstrate that changes in the resonance frequency are indicative of bone fracture and healing, i.e., the fractured bone exhibits a lower resonance frequency than the intact bone, and the resonance frequency of the bonded bone approaches that of the intact bone. Conclusion. It is concluded that the proposed radiation force method may be used as a remote and noninvasive tool for monitoring bone fracture and healing process, and the use of focused ultrasound enables one to selectively evaluate individual bones. [DOI: 10.1115/1.2187037] Keywords: bone, bone fracture, bone density, radiation force, vibration, ultrasound

Activating receptor activator of NF-[kappa]B (RANK) and TNF receptor (TNFR) promote osteoclast differentiation. A critical ligand contact site on the TNFR is partly conserved in RANK. Surface plasmon resonance studies [...]

Byline: Kerry J. Schulze (1,2), Carrie Cutchins (1,3), Beryl J. Rosenstein (1,4), Emily L. Germain-Lee (1,5), Kimberly O. O'Brien (1,2) Keywords: Bone; Ca; Cystic fibrosis; Puberty; IGF-1; Lung function Abstract: Few longitudinal data are available characterizing bone development in adolescents with cystic fibrosis (CF) although this is a critical time for bone mineralization. Dual energy X-ray absorptiometry (DXA) scans were obtained at 1- to 4-year intervals in 18 prepubertal and pubertal girls (age 7--18 years) with CF to determine calcium (Ca) accretion rates and changes (I) in total body bone mineral content (TBBMC) and lumbar spine bone mineral density (LS BMD) Z-scores. Daily Ca acquisition rates were calculated assuming TBBMC was composed of 32.2% Ca. Bone Ca accretion averaged 82 mg/day (2.05 mmol/day) [(range:--38 to +197 mg/day (--0.95 to 4.9 mmol/day)] on [proportional to]1,200 mg/day (30 mmol/day) Ca intakes. Estimated mean peak Ca accretion was 160 mg/day (4 mmol/day) at age 13 years losses of bone Ca occurred in late puberty. Gains in insulin-like growth factor 1 (IGF-1) predicted Ca accretion (p&lt 0.06). Body mass index (BMI) Z-score predicted LS BMD and TBBMC Z-score cross-sectionally but did not predict ITBBMC Z-score. Changes in TBBMC Z-score paralleled Ca accretion rates with age. Bone Ca accretion in girls with CF fell below rates in healthy girls during prepuberty and late puberty despite Ca intakes approaching recommendations. IGF-1 and BMI Z-scores may identify children with CF at risk of compromised bone accretion, and more data are required to elucidate roles of lung function and glucocorticoid use in compromised bone health. Author Affiliation: (1) Center for Human Nutrition, Johns Hopkins University School of Medicine, Department of Pediatrics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA (2) Johns Hopkins Bloomberg School of Public Health, Center for Human Nutrition, Room W2041, 615 Wolfe Street, Baltimore, MD, 21205-2179, USA (3) Johns Hopkins Bloomberg School of Public Health, Department of International Health, 615 N. Wolfe Street, Baltimore, MD, 21205-2179, USA (4) Department of Pediatric Pulmonary Medicine, The Johns Hopkins University School of Medicine, Park Building 315, 600 N. Wolfe Street, Baltimore, MD, 21287, USA (5) Pediatric Endocrinology, Johns Hopkins University School of Medicine, Park Building 211, 600 N. Wolfe Street, Baltimore, MD, 21287, USA Article History: Registration Date: 21/06/2005 Received Date: 01/06/2005 Accepted Date: 18/11/2005 Online Date: 28/02/2006 Article note: Supported by the Cystic Fibrosis Foundation and the National Center for Research Resources (NCRR)/General Clinical Research Center, RR00052, Johns Hopkins Hospital

Tissue engineering combines principles of the life sciences and engineering to replace and repair damaged human tissue. Present tissue engineering methods generally require the use of porous, bioresorbable scaffolds to serve as temporary three-dimensional templates to guide cell attachment, differentiation, proliferation, and subsequent regenerate tissue formation. Such scaffolds are anticipated to play an important role in allowing physicians to simultaneously reconstruct and regenerate damaged human tissues such as bone, cartilage, ligament, and tendon. Recent research strongly suggests that the choice of scaffold material and its internal porous architecture significantly influence regenerate tissue structure and function. However, a lack of versatile biomaterials processing and manufacturing methods capable of meeting the complex geometric and compositional requirements of tissue engineering scaffolds has slowed progress towards fully testing these promising findings. It is widely accepted that layered manufacturing methods such as selective laser sintering (SLS) have the potential to address these requirements. We have investigated SLS as a technique to fabricate tissue engineering scaffolds composed of polycaprolactone (PCL), one of the most widely investigated biocompatible, bioresorbable materials for tissue engineering applications. In this article, we report on our development of optimal SLS processing parameters for CAPA[R] 6501 PCL powder using systematic factorial design of experiments. Using the optimal parameters, we manufactured test scaffolds with designed porous channels and achieved dimensional accuracy to within 3%-8% of design specifications and densities approximately 94% relative to full density. Finally, using the optimal SLS process parameters, we demonstrated the successful fabrication of bone tissue engineering scaffolds based on actual minipig and human condyle scaffold designs.

Background. Lower bone mineral density (BMD) has been documented in clinically depressed populations, and depression is the second most common chronic medical condition in general medical practice. Therefore, the purpose of this study was to determine whether depressive symptoms, vitality, and body weight changes were related to 1-year BMD changes after accounting for covariates. Methods. Healthy postmenopausal women (n = 320; 40-65 years) were recruited, and 266 women completed the study. Participants were 3-10 years postmenopausal, sedentary, and either taking hormone replacement therapy (1-3.9 years) or not taking it (at least 1 year). Exclusion criteria were: current smoking status, history of fractures, low BMD, body mass index >32.9 or Results. Both the vitality and depressive symptoms scores were related to BMD changes at the femur neck but not at the greater trochanter or spine. Weight change was a predictor of BMD changes in the trochanter and spine but not in the femoral neck. Weight change and vitality and/or depressive symptoms had differential and site-specific effects on BMD changes at the hip. Vitality and depressive symptoms related to femoral neck changes and weight change related to greater trochanter changes. Conclusions. The negative impact of depressive symptoms on BMD in this population of postmenopausal women was independent of body weight or other behavioral factors such as calcium compliance or exercise.

The introduction of sit-stand worktables was examined in this study. Purchasers at four companies were interviewed regarding preparations prior to purchase, follow-up after installation, and if expectations had been fulfilled. Personnel at the four companies answered a questionnaire examining use of the worktables' sit-stand function, and the influence of some variables on this. Utilisation of the sit-stand function was less than what could be expected to relieve static musculoskeletal loading during VDU work. Pain experienced during the past year, and education on the use of the worktable gave rise to modest increases in utilisation. Investment in sit-stand worktables was satisfactory to purchasers, in terms of providing flexible furniture to suit modern organisational dynamics. Users were, in general, positive to the worktables, but showed poor compliance in using them. User and purchaser satisfaction with regard to improving individual health ergonomics was questionable in respect of the low level of usage. Keywords: Sit-stand worktables; Ergonomics; VDU work

A comparative, experimental study with repeated measures has been conducted to evaluate the effect of the use of speech recognition on working postures, productivity and the perception of user friendliness. Fifteen subjects performed a standardised task, first with keyboard and mouse and, after a six week training period, with speech recognition. The use of speech recognition leads to improved postures of wrist, forearm, upper arm and shoulder and improvement of neck movements when compared to the use of keyboard and mouse. Although the observation method was basic, this study provides insight into the potential benefits speech recognition has for posture. However, productivity decreased for most subjects and speech recognition appears to be usable for specific tasks only. From the perspective of productivity and the perception of user friendliness further development of speech recognition software is necessary. Up to now, speech recognition seems especially beneficial for people with WMSD complaints. Keywords: Speech recognition; Working postures; Work-related musculoskeletal disorders

A reduction in stature (shrinkage) has been used as a measure of the load on the spine. Musculoskeletal effects of ageing may influence individual responses to compressive loading on the spine and the resultant loss in stature. The aim was to apply the technique of precision stadiometry for assessment of spinal shrinkage in a comparison of responses of two different age groups performing a regimen of circuit weight training. In all, 20 subjects (10 aged 18-25 and 10 aged 47-60 years) participated in the study. Each performed two sets of a 12-station circuit of exercises, the loading being established relative to individual capabilities. Recovery procedures using a semi-supine posture intervened between the two sets and again post-exercise; altogether seven measures of change in stature were obtained using precision stadiometry. The two groups showed a similar pattern of spinal shrinkage, losses in stature being greater for the first set compared to the later set of exercises. Subjects gained height whilst in the formal recovery posture, but responses were inconsistent during warm-up, cool-down and active recovery. Irrespective of age, the spine was less responsive to loading as the duration of activity was increased. It was concluded that provided loading is related to individual capability, healthy older operators are not necessarily compromised by their age in activities that include handling and lifting weights. Keywords: Exercise; Manual handling; Stature; Weight training

Wnt proteins are a family of secreted proteins that regulate many aspects of cell growth, differentiation, function, and death. Considerable progress has been made in our understanding of the molecular [...]