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Skin and bone--what comes to mind at hearing this phrase? While certainly a metaphor for disease, it also defines two very different tissues, one a flexible and contiguous outer covering, [...]

A 50-year-old man was referred to the cancer center because of a painful bone mass and lesions in the liver identified on computed tomography (CT). He was diagnosed as to be suffering form Fanconi's anemia and hepatocellular carcinoma, metastatic to bone.

Postmenopausal osteoporosis, a global public health problem, is attributed solely to estrogen levels, and although FSH levels rise sharply in parallel, a direct effect of FSH on the skeleton is never explored. After menopause, resorption significantly exceeds formation, and this imbalance results in net bone loss, while estrogen replacement slows postmenopausal bone loss, thus reducing the risk of fracture.

We originally identified senescence marker protein 30 (SMP30) as a distinctive protein whose expression decreases in an androgenindepen dent manner with aging. Here, we report its sequence homology found in two kinds of bacterial gluconolactonases (GNLs) by using the BLAST search. Then, through a biochemical study, we identify SMP30 as the lactone-hydrolyzing enzyme GNL of animal species. SMP30 purified from the rat liver had lactonase activity toward various aldonolactones, such as D- and L-glucono[delta]-Iactone, D- and L-gulono-[gamma]-Iactone, and D- and L-galactono-[gamma]-lactone, with a requirement for [Zn.sup.2+] or [Mn.sup.2+] as a cofactor. Furthermore, in SMP30 knockout mice, no GNL activity was detectable in the liver. Thus, we conclude that SMP30 is a unique GNL in the liver. The lactonase reaction with L-gulono-[gamma]-lactone is the penultimate step in L-ascorbic acid (AA) biosynthesis, and the essential role of SMP30 in this synthetic process was verified here by a nutritional study using SMP30 knockout mice. These knockout mice (n = 6), fed a vitamin C-deficient diet, did not thrive; i.e., they displayed symptoms of scurvy such as bone fracture and rachitic rosary and then died by 135 days after the start of receiving the deficient diet. The AA levels in their livers and kidneys at the time of death were aging | osteogenic disorder | vitamin C

Hormonal replacement therapy (HRT) helps to prevent osteoporosis. The effect of short-term discontinuation of a long-term HRT on bone mineral density (BMD) in healthy post-menopausal women is unknown. Fifteen women on HRT (HRT users), 17 who never used HRT (non-users) and 8 former HRT users (past-HRT users) were recruited. BMD was measured by DXA. Our results allow to hypothesize that BMD may decline after short-term HRT discontinuation, which would increase the fracture risks. Indeed, our results show that past-HRT users are osteopenic just as non-users. However, these results should be re-examined using a prospective trial and a larger sample size. doi: 10.1300/J074v18n04_03 KEYWORDS. Bone mineral density, menopause, hormonal replacement therapy

Recent studies have demonstrated that adipose-derived mesenchymal cells (AMCs) offer great promise for cell-based therapies because of their ability to differentiate toward bone, cartilage, and fat. Given that cartilage is an avascular tissue and that mesenchymal cells experience hypoxia during prechondrogenic condensation in endochondral ossification, the goal of this study was to understand the influence of oxygen tension on AMC differentiation into bone and cartilage. In vitro chondrogenesis was induced using a three-dimensional micromass culture model supplemented with TGF-[beta]1. Collagen II production and extracellular matrix proteoglycans were assessed with immunohistochemistry and Alcian blue staining, respectively. Strikingly, micromasses differentiated in reduced oxygen tension (2% [O.sub.2]) showed markedly decreased chondrogenesis. Osteogenesis was induced using osteogenic medium supplemented with retinoic acid or vitamin D and was assessed with alkaline phosphatase activity and mineralization. AMCs differentiated in both 21 and 2% [O.sub.2] environments. However, osteogenesis was severely diminished in a low-oxygen environment. These data demonstrated that hypoxia strongly inhibits in vitro chondrogenesis and osteogenesis in AMCs. cartilage; bone

The development of bone mass during childhood through young adulthood is an important determinant of bone health later in life, and calcium is the major building block. Most randomized, double-blind, placebo-controlled trials of calcium supplementation have been done in girls; however, calcium supplementation in boys has been investigated in recent studies. Positive short-term effects on bone measures during growth has been shown in boys and girls, particularly in weight-bearing appendicular bone, although the lifelong effect is not certain.

Background: In recent years interest in bone densitometry in children has increased. Objective: To evaluate the clinical application of digital X-ray radiogrammetry (DXR) and compare the results with those of dual-energy X-ray absorptiometry (DXA). Materials and methods: A total of 41 children with acute lymphoblastic leukaemia (ALL) and 26 children with growth hormone deficiency (GHD) were included in this longitudinal study. Radiographs of the left hand were obtained and used for DXR. DXA of the total body and of the lumbar spine was performed. Results: In both study populations significant correlations between DXR and DXA were found, and, with the exception of the correlation between DXR bone mineral density (DXR-BMD) and bone mineral apparent density in the GHD population, all correlations had a P-value of Keywords Bone densitometry * DXR * DXA * Child DOI 10.1007/s00247-005-0080-3

The goal of this study was to determine, through a longitudinal follow-up, whether sex influences bone adaptation during simulated weightlessness. Twelve-week-old male and female Wistar rats were hindlimb unweighted for 2 wk, and the time course of bone alteration was monitored in vivo by means of densitometry and unbiased three-dimensional quantitative microcomputed tomography at 7 and 14 days. Compared with male rats, female rats had twice more cancellous bone volume at the proximal tibia at baseline, and this bone volume continued to increase, whereas in males it stabilized. Conversely, cortical area was greater in males than in females, and in both sexes cortical bone was still expanding. Hindlimb unloading resulted in larger reductions in males than in females in both cortical and cancellous compartments. In females, trabecular thickness and number decreased mildly, whereas in males trabecular number was dramatically reduced. In both sexes, the trabecular network became less connected and more rod-like shaped. Bone cellular activities evaluated by histomorphometry showed decreased bone formation rate in both sexes and increased resorption activity only in males. In conclusion, in female rats unloaded-related cancellous alterations reversed the growing process, whereas in males, which show lower growth process, it induced an accentuation of age-related cancellous bone changes for most of the parameters. in vivo microcomputed tomography; dual-energy X-ray absorptiometry; histomorphometry; cancellous; cortical

Abstract Steroid treatment has several side effects, including the deterioration of the bone and mineral metabolism in children with nephrotic syndrome. This randomized prospective study was conducted to determine the [...]

This study instituted a unique approach to bone tissue engineering by combining effects of mechanical stimulation in the form of fluid shear stresses and the presence of bone-like extracellular matrix (ECM) on osteodifferentiation. Rat marrow stromal cells (MSCs) harvested from bone marrow were cultured on titanium (Ti) fiber mesh discs for 12 days in a flow perfusion system to generate constructs containing bone-like ECM. To observe osteodifferentiation and bone-like matrix deposition, these decellularized constructs and plain Ti fiber meshes were seeded with MSCs (Ti/ECM and Ti, respectively) and cultured in the presence of fluid shear stresses either with or without the osteogenic culture supplement dexamethasone. The calcium content, alkaline phosphatase activity, and osteopontin secretion were monitored as indicators of MSC differentiation. Ti/ECM constructs demonstrated a 75-fold increase in calcium content compared with their Ti counterparts after 16 days of culture. After 16 days, the presence of dexamethasone enhanced the effects of fluid shear stress and the bone-like ECM by increasing mineralization 50-fold for Ti/ECM constructs; even in the absence of dexamethasone, the Ti/ECM constructs exhibited approximately a 40-fold increase in mineralization compared with their Ti counterparts. Additionally, denatured Ti/EC[M.sup.*] constructs demonstrated a 60-fold decrease in calcium content compared with Ti/ECM constructs after 4 days of culture. These results indicate that the inherent osteoinductive potential of bone-like ECM along with fluid shear stresses synergistically enhance the osteodifferentiation of MSCs with profound implications on bone-tissue-engineering applications. bone tissue engineering | marrow stromal cells | flow perfusion bioreactor

Background. Prospective and cross-sectional studies have confirmed a significant association between bone mineral density (BMD) measurements and fracture risk. However, the relationship among incident fracture risk, mortality. BMD, and quantitative ultrasound is controversial and less studied. Methods. At baseline, 275 postmenopausal elderly women were evaluated by clinical questionnaire regarding fracture risk factors and had radiological analysis of the spine, spine and femur dual energy x-ray absorptiometry, and calcaneous quantitative ultrasound measurements. Five years later, 42 (15.3%) women bad died. 25 (9.1%) were lost to follow-up, and 208 (75.6%) continued the study. Specific questionnaire items regarding fracture risk were reevaluated, and thoracic and lumbar spine x-rays were taken to identify new fractures. Causes of mortality in this population were also assessed. All reported deaths were confirmed by review of death certificates or hospital records and were classified according to International Classifications of Diseases, 10th Revision (ICD-10) code. Results. After adjustments for age, weight, body mass index, smoking stains, previous fracture, physical activity, drug use, and presence of chronic diseases, each 1 standard deviation (SO) reduction in stiffness index (SI) at baseline was significantly associated with future fracture (hazard ratio [HR] 2.23: 95% confidence interval [CI]. 1.30-3.83) and total mortality 5 years later (HR = 1.57: 95% CI, 1.10-2.47). Femoral neck and trochanter BMD vales at baseline were also related to new fracture (HR = 2.01: 95% CI, 1.27-3.18 and HR 1.62: 95% CI, 1.08-2.42, respectively) and total mortality (HR 1.44; 95% CI, 1.06-2.22 and HR = 1.59: 95%, CI, 1.07-2.36. respectively). Cardiovascular mortality was associated with decreased baseline femur BMD (HR = 1.28: 95% CI, 1.08-2.26) and lower SI values (HR = 1.54: 95% CI, 1.08-2.79). Conclusions. Our results demonstrate that low femoral BMD and low SI are able to predict fracture risk and are related to non cause specific and cardiovascular mortality, independently of other factors associated with osteoporosis, death. or aging.

The foetal skull bone as a biological graft was investigated. This study was conducted on Fifteen adult mixed--breed normal dogs 12 to 24 months with weighing 21.4=3.6 Kg .Dogs were randomly divided into 3 groups of 5 animals each. The foetal skull bone of 45 days old was collected from one pregnant bitch via cesarean method. The right femoral head cartilage was removed completely in all dogs of 3 groups. Group I acted as control one, whereas in II group, resurfacing was done by using foetal skull bone which was fixed by using 0.8 mm cerclage wire in criss-cross fashion, but in III group, it was done similar to II group and the hip joint additionally was fixed by using 2 mm steinmenn pin.The clinical observations was made accordingly for 60 days in all groups. The gross changes of femoral head in group I & II were quite smooth and slippy, but in III group were uneven and rough due to secondary changes and ankylosis, but on micropscopic interpertation there was a remarkable compatibility of the graft with femoral head.The reconstruction of articular cartilage was faster in group II and even group III animals than group I animals. There was single row of chondrocyte in scatter area of samples in group . The complete and uniform hyaline cartilage in group II and fibro--cartilage and mixture of connective tissues in group III animals were observed. The results indicated that the foetal skull bone due to its pleuripotent calvarium easily can orient itself into the chondrocytes and cartilagenous tissues in articular surface of the hip joint, if there is suitable enviroment before complete ossification, so that normal joint motion could expect. Key words: Histomorphology, femoral head, resurfacing, foetal skull bone, INTRODUCTION To improve the reparative response in full thickness cartilage defects, grafting of the denuded area has been performed [1,2].The grafting area will result in regenerative tissue that is hyaline [...]

Background. The effect of changes in physical exercise on progression of musculoskeletal disability in seniors has rarely been studied. Methods. We studied a prospective cohort annually from 1984 to 2000 using the Health Assessment Questionnaire Disability Index (HAQ-DI). The cohort included 549 participants, 73% men, with average end-of-study age of 74 years. At baseline and at the end of the study, participants were classified as 'High' or ''Low' vigorous exercisers using a cutpoint of 60 min/wk. Four groups were formed: 'Sedentary' (Low [right arrow] Low; N = 71), 'Exercise Increasers' (Low [right arrow] High; N = 27), 'Exercise Decreasers' (High [right arrow] Low; N = 73), and 'Exercisers' (High [right arrow] High; N = 378). The primary dependent variable was change in HAQ-DI score (scored 0-3) from 1984 to 2000. Multivariate statistical adjustments using analysis of covariance included age, gender, and changes in three risk factors, body mass index, smoking status, and number of comorbid conditions. Participants also prospectively provided reasons for exercise changes. Results. At baseline, Sedentary and Increasers averaged little exercise (16 and 22 exercise min/wk), whereas Exercisers and Decreasers averaged over 10 times more (285 and 212 exercise min/wk; p < .001). All groups had low initial HAQ-DI scores, ranging from 0.03 to 0.08. Increasers and Exercisers achieved the smallest increments in HAQ-DI score (0.17 and 0.11) over 16 years, whereas Decreasers and Sedentary fared more poorly (increments 0.27 and 0.37). Changes in HAQ-DI score for Increasers compared to Sedentary, were significantly more favorable (p < .05) even after multivariate statistical adjustment. Conclusions. Inactive participants who increased exercise achieved excellent end-of-study values with increments in disability similar to those participants who were more active throughout. These results suggest a beneficial effect of exercise, even when begun later in life, on postponement of disability.

Mounting evidence indicates that the amount and type of fat in the diet can have important effects on bone health. Most of this evidence is derived from animal studies. Of the few human studies that have been conducted, relatively small numbers of subjects and/or primarily female subjects were included. The present study assessed the relation of dietary fat to hip bone mineral density (BMD) in men and women using NHANES III data (n = 14,850). Multivariate models using SAS-callable SUDAAN were used to adjust for the sampling scheme. Models were adjusted for age, sex, weight, height, race, total energy and calcium intakes, smoking, and weight-bearing exercise. Data from women were further adjusted for use of hormone replacement therapy. Including dietary protein, vitamin C, and [beta]-carotene in the model did not influence the outcome. Analysis of covariance was used to generate mean BMD by quintile of total and saturated fat intake for 4 sex/age groups. Saturated fat intake was negatively associated with BMD at several hip sites. The greatest effects were seen among men < 50 y old (linear trend P = 0.004 for the femoral neck). For the femoral neck, adjusted mean BMD was 4.3% less among men with the highest compared with the lowest quintile of saturated fat intake (BMD, 95% CI: highest quintile: 0.922 g/[cm.sup.2], 0.909-0.935; lowest quintile: 0.963 g/[cm.sup.2], 95% CI: 0.950-0.976). These data indicate that BMD is negatively associated with saturated fat intake, and that men may be particularly vulnerable to these effects. KEY WORDS: * bone density * osteoporosis * dietary fat * saturated fat * NHANES

The characteristic toughness and strength of bone result from the nature of bone matrix, the mineralized extracellular matrix produced by osteoblasts. The mechanical properties and composition of bone matrix, along with bone mass and architecture, are critical determinants of a bone's ability to resist fracture. Several regulators of bone mass and architecture have been identified, but factors that regulate the mechanical properties and composition of bone matrix are largely unknown. We used a combination of high-resolution approaches, including atomic-force microscopy, x-ray tomography, and Raman microspectroscopy, to assess the properties of bone matrix independently of bone mass and architecture. Properties were evaluated in genetically modified mice with differing levels of TGF-[beta] signaling. Bone matrix properties correlated with the level of TGF-[beta] signaling. Smad3+/- mice had increased bone mass and matrix properties, suggesting that the osteopenic Smad3-/- phenotype may be, in part, secondary to systemic effects of Smad3 deletion. Thus, a reduction in TGF-[beta] signaling, through its effector Smad3, enhanced the mechanical properties and mineral concentration of the bone matrix, as well as the bone mass, enabling the bone to better resist fracture. Our results provide evidence that bone matrix properties are controlled by growth factor signaling. osteoblast | Smad3 | atomic force microscopy

Bone remodeling involves the interplay of bone resorption and formation and is accurately controlled to maintain bone mass. Both processes require transcellular [Ca.sup.2+] transport, but the molecular mechanisms engaged remain largely elusive. The epithelial [Ca.sup.2+] channel TRPV5 is one of the most [Ca.sup.2+]-selective transient receptor potential (TRP) channels. In this study, the functional role of TRPV5 in bone was investigated. TRPV5 mRNA was expressed in human and murine bone samples and in osteoclasts along with other genes involved in transcellular [Ca.sup.2+] transport, including calbindin[D.sub.9K] and calbindin-[D.sub.28K], [Na.sup.+]/[Ca.sup.2+] exchanger 1, and plasma membrane [Ca.sup.2+]-ATPase 1b. TRPV5 expression in murine osteoclasts was confirmed by immunostaining and showed predominant localization to the ruffled border membrane. However, TRPV5 was absent in osteoblasts. Analyses of femoral bone sections from TRPV5 knockout (TRPV[5.sup.-/-]) mice revealed increased osteoclast numbers and osteoclast area, whereas the urinary bone resorption marker deoxypyridinoline was reduced compared with WT (TRPV[5.sup.+/+]) mice. In an in vitro bone marrow culture system, the amount of osteoclasts and number of nuclei per osteoclast were significantly elevated in TRPV[5.sup.-/-] compared with TRPV[5.sup.+/+] mice. However, using a functional resorption pit assay, we found that bone resorption was nearly absent in osteoclast cultures from TRP[V.sup.5-/-] mice, supporting the impaired resorption observed in vivo. In conclusion, TRPV5 deficiency leads to an increase in osteoclast size and number, in which [Ca.sup.2+] resorption is nonfunctional. This report identifies TRPV5 as an epithelial [Ca.sup.2+] channel that is essential for osteoclastic bone resorption and demonstrates the significance of transcellular [Ca.sup.2+] transport in osteoclastic function. tartrate-resistant acid phosphatase | 1,25[(OH).sub.2][D.sub.3] | osteoblast | Coomassie blue | laser scanning confocal microscopy

Two of the most commonly used immunosuppressants, cyclosporine A and tacrolimus (FK506), inhibit the activity of a ubiquitously expressed Ca[2.sup.+]/calmodulin-sensitive phosphatase, calcineurin. Because both drugs also cause profound bone loss in humans and in animal models, we explored whether calcineurin played a role in regulating skeletal remodeling. We found that osteoblasts contained mRNA and protein for all isoforms of calcineurin A and B. TAT-assisted transduction of fusion protein TAT-calcineurin Aa into osteoblasts resulted in the enhanced expression of the osteoblast differentiation markers Runx-2, alkaline phosphatase, bone sialoprotein, and osteocalcin. This expression was associated with a dramatic enhancement of bone formation in intact calvarial cultures. Calcineurin A[[alpha].sup.-/-] mice displayed severe osteoporosis, markedly reduced mineral apposition rates, and attenuated colony formation in 10-day ex vivo stromal cell cultures. The latter was associated with significant reductions in Runx2, bone sialoprotein, and osteocalcin expression, paralleled by similar decreases in response to FK506. Together, the gain- and loss-of-function experiments indicate that calcineurin regulates bone formation through an effect on osteoblast differentiation. FK506 | osteoporosis | runx-2

Multilevel modeling procedures were used to model longitudinal adolescent growth of the humerus, radius, femur, and tibia in boys and girls. Growth velocity variation is much higher among the girls and the tibia is the most variable of the four long bones.

Diabetic osteoporosis is increasingly recognized as a significant comorbidity of type 1 diabetes mellitus. In contrast, type 2 diabetes mellitus is more commonly associated with modest increases in bone mineral density for age. Despite this dichotomy, clinical, in vivo, and in vitro data uniformly support the concept that new bone formation as well as bone microarchitectural integrity are altered in the diabetic state, leading to an increased risk for fragility fracture and inadequate bone regeneration following injury. In this review, we examine the contribution that insulin, as a potential anabolic agent in bone, may make to the pathophysiology of diabetic bone disease. Specifically, we have assimilated human and animal data examining the effects of endogenous insulin production, exogenous insulin administration, insulin sensitivity, and insulin signaling on bone. In so doing, we present evidence that insulin, acting as an anabolic agent in bone, can preserve and increase bone density and bone strength, presumably through direct and/or indirect effects on bone formation. type 1 diabetes mellitus; type 2 diabetes mellitus; osteoblasts; osteoporosis; insulin receptors; hyperinsulinism

This article provides a review of the evidence identifying the factors related to vitamin D status in adolescents. The prevalence of vitamin D deficiency based on 25-hydroxyvitamin D [25(OH)D] of KEY WORDS: * vitamin D * adolescents * bone density * bone accrual * parathyroid hormone

In earlier observational work, the dietary calcium:protein ratio was directly related to bone accrual in healthy postadolescent women. In this study, we sought to test the hypothesis that augmented calcium intake would increase postadolescent skeletal consolidation, using a double-blind, randomized, placebo-controlled design. We recruited 152 healthy young women (age 23.1 [+ or -] 2.7 y, BMI 22.5 [+ or -] 3.0 kg/[m.sup.2]); their usual diets, as assessed by 7-d food diaries, were low in calcium (605 [+ or -] 181 mg/d; 15.1 [+ or ] 4.5 mmol/d) and in the calcium:protein ratio (10.1 [+ or -] 2.0 mg/g). The subjects were randomly assigned to supplemental calcium [500 mg calcium (12.5 mmol) as the carbonate, 3 times/d, with meals] or placebo capsules identical in appearance; all participants also took a daily multivitamin, and they were followed for up to 36 mo with bone densitometry (dual energy X-ray absorptiometry; DXA) at 6-mo intervals. A total of 121 subjects remained in the study for at least 12 mo (median time in the study, 35 mo), with a mean compliance level (observed/expected tablet consumption) of 87.7%. DXA data for these 121 subjects indicated modest but significant mean rates of increase (i.e., 0.24 to 1.10%/y) in bone mineral content (BMC; total body, total hip, and lumbar spine) and in lumbar spine bone mineral density (BMD) but no change in total hip BMD. None of these rates of change differed by group, i.e., calcium supplementation did not have any measurable effect on bone mass accrual. By midstudy, the calcium content of the subjects' usual diets for both groups had risen by ~15%. The combined effect of improved intakes of dietary calcium and the small amount of calcium added by the multivitamin tablets resulted in a mean calcium intake for the control group > 800 mg (20 mmol)/d, possibly at or near the threshold beyond which additional calcium has no further effect on bone accrual. KEY WORDS: * calcium nutrition * calcium supplementation * young adults * bone mass * peak bone mass

A new method is presented for measuring joint kinematics by optimally matching modeled trajectories of geometric surface models of bones with cine phase contrast (cine-PC) magnetic resonance imaging data. The incorporation of the geometric bone models (GBMs) allows computation of kinematics based on coordinate systems placed relative to full 3-D anatomy, as well as quantification of changes in articular contact locations and relative velocities during dynamic motion. These capabilities are additional to those of cine-PC based techniques that have been used previously to measure joint kinematics during activity. Cine-PC magnitude and velocity data are collected on a fixed image plane prescribed through a repetitively moved skeletal joint. The intersection of each GBM with a simulated image plane is calculated as the model moves along a computed trajectory, and cine-PC velocity data are sampled from the regions of the velocity images within the area of this intersection. From the sampled velocity data, the instantaneous linear and angular velocities of a coordinate system fixed to the GBM are estimated, and integration of the linear and angular velocities is used to predict updated trajectories. A moving validation phantom that produces motions and velocity data similar to those observed in an experiment on human knee kinematics was designed. This phantom was used to assess cine-PC rigid body tracking performance by comparing the kinematics of the phantom measured by this method to similar measurements made using a magnetic tracking system. Average differences between the two methods were measured as 2.82 mm rms for anterior/posterior tibial position, and 2.63 deg rms for axial rotation. An intertrial repeatability study of human knee kinematics using the new method produced rms differences in anterior/posterior tibial position and axial rotation of 1.44 mm and 2.35 deg. The performance of the method is concluded to be sufficient for the effective study of kinematic changes caused to knees by soft tissue injuries. [DOI: 10.1115/1.1992524]

Background: Whole bone in vitro biomechanical compressive testing can be complicated by three factors: sample asymmetry, heterogeneous material properties, and unknown effective centroid location. Method of approach: The technique presented here facilitates the calculation of effective centroid position, modulus of elasticity and equivalent uniform strain magnitude for a cross section of bone from a simple whole bone compressive test. Simplification of section response to load is achieved through a combination of linear beam and simple planer geometry theory. The technique requires three longitudinal strain gauges be affixed around the test specimen cross section of interest, gauge position need not be determined. Sample loading is then accomplished using a simple four point loading jig. Results: Results of the technique are presented on an object with known elasticity and geometry, an aluminium tube, and seven pairs of equine third metacarpal whole bones. Conclusions: Average cross section modulus of elasticity, equivalent uniform cross section strain, and effective centroid locations were all predicted to within the range of published values. Employing the testing setup and analysis technique presented in this paper resulted in a significant savings in both implementation complexity and cost over previously available techniques. [DOI: 10.1115/1.1993663] Keywords: Neutral Axis, Modulus of Elasticity, Linear Beam Theory, Effective Centroid

Osteogenesis by the bone marrow stromal stem cells (BMSSCs) supports continuous bone formation and the homeostasis of the bone marrow microenvironment. The mechanism that controls the proliferation and differentiation of BMSSCs is not fully understood. Here, we report that CD18, a surface protein present primarily on hematopoietic cells, but not on differentiated mesenchymal cells, is expressed by the stromal stem cells and plays a critical role in the osteogenic process. Constitutive expression of CD18 on BMSSCs using a retroviral promoter significantly enhances bone formation in vivo, whereas genetic inactivation of CD18 in mice leads to defective osteogenesis due to decreased expression of the osteogenic master regulator Runx2/Cbfa1. The defective osteogenesis of the CD18-null BMSSCs can be restored by expressing full-length, but not cytoplasmic domain-truncated, CD18. Radiographic analyses with dual-energy x-ray absorptiometry and 3D microcomputed tomography show that mice lacking CD18 have decreased bone mineral density and exhibit certain features of osteoporosis. Altogether, this work demonstrates that CD18 functions critically in the osteogenesis of BMSSCs, and thus lack of CD18 expression in the leukocyte adhesion deficiency patients may predispose them to osteoporosis. integrin | leukocyte adhesion deficiency | bone

Glycogen synthase kinase 3 (GSK3) inhibits signaling pathways that are essential for bone development. To study the requirement for GSK activity during endochondral bone development, we inhibited GSK3 in cultured metatarsal bones with pharmacological antagonists. Interestingly, we find that inhibition of GSK3 strongly repressed chondrocyte and perichondrial osteoblast differentiation. Moreover, chondrocyte proliferation was inhibited, whereas perichondrial cell proliferation was stimulated. These results mirror the effects of fibroblast growth factor signaling (FGF), suggesting the FGF expression is induced. Indeed, we showed that (1) FGF18 expression is stimulated following inhibition of GSK3 and (2) GSK3 regulates FGF18 expression through the control of [beta]-catenin levels. Stimulation of cultured metatarsal with FGF18 had similar effects on the differentiation and proliferation of chondrocytes and perichondrial cells as GSK3 repression. This suggests that the regulation of FGF18 expression is a major function of GSK3 during endochondral bone development. Consistent with this, we showed that the effect of GSK3 inhibition on chondrocyte proliferation is repressed in tissues lacking a receptor for FGFI8, FGF receptor 3. Keywords: Glycogen synthase kinase; FGF18; Bone; Cartilage; Chondrocyte; [beta]-catenin

A study demonstrates that clock genes in osteoblasts mediate the leptin-dependant sympathetic inhibition of bone formation. The regulation of bone-formation by leptin through two antagonistic pathways is reminiscent of the dual mechanism that leptin uses to regulate bone resorption.

Archaeologists are interested in how human prey choice decisions vary both spatially and temporally where research is focused on the role of climate and human overhunting play in the process. The faunal record from two Fremont residential sites located in Utah's Parowan Valley shows patterns of taxonomic representation, age structure, element representation, and fragmentation which covary through time both with each other and with local tree-ring records.

Osteocytes, former osteoblasts entombed in the bone matrix, form an extensive cell communication network that is thought to detect microdamage and mechanical strains and to transmit signals leading to repair and compensatory bone augmentation or reduction. Bone active hormones and drugs control the integrity of this network by regulating osteocyte apoptosis, which might be a determinant of bone strength. Herein we demonstrate that mechanical stimulation by stretching activates the ERKs, which in turn are responsible for the attenuation of osteocyte apoptosis. The effect of osteocyte stretching is transmitted by integrins and cytoskeletal and catalytic molecules, such as Src kinases. Stretch-induced antiapoptosis also requires nuclear translocation of ERKs and new gene transcription. The evidence linking mechanical stimulation, activation of an integrin/cytoskeleton/Src/ERK signaling pathway, and osteocyte survival provides a mechanistic basis for the profound role of mechanical forces, or lack thereof, on skeletal health and disease. bone; mechanotransduction; osteoblastic cells; caveolae; stretching

Treatment of large defects requires the harvest of fresh living bone from the iliac crest. Harvest of this limited supply of bone is accompanied by extreme pain and morbidity. This has prompted the exploration of other alternatives to generate new bone using traditional principles of tissue engineering, wherein harvested cells are combined with porous scaffolds and stimulated with exogenous mitogens and morphogens in vitro and/or in vivo. We now show that large volumes of bone can be engineered in a predictable manner, without the need for cell transplantation and growth factor administration. The crux of the approach lies in the deliberate creation and manipulation of an artificial space (bioreactor) between the tibia and the periosteum, a mesenchymal layer rich in pluripotent cells, in such a way that the body's healing mechanism is leveraged in the engineering of neotissue, Using the 'in vivo bioreactor' in New Zealand White rabbits, we have engineered bone that is biomechanically identical to native bone. The neobone formation followed predominantly an intramembraneous path, with woven bone matrix subsequently maturing into fully mineralized compact bone exhibiting all of the histological markers and mechanical properties of native bone. We harvested the bone after 6 weeks and transplanted it into contralateral tibial defects, resulting in complete integration after 6 weeks with no apparent morbidity at the donor site. Furthermore, in a proof-of-principle study, we have shown that by inhibiting angiogenesis and promoting a more hypoxic environment within the 'in vivo bioreactor space,' cartilage formation can be exclusively promoted. cartilage | tissue engineering | hard tissue | vascularized organs

The subjects of this study (n = 20; 16 women, 4 men) performed 10 weeks of leg press training using one of two exercise modes (isoload or isotonic) with no crossover. Their workouts, which were performed 3 times per week, involved 4 sets of 8 repetitions with maximal voluntary effort. Testing was performed pre- and posttraining to examine bone and muscle changes. Posttraining, both groups incurred significant concentric knee extensor strength and leg muscle mass gains, while the percentage of body fat and total body fat mass each decreased. Leg and total body bone mineral densities showed group-by-time interactions, as isoload exercise caused posttraining gains, while isoinertial values were unchanged. Bone resorption assays showed insignificant changes. Isoload training likely involved greater strain magnitudes and rates to evoke higher peak forces and osteogenesis. Transduction of the training stimulus may have involved (a) formation in response to microdamage, and (b) piezoelectric-induced potentials that stimulated site-specific osteoblast activity and osteogenesis. Key Words. isoinertial, isoload, osteogenesis, weight training

Calcium supplementation has been shown to increase bone mineralization in children and adolescents. However, catch-up mineralization later in puberty appears likely if intake is consistent with usual average intakes in the United States. Ultimately, individualized risk assessment will be developed based on genetic and lifestyle factors that can be used to guide optimal calcium intake during childhood. Key words: calcium absorption, dietary requirements, puberty, bone mass

Exposure to microgravity causes bone loss in humans, and the underlying mechanism is thought to be at least partially due to a decrease in bone formation by osteoblasts. In the present study, we examined the hypothesis that microgravity changes osteoblast gene expression profiles, resulting in bone loss. For this study, we developed an in vitro system that simulates microgravity using the Random Positioning Machine (RPM) to study the effects of microgravity on 2T3 preosteoblast cells grown in gas-permeable culture disks. Exposure of 2T3 cells to simulated microgravity using the RPM for up to 9 days significantly inhibited alkaline phosphatase activity, recapitulating a bone loss response that occurs in real microgravity conditions without altering cell proliferation and shape. Next, we performed DNA microarray analysis to determine the gene expression profile of 2T3 cells exposed to 3 days of simulated microgravity. Among 10,000 genes examined using the microarray, 88 were downregulated and 52 were upregulated significantly more than twofold using simulated microgravity compared with the static 1-g condition. We then verified the microarray data for some of the genes relevant in bone biology using real-time PCR assays and immunoblotting. We confirmed that microgravity downregulated levels of alkaline phosphatase, runt-related transcription factor 2, osteomodulin, and parathyroid hormone receptor 1 mRNA; upregulated cathepsin K mRNA; and did not significantly affect bone morphogenic protein 4 and cystatin C protein levels. The identification of gravisensitive genes provides useful insight that may lead to further hypotheses regarding their roles in not only microgravity-induced bone loss but also the general patient population with similar pathological conditions, such as osteoporosis. microarray; bone loss; alkaline phosphatase; runx2; osteomodulin

We report the characterization of factor inhibiting activating transcription factor 4 (ATF4)--mediated transcription (FIAT), a leucine zipper nuclear protein. FIAT interacted with ATF4 to inhibit binding of ATF4 to DNA and block ATF4-mediated transcription of the osteocalcin gene in vitro. Transgenic mice overexpressing FIAT in osteoblasts also had reduced osteocalcin gene expression and decreased bone mineral density, bone volume, mineralized volume, trabecular thickness, trabecular number, and decreased rigidity of long bones. Mineral homeostasis, osteoclast number and activity, and osteoblast proliferation and apoptosis were unchanged in transgenics. Expression of osteoblastic differentiation markers was largely unaffected and type 1 collagen synthesis was unchanged. Mineral apposition rate was reduced in transgenic mice, suggesting that the lowered bone mass was due to a decline in osteoblast activity. This cell-autonomous decrease in osteoblast activity was confirmed by measuring reduced alkaline phosphatase activity and mineralization in primary osteoblast cultures. These results show that FIAT regulates bone mass accrual and establish FIAT as a novel transcriptional regulator of osteoblastic function.

An experiment was conducted to investigate maximum forearm pronation and supination torques and forearm discomfort, for intermittent torque exertions in supine and prone forearm angles for the right arm. The results indicated that maximum forearm pronation and supination torque was affected by forearm angle and the direction of exertion.

Osteoporosis is a disease that is strongly genetically determined. Aromatase converts androgens to estradiol in postmenopausal women, therefore polymorphisms of the gene for this enzyme may be associated with bone mass and fracture. We investigated the association of the TTTA microsatellite polymorphism in intron 4 of the aromatase (CYP19) gene with bone mineral density (BMD) and fracture in 1,257 women aged 70 yr and greater. The data obtained were stratified based on the presence or absence of a [TTTA]n of 7 (A2), determined from a preliminary analysis of hip dual-energy X-ray absorptiometry BMD, which was present in 27% of the population. The presence of an A2 allele was associated with a higher free estradiol index (0.52 [+ or -] 0.49, P = 0.049) compared with the absence of an A2 allele (0.47 [+ or -] 0.45); higher BMD at all sites of the hip (3.4% total hip, 2.3% femoral neck, 3.6% intertrochanter, 4.1% trochanter) and the lumbar spine (12.7%); higher values for the calcaneal quantitative ultrasound parameters broadband ultrasound (1.3%), speed of sound (0.4%), and stiffness (3.7%); and higher peripheral quantitative computed tomography measures for total (3.4%), trabecular (3.3%), and cortical BMD (3.3%) and the derived stress strain index (SSI) parameters SSI polar (6.4%) and SSI x (6.8%) values. A lower deoxypryridinoline creatinine ratio was observed in subjects with an A2 allele (30.3 [+ or -] 10.4 vs. 27.1 [+ or -] 9.1, P = 0.03). The A2 allele was associated with a lower prevalence of vertebral fracture in subjects who were osteoporotic (odds ratio 0.27, confidence interval 0.09-0.79). Therefore, a common polymorphism of the aromatase gene, perhaps in linkage disequilibrium with a functionally significant CYP19 polymorphism, is associated with bone structure and bone turnover, either by local effects or by effects on circulating bioactive estrogen. estradiol; fracture; bone density

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jada.2005.02.046 Byline: Wendy Bounds, Jean Skinner, Betty Ruth Carruth, Paula Ziegler Abstract: To identify factors related to childrenas bone mineral indexes at age 8 years, and to assess bone mineral indexes in the same children at ages 6 and 8 years.

How do developmental mechanisms evolve to control changing skeletal morphology, the shapes and sizes of individual bones? We address this question with studies of the opercle (OP), a large facial bone that has undergone marked morphological evolution in the ray-finned fish. Attributes for developmental analysis motivated us to examine how OP shape and size evolve and develop in threespine sticklebacks, a model system for understanding vertebrate evolution. We find that when Alaskan anadromous fish take up permanent residence in lakes, they evolve smaller and reshaped OPs. The change is a reduction in the amount of bone laid down along one body axis, and it arises at or shortly after the onset of OP development. A quantitative trait locus is present on linkage group 19 that contributes in a major way to this phenotype. quantitative trait locus | major effect locus | opercle craniofacial patterning | hyoid arch

Previous studies have demonstrated the ability of bone morphogenetic proteins (BMPs) to promote chondrogenic differentiation in vitro. However, the in vivo role of BMP signaling during chondrogenesis has been unclear. We report here that BMP signaling is essential for multiple aspects of early chondrogenesis. Whereas mice deficient in type 1 receptors Bmpr1a or Bmpr1b in cartilage are able to form intact cartilaginous elements, double mutants develop a severe generalized chondrodysplasia. The majority of skeletal elements that form through endochondral ossification are absent, and the ones that form are rudimentary. The few cartilage condensations that form in double mutants are delayed in the prechondrocytic state and never form an organized growth plate. The reduced size of mutant condensations results from increased apoptosis and decreased proliferation. Moreover, the expression of cartilage-specific extracellular matrix proteins is severely reduced in mutant elements. We demonstrate that this defect in chondrocytic differentiation can be attributed to lack of Sox9, L-Sox5, and Sox6 expression in precartilaginous condensations in double mutants. In summary, our study demonstrates that BMPR1A and BMPR1B are functionally redundant during early chondrogenesis and that BMP signaling is required for chondrocyte proliferation, survival, and differentiation in vivo. bone morphogenetic protein | cartilage endochondral ossification | Sox proteins | skeletal development