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Effects of simulated weightlessness on the kinase activity of MEK1 induced by bone morphogenetic protein-2 in rat osteosarcoma cells  

NASA Astrophysics Data System (ADS)

Objective The mRNA expression of alpha 1 chain of type I collagen COL-I alpha 1 in rat osteosarcoma ROS17 2 8 cells induced by bone morphogenetic protein-2 BMP-2 was reduced under simulated microgravity The protein kinase MEK1 of MAPK signal pathway plays an important role in the expression of COL-I alpha 1 mRNA The purpose of this study is to investigate the effects of simulated weightlessness on the activity of MEK1 induced by BMP-2 in ROS17 2 8 cells Methods ROS17 2 8 cells were cultured in 1G control and rotating clinostat simulated weightlessness for 24 h 48 h and 72 h BMP-2 500 ng ml was added into the medium 1 h before the culture ended There was a control group in which ROS17 2 8 cells were cultured in 1G condition without BMP-2 Then the total protein of cells was extracted and the expression of phosphated-ERK1 2 p-ERK1 2 protein was detected by means of Western Blotting to show the kinase activity of MEK1 Results There were no significant differences in the expression of total ERK1 2 among all groups The expression of p-ERK1 2 was unconspicuous in the control group without BMP-2 but increased significantly when BMP-2 was added P 0 01 The level of p-ERK1 2 in simulated weightlessness group was much more lower than that in 1G group in every time point P 0 01 The expression of p-ERK1 2 gradually decreased along with the time of weightlessness simulation P 0 01 Conclusions The kinase activity of MEK1 induced by BMP-2 in rat osteosarcoma cells was reduced under simulated weightlessness

Zhang, S.; Wang, B.; Cao, X. S.; Yang, Z.



NASA Astrophysics Data System (ADS)

The phenomenon of weightlessness is clearly demonstrated if the ball is thrown. A diagram shows an astronaut as he would be seen by an observer inside a ship. With his left arm he is throwing a ball horizontally and with his right arm he is throwing a ball diagonally upwards. In space the ball thrown horizontally does not fall but maintains its level flight, and similarly the ball thrown diagonally upwards continues in a straight line. On the ground the familiar parabolic curves resulting from the action of gravity are seen. At low speeds the condition of weightlessness can be reproduced using simple, small scale apparatus. The spaceship is replaced by a large, open sided, wooden box, the arm of the astronaut by a small catapult, the ball by an ordinary marble (1.27 cm diameter) and the observer by a camera. The success of the experiment depends upon the efficient working of the catapult. The box is allowed to fall from the ceiling of an attic in a cottage, on to a mattress on the floor, to reproduce conditions of weightlessness.

Shiells, Robin



[Effects of weightlessness on phosphorus and calcium metabolism and bone remodeling].  


Weightlessness results in negative calcium balance which can only reflect a redistribution of calcium in the body: the loss of calcium in the faeces and/or urine is constant, but an increase in urinary hydroxyproline indicating bone collagen destruction is not always detectable; moreover, a slowing down of collagen maturation may be suspected. Bone analysis by histomorphometry in animals and by indirect, non-invasive methods in man shows a decrease in bone mass. However, this bone tissue atrophy might only reflect excessive ageing of the bone during weightlessness, as suggested by slow bone formation and lack of variation in bone resorption. Since the experimental results obtained in men and animals during simulated weightlessness on earth are not strictly identical with those observed in space- flights, their validity may be questioned. Additional studies (notably histomorphometric studies) are therefore required for a better knowledge, as well as prevention, of the problems raised by human life in space. PMID:2940573

Alexandre, C; Chappard, D; Vico, L; Minaire, P; Riffat, G



Bone Proteomics experiment (BOP): the first proteomics analysis of mammalian cells cultivated in weightlessness conditions  

NASA Astrophysics Data System (ADS)

Bone mass loss is a major consequence of extended periods of weightlessness Many studies have been performed on astronauts and animal models establishing that a decrease of the maturation process and of the bone synthesising activity of osteoblast cells play a key role in microgravity-dependent bone mass loss Several experiments on single cells and tissues showed that weightlessness can also influence cells cultivated in vitro Many molecular mechanisms are affected among which the cytoskeleton and intracellular signal transduction cascades However the underlying mechanisms of these changes and their molecular consequences are far from being fully understood and the cellular gravisensing machinery is still unknown In contrast to weightlessness dynamic mechanical loading increases bone density and strength and promotes osteoblast proliferation differentiation and matrix production by acting at the gene expression level However the molecular mechanisms by which mechanical forces are converted into biochemical signalling in bone are also poorly understood A growing body of evidence points to extracellular nucleotides i e ATP and UTP as soluble factors that are released by several cell types in response to mechanical stimulation and that eventually trigger an intracellular signal We have recently demonstrated in the HOBIT osteoblast cell line that ATP and UTP treatments can activate two fundamental transcription factors that promote osteoblast differentiation and physiology Runx2 and Egr-1 as well as their target genes galectin-3 and

Costessi, A.; Vascotto, C.; Pines, A.; Romanello, M.; Schonenborg, R.; Schiller, P.; Moro, L.; Tell, G.


Mechanical Factors and Bone Health: Effects of Weightlessness and Neurologic Injury  

Microsoft Academic Search

Bone is a dynamic tissue with homeostasis governed by many factors. Among them, mechanical stimuli appear to be particularly\\u000a critical for bone structure and strength. With removal of mechanical stimuli, a profound bone loss occurs, as best observed\\u000a in the extreme examples following exposure to space flight or neurologic impairment. This review provides an overview of the\\u000a changes in bone

Shreyasee Amin



Morphological Study of Early Changes in Rat Bones in Simulated Weightlessness.  

National Technical Information Service (NTIS)

By histomorphometric methods tibial bones and lumbar vertebrae of rats exposed for 7 days to hypokinesia or head-down suspension were investigated. Both hypokinesia and suspension led to osteoporosis of the tibial metaphyseal spongiosa which was primarily...

A. S. Kaplanskiy Z. F. Sakharova Y. I. Ilyinakakuyeva G. N. Durnova



Discussion of the combined effect of weightlessness and ionizing radiation on the mammalian body: morphological data.  


The combined effect of weightlessness and ionizing radiation, from the Cs137 source at 800 rads for 24 h, on the animal body was studied. The morphological examination of organs and tissues of rats flown aboard the biosatellite Cosmos-690, kept in the ground-based simulation experiment, and kept in the vivarium, indicated prevalence of radiation-induced changes in both experimental groups of rats. An exposure of animals to space flight factors did not produce a substantial aggravation of radiation-induced effects. This is indicated by the lack of significant differences in the weight of testes, thymus, and spleen of flight and simulation rats. However, this exposure affected adversely the development of reparative processes in the hemopoietic tissue of bone marrow. Inflight irradiation aggravated weightlessness-induced changes. A combined effect of weightlessness and irradiation did not result in the summation of the effects exerted on skeletal muscles by either factor alone. PMID:831710

Portugalov, V V; Savina, E A; Kaplansky, A S; Yakovleva, V I; Durnova, G N; Pankova, A S; Shvets, V N; Alekseyev, E I; Katunyan, P I



Endoscopic surgery in weightlessness  

Microsoft Academic Search

Background: Performing a surgical procedure in weightlessness, also called 0-gravity (0-g), has been shown to be no more difficult than in a 1-g environment if the requirements for the restraint of the patient, operator, surgical hardware, are observed. The performance of laparoscopic and thorascopic procedures in weightlessness, if feasible, would offer several advantages over the performance of an open operation.

M. R. Campbell; A. W. Kirkpatrick; R. D. Billica; S. L. Johnston; R. Jennings; D. Short; S. A. Dulchavsky



Effect of simulated weightlessness on the expression of Cbf?1 induced by fluid shear stress in MG-63 osteosarcoma cells.  

NASA Astrophysics Data System (ADS)

Objective The role of mechanical load in the functional regulation of osteoblasts becomes an emphasis in osseous biomechanical researches recently This study was aim to explore the effect of flow shear stress on the expression of Cbf alpha 1 in human osteosarcoma cells and to survey its functional alteration in simulated weightlessness Method After cultured for 72 h in two different gravitational environments i e 1G terrestrial gravitational condition and simulated weightlessness condition human osteosarcoma cells MG-63 were treated with 0 5 Pa or 1 5 Pa fluid shear stress FSS in a flow chamber for 15 30 60 min respectively The total RNA in cells was isolated Transcription PCR analysis was made to examine the gene expression of Cbf alpha 1 And the total protein of cells was extracted and the expression of Cbf alpha 1 protein was detected by means of Western Blotting Results MG-63 cultured in 1G condition reacted to FSS treatment with an enhanced expression of Cbf alpha 1 Compared with no FSS control group Cbf alpha 1 mRNA and protein expression increased significantly at 30 and 60 min with the treatment of FSS P 0 01 And there was remarkable difference on the Cbf alpha 1 mRNA and protein expression between the treatments of 0 5 Pa and 1 5 Pa FSS at 30 min or 60 min P 0 01 As to the osteoblasts cultured in simulated weightlessness by using clinostat the expression of Cbf alpha 1 was significantly different between 1G and simulated weightlessness conditions at each test time P 0 05 Compared with no FSS

Yang, Z.; Zhang, S.; Wang, B.; Sun, X. Q.


Weightless solar energy collection  

Microsoft Academic Search

Weightless, tracking, concentrating solar collectors are described emphasizing balloon shape, balloon materials, balloon fill gas, balloon tethering, probes for collecting solar energy as heat, probes for direct conversion to electricity, probe cooling systems, tracking mounts, thin-wall conical reinforced concrete bases, lightning rods, aircraft warning lights, estimated costs and anticipated performance.




Plants and Weightlessness.  

National Technical Information Service (NTIS)

The growth of two plants, wall cress and short-day red goosefoot, was traced for their entire lifetime in weightlessness. In the beginning both plants grew normally: the seeds sprouted in the normal periods, and the shoots did not differ in any way from t...

V. Karminskiy V. Tarkhanovskiy



Weightlessness Simulation System and Process.  

National Technical Information Service (NTIS)

A weightlessness simulator has a chamber and a suit in the chamber. O-rings and valves hermetically seal the chamber. A vacuum pump connected to the chamber establishes a pressure in the chamber less than atmospheric pressure. A water supply tank and wate...

H. C. Vykukal



Gravity in the Weightless Economy  

Microsoft Academic Search

This paper studies the international mobility of technology through the lens of multinational firms. We show that gravity applies to the activity of multinational firms, and the strength of gravity is greatest in technologically-complex, research and development intensive industries. To explain gravity in the weightless economy, we develop a model in which a multinational's production can be fragmented into intermediates

Wolfgang Keller; Stephen R Yeaple



Calcium influx through stretch-activated channels mediates microfilament reorganization in osteoblasts under simulated weightlessness  

NASA Astrophysics Data System (ADS)

We have explored the role of Ca2+ signaling in microfilament reorganization of osteoblasts induced by simulated weightlessness using a random positioning machine (RPM). The RPM-induced alterations of cell morphology, microfilament distribution, cell proliferation, cell migration, cytosol free calcium concentration ([Ca2+]i), and protein expression in MG63 osteoblasts were investigated. Simulated weightlessness reduced cell size, disrupted microfilament, inhibited cellular proliferation and migration, and induced an increase in [Ca2+]i in MG63 human osteosarcoma cells. Gadolinium chloride (Gd), an inhibitor for stretch-activated channels, attenuated the increase in [Ca2+]i and microfilament disruption. Further, the expression of calmodulin was significantly increased by simulated weightlessness, and an inhibitor of calmodulin, W-7, aggravated microfilament disruption. Our findings demonstrate that simulated weightlessness induces Ca2+ influx through stretch-activated channels, then results in microfilament disruption.

Luo, Mingzhi; Yang, Zhouqi; Li, Jingbao; Xu, Huiyun; Li, Shengsheng; Zhang, Wei; Qian, Airong; Shang, Peng



Proprioceptive information processing in weightlessness  

Microsoft Academic Search

The ”illusions” experiment carried out on five astronauts during the last two French-Russian flights (Antars in 1992 and\\u000a Alta???r in 1993) and in the Russian Post-Antars mission (1993) was designed to investigate the adaptive changes in human\\u000a proprioceptive functions occurring in weightlessness at both the sensorimotor and cognitive levels, focusing on two kinds\\u000a of responses: (1) whole-body postural reflexes, and

R. Roll; J. C. Gilhodes; J. P. Roll; K. Popov; O. Charade; V. Gurfinkel



Gravity in the Weightless Economy  

Microsoft Academic Search

We show that gravity applies to the activity of multinational …rms, and the strength of gravity is greatest in technologically-complex, research and development intensive industries. To explain gravity in the weightless economy, we develop a model in which a multinational's production can be fragmented into intermediates that vary in the codi…ability of their technology. Poorly codi…ed technology requires face-to-face communication

Wolfgang Keller; Stephen R. Yeaple



Effects of weightlessness in man.  


The program for the Apollo 16 flight was designed to include both safeguards against and investigations of the physiological problems arising from increase in the period of manned space flight. Precautions included the provision of a controlled diet with high potassium content, carefully controlled work loads and work-rest cycles and an emergency cardiology consultation service, and investigations were made to enable pre-flight-post-flight comparisons of metabolic, cardiovascular and central nervous system data. Results of these investigations indicate that adjustment to weightlessness can be satisfactorily assisted by appropriate countermeasures including attention to diet. PMID:12001951

Berry, C A



Effect of Load Levels of Subject Loading Device on Gait, Ground Reaction Force, and Kinematics during Human Treadmill Locomotion in a Weightless Environment.  

National Technical Information Service (NTIS)

Prolonged exposure to weightlessness associated with spaceflight provokes profound physiological changes in humans. Two areas of significant concern are bone loss and neuromuscular deconditioning. Changes in lower-limb neuromuscular activation patterns ha...

G. Schaffner J. DeWitt J. Bentley E. Yarmanova I. Kozlovskaya G. Schaffner J. DeWitt J. Bentley E. Yarmanova I. Kozlovskaya D. Hagan



Acute hemodynamic responses to weightlessness in humans.  


As NASA designs space flights requiring prolonged periods of weightlessness for a broader segment of the population, it will be important to know the acute and sustained effects of weightlessness on the cardiovascular system since this information will contribute to understanding of the clinical pharmacology of drugs administered in space. Due to operational constraints on space flights, earliest effects of weightlessness have not been documented. We examined hemodynamic responses of humans to transitions from acceleration to weightlessness during parabolic flight on NASA's KC-135 aircraft. Impedance cardiography data were collected over four sets of 8-10 parabolas, with a brief rest period between sets. Each parabola included a period of 1.8 Gz, then approximately 20 seconds of weightlessness, and finally a period of 1.6 Gz; the cycle repeated almost immediately for the remainder of the set. Subjects were semi-supine (Shuttle launch posture) for the first set, then randomly supine, sitting and standing for each subsequent set. Transition to weightlessness while standing produced decreased heart rate, increased thoracic fluid content, and increased stroke index. Surprisingly, the onset of weightlessness in the semi-supine posture produced little evidence of a headward fluid shift. Heart rate, stroke index, and cardiac index are virtually unchanged after 20 seconds of weightlessness, and thoracic fluid content is slightly decreased. Semi-supine responses run counter to Shuttle crewmember reports of noticeable fluid shift after minutes to hours in orbit. Apparently, the headward fluid shift commences in the semi-supine posture before launch. is augmented by launch acceleration, but briefly interrupted immediately in orbit, then resumes and is completed over the next hours. PMID:2760255

Lathers, C M; Charles, J B; Elton, K F; Holt, T A; Mukai, C; Bennett, B S; Bungo, M W



Weightlessness experiments on Biosatellite II.  


Four experiments in the aft compartment of Biosatellite II investigated the broad question of the effect of nearly zero gravity on the development, morphology and metabolism of plants and animals. The fertilization and development of the egg of a vertebrate (the frog, Rana pipiens), the feeding and growth of a protozoan (the giant amoeba, Pelomyxa carolinensis), the orientation of leaves and petioles of a young dicotyledon (pepper plants, Capsicum annuum) and the morphogenesis, orientation, histochemistry and biochemistry of a monocotyledon seedling (wheat, Triticum vulgare) gave a broad scope. All are known to have specific responses to normal gravity and changes in them might be expected to reflect the effects of orbital flight on living organisms. No differences in development of the frog eggs could be detected. Unfortunately, the 3 1/2 hour delay in launch allowed the first cleavage (the stage most sensitive to inversion) to appear before launch. Although the orbited embryos were somewhat slower to reach certain stages of development, recovered embryos developed just as did the controls. The amoebae fed normally while in orbit, and specimens fixed in orbit retained the ordinary heteropodal shape. Growth rates of orbited amoebae, both fed and starved, were slower than controls following reentry and recovery procedures. In continuous-fed organisms there was little or no effect of flight detectable in growth rate or actual number of divisions. Electron micrographs showed no abnormalities and few differences between flight and control organisms. The pepper plants were photographed in orbit at ten-minute intervals, as were the clinostat and erect controls. The subsequent measurement of photographs showed that in the orbited plants all leaves showed epinasty, the interaxial angle decreasing by 20-60 degrees C. Plants on the horizontal clinostat behaved comparably, but recovered more rapidly than orbited plants when returned to the normal erect position. Although the maximum age of wheat seedlings was only 65 hours, coleoptile and root growth rates during that time had not been significantly altered by flight or by slow rotation on a horizontal clinostat. There was some evidence that growth was accelerated after normal gravity was restored. The orientation of coleoptiles and of primary and lateral roots of orbited plants varied significantly from the normal erect seedlings but was almost identical with that of clinostat plants. The Periodic-Acid-Schiff technique on sectioned material showed starch grains at the bottom of cells of erect control coleoptile and root tips, while in orbited and clinostated plants the grains were located more or less at random. Histochemical differences between clinostat and orbited tissues are apparent however. Peroxidase localization varied and its activity was higher in both clinostat and orbited tissues; five other enzymes studied biochemically showed no differences. These experiments all suggest that there is no deleterious effect on living organisms or their activities from short-term weightlessness. Several results indicate that the horizontal clinostat may simulate the weightless state effectively here on Earth. PMID:11949691

Edwards, B F



Demonstration of Electrostatic Orbits in Weightlessness  

NASA Astrophysics Data System (ADS)

In August 2006, a team of students from Rhodes College performed an experiment in microgravity aboard NASA’s specialized C-9B aircraft known as the “Weightless Wonder.” The goal of the experiment was to establish an orbit between two electrically charged spheres. The similar forms of Newton’s Law of Gravitation and Coulomb’s Law suggest that such electrostatic orbits are possible. However, to our knowledge, an electrostatic orbit has not previously been demonstrated. This presentation will describe our experiment and show video footage of the electrostatic orbits that we achieved in weightlessness. Professor Brent Hoffmeister is the AAPT sponsor.

Janeski, John; Andring, K.; Banerjee, S.; Campbell, D.; Keedy, D.; Hoffmeister, B.; Quinn, S.



Embryonic Development of Guppy in Weightlessness.  

National Technical Information Service (NTIS)

The program of the Cosmos-1514 flight included an experiment, the purpose of which was to study the effect of weightlessness on the embryonic development of the live-bearing guppy: three pregnant females were flown for 5 days. Prelaunch their embryos were...

Y. M. Cherdantseva



Adaptation of postural control to weightlessness  

Microsoft Academic Search

Adaptation of motor control to weightlessness was studied during a 7-day spaceflight. The maintenance of control of upright posture was examined during a voluntary raising movement of the arm and during the voluntary raising on tiptoe. In order to evaluate the contribution of visual cues, three types of visual situations were examined: normal vision, central vision, and without vision. On

G. Clément; V. S. Gurfinkel; F. Lestienne; M. I. Lipshits; K. E. Popov



How are osteoclasts induced to resorb bone?  


Although much is known about how osteoclasts are formed, we know little about how they are activated, or how they recognize bone as the substrate appropriate for resorption. Bone mineral is considered to be essential to this recognition process, but a "mineral receptor" has never been identified. Recently, we found that resorptive behavior, as judged by the formation of ruffled borders and actin rings, occurs on ordinary tissue culture substrates if they are first coated with vitronectin. Similarly, vitronectin-coated substrates induce osteoclasts to secrete tartrate-resistant acid phosphatase and to form podosome belts, and to make resorption trails in the protein that coat the substrate. The same applies to bone mineral, which only induces resorptive behavior if coated with vitronectin. In contrast, fibronectin has none of these effects, despite inducing adhesion and spreading. It appears that osteoclasts recognize bone as the substrate appropriate for resorption through the high affinity of vitronectin-receptor ligands for bone mineral. PMID:22172032

Chambers, T J; Fuller, K



Bisphosphonates in phenytoin-induced bone disorder  

Microsoft Academic Search

Chronic administration of phenytoin (PHT) has been associated with bone loss. Bisphosphonates [alendronate (ALD), ibandronate (IBD) and risedronate (RSD)] are potential candidates to prevent PHT-induced bone disorders, and the present study evaluated their effect on the antiepileptic efficacy of PHT. The PHT-induced depletion in folic acid (FA), vitamin B6 and vitamin B12 results in hyperhomocysteinemia. The elevated circulating homocysteine (hcy)

Suruchi Khanna; Krishna K. Pillai; Divya Vohora



Weightlessness and the developing frog egg.  


This paper describes the results of the flight of fertilized frog eggs in the manned orbital flights Gemini 8 and Gemini 12. The experiment was designed to determine the effect of weightlessness or near weightlessness on the ability of the cell to divide normally and on subsequent differentiation and embryogenesis. Eggs were fixed periodically in flight so that recovered material could be carefully compared to simultaneous ground controls with respect to gross morphology and histology. Some embryos were recovered alive after 4 days in orbit. In general, no abnormalities were detected which were inconsistent with the controls. Death, shortly after recovery, of the embryos recovered alive in Gemini 12, remains unexplained. The protocol of the experiment and the experimental hardware is described. Rationale for future experiments is discussed. PMID:11982030

Young, R S; Tremor, J W



Inducible nitric oxide synthase mediates bone development and P. gingivalis-induced alveolar bone loss  

Microsoft Academic Search

The role of inducible nitric oxide synthase (iNOS) in bone development and bacterially induced periodontal bone loss was examined using mice with targeted mutation of the iNOS gene. Femurs of iNOS KO mice showed 30% and 9% higher bone mineral density compared to wild type (WT) at 4 and 9 weeks of age, respectively. Micro-computed tomography revealed that cortical thickness

R. Gyurko; H. Shoji; R. A. Battaglino; G. Boustany; F. C. Gibson; C. A. Genco; P. Stashenko; T. E. Van Dyke



Bone healing induced by ESWT  

PubMed Central

It has been at least two decades since the introduction of Extracorporeal Shock-Wave Treatment (ESWT) for the treatment of non-unions; despite conflicting opinions in the literature, it is recently achieving good results also in acute fractures. This paper reports Authors’ clinical experience with electromagnetic shock-waves in the treatment of delayed unions and fresh fractures. Nonunion cases experienced remarkable successful results at an average of 8-10 weeks after ESWT; high success rate is been also found for the acute fractures. It can be concluded that this therapy constitutes an important aid in treatment of non-unions and can be useful also in fresh bone fractures.

Moretti, Biagio; Notarnicola, Angela; Moretti, Lorenzo; Patella, Silvio; Tato, Ilaria; Patella, Vittorio



Glucocorticoid-induced bone loss in children  

Microsoft Academic Search

This article defines what is meant by glucocorticoid-induced bone loss (GIBL) in children, as opposed to glucocorticoid-induced\\u000a osteoporosis. G1BL is found in various conditions, including therapy of chronic inflammatory states, antenatal and postnatal\\u000a glucocorticoid administration to reduce respiratory distress syndrome risk, pre- and postorgram transplantation, and in certain\\u000a malignancies. The prevalence of G1BL has not been determined for all conditions,

Gordon L. Klein



Islet in weightlessness: biological experiments on board COSMOS 1129 satellite  

SciTech Connect

Biological experiments planned as an international venture for COSMOS 1129 satellite include tests of: (1) adaptation of rats to conditions of weightlessness, and readaption to Earth's gravity, (2) possibility of fertilization and embryonic development in weightlessness, (3) heat exchange processes, (4) amount of gravity force preferred by fruit flies for laying eggs (given a choice of three centrifugal zones), (5) growth of higher plants from seeds, (6) effects of weightlessness on cells in culture, and (7) radiation danger from heavy nuclei, and electrostatic protection from charged particles.

Zhuk, Y.



Axial Jet Mixing of Ethanol in Spherical Containers During Weightlessness.  

National Technical Information Service (NTIS)

An experimental program was conducted to examine the liquid flow patterns that result from the axial jet mixing of ethanol in 10-centimeter-diameter spherical containers in weightlessness. Complete liquid circulation flow patterns were easily established ...

J. C. Audelott



The importance of weightlessness and tides in teaching gravitation  

NASA Astrophysics Data System (ADS)

We examine the presentation of the weight, weightlessness, and tides in university-level physics textbooks. Introductory textbooks often do not discuss tidal forces even though their understanding would be useful for understanding weightlessness. The explanations of tides often miss the free gravitational motion of both interacting objects, which is essential for the symmetry of tidal deformation. The shortcomings in the explanations of weightlessness and tides as provided by students and teachers are compared to textbook discussions. We suggest that an explicit discussion of the different definitions of weight and a synergetic presentation of weightlessness and tides might lead to a better understanding of gravitation. Our approach is illustrated by examples of tidal effects appropriate for introductory courses.

Galili, I.; Lehavi, Y.



Unique Problem of Muscle Adaptation from Weightlessness: The Deceleration Deficiency.  

National Technical Information Service (NTIS)

Decelerator problems of the knee are emphasized since the lower leg musculature is known to atrophy in response to weightlessness. However, other important decelerator functions are served by the shoulder muscles, in particular the rotator cuff muscles. P...

W. T. Stauber



Mechanisms of Radiation-Induced Bone Loss and Effect on Prostate Cancer Bone Metastases.  

National Technical Information Service (NTIS)

Patients with tumors in the pelvic region frequently receive radiation therapy, and as a result, bystander bone may experience adverse effects. Earlier reports demonstrated that radiation-induced bone loss occurs via increased osteoclast activation in a m...

H. S. Kim



Biomedical research on the International Space Station postural and manipulation problems of the human upper limb in weightlessness  

NASA Astrophysics Data System (ADS)

Accumulated evidence, based on information gathered on space flight missions and ground based models involving both humans and animals, clearly suggests that exposure to states of microgravity conditions for varying duration induces certain physiological changes; they involve cardiovascular deconditioning, balance disorders, bone weakening, muscle hypertrophy, disturbed sleep patterns and depressed immune responses. The effects of the microgravity on the astronauts' movement and attitude have been studied during different space missions, increasing the knowledge of the human physiology in weightlessness. The purpose of the research addressed in the present paper is to understand and to assess the performances of the upper limb, especially during grasp. Objects of the research are the physiological changes related to the long-term duration spaceflight environment. Specifically, the changes concerning the upper limb are investigated, with particular regard to the performances of the hand in zero-g environments. This research presents also effects on the Earth, improving the studies on a number of pathological states, on the health care and the rehabilitation. In this perspective, a set of experiments are proposed, aimed at the evaluation of the effects of the zero-g environments on neurophysiology of grasping movements, fatigue assessment, precision grip. .

Neri, Gianluca; Zolesi, Valfredo



Crucial effects of weightlessness on human orientation.  


This contribution examines the consequences of two remarkable experiences of subjects in weightlessness, 1) the missing of sensations of trunk tilt and of the respective concomitant reflexes when the head is tilted with respect to the trunk, and 2) the persistence of a perception of "up" and "down," that is, of the polarity of the subjective vertical (SV) in the absence of, as well as in contradiction to, visual cues. The first disproves that the necessary head-to-trunk coordinate transformation be achieved by adding representations of the respective angles gained by utricles and neck receptors, but corroborates an extant model of cross-multiplication of utricular, saccular, and neck receptor components. The second indicates the existence of force-independent components in the determination of the SV. Although the number of subjects is still small and experimental conditions are not as homogeneous as desired, measurements and/or reports on the ground, in parabolic, and in space flight point to the decisive role of the saccular z-bias, that is, of a difference of the mean resting discharges of saccular units polarized in the rostrad and the caudad (+/- z-) direction. PMID:8275265

Mittelstaedt, H; Glasauer, S



Radiation-induced osteosarcoma of the sphenoid bone  

SciTech Connect

The case of a patient who developed osteosarcoma in the sphenoid bone 15 years after radiation therapy for a craniopharyngioma is reported. Radiation-induced osteosarcoma of the sphenoid bone has not been reported previously. Reported cases of radiation-induced osteosarcomas are reviewed.

Tanaka, S.; Nishio, S.; Morioka, T.; Fukui, M.; Kitamura, K.; Hikita, K. (Kyushui Univ., Fukuoka (Japan))



Axial jet mixing of ethanol in spherical containers during weightlessness  

Microsoft Academic Search

An experimental program was conducted to examine the liquid flow patterns that result from the axial jet mixing of ethanol in 10-centimeter-diameter spherical containers in weightlessness. Complete liquid circulation flow patterns were easily established in containers that were less than half full of liquid, while for higher liquid fill conditions, vapor was drawn into the inlet of the simulated mixer

J. C. Audelott



Study Of Water Hammer Effect On Weightlessness Condition  

NASA Astrophysics Data System (ADS)

Research on fluid mechanics phenomenon called Water hammer Effect in microgravity conditions, making a comparison between several flow rates. To show how critical is in this environment and to establish a baseline of hardness in weightlessness trying to be a kick-off point in space engineering pipes development.

Elvira, R.; Monzón, A.; Riesgo, I.; Fernández-Cabrera, J.



Weightlessness - a model to understand how gravity modulates cardiovascular function  

Microsoft Academic Search

Gravity stresses the cardiovascular system in humans by decreasing the blood supply to the heart. As a consequence of this, reflexes are constantly activated to increase heart rate, constrict the blood vessels and diminish the renal output of fluid. To explore how gravity modulates cardiovascular function, longterm weightlessness in space is a useful tool. Therefore, we have participated in space

Peter Norsk


The Problem of Equilibrium in the Weightless State.  

National Technical Information Service (NTIS)

The effect of weightlessness on the functioning of the vestibular apparatus of the inner ear is studied. It is shown that the absence of gravity, particularly in combination with other accelerations, can lead to a number of physical and psychological dist...

M. Simonovic J. Simonovic



Interpretation of students' understanding of the concept of weightlessness  

NSDL National Science Digital Library

Investigated students' understanding of the concept of weightlessness and found it to be influenced by the confusion between the concepts of weight and gravitational force. The causal structure of students' knowledge presents a platform for interpreting students' alternative ideas about weight and related physical concepts, which could guide physics educators in presenting weight and gravity topics. (49 references)

Galili, Igal



Mechanical stretch induced calcium efflux from bone matrix stimulates osteoblasts.  


The mechanisms by which bone cells sense critically loaded regions of bone are still a matter of ongoing debate. Animal models to investigate response to microdamage involve post mortem immunohistological analysis and do not allow real-time monitoring of cellular response during the emergence of the damage in bone. Most in vitro mechanical stimulation studies are conducted on non-bone substrates, neglecting the damage-related alterations in the pericellular niche and their potential effects on bone cells. The current study reports spontaneous efflux of calcium ions (Ca(2+)) (1.924±0.742 pmol cm(-2)s(-1)) from regions of devitalized bone matrix undergoing post-yield strains, induced by a stress concentrator. When these samples are seeded with MC3T3-E1 osteoblasts, the strain-induced Ca(2+) efflux from bone elicits cell response at the stress concentration site as manifested by activation of intracellular calcium signaling (increase in fluorescence by 52%±27%). This activity is associated with extracellular calcium because the intracellular calcium signaling in response to mechanical loading subsides when experiments are repeated using demineralized bone substrates (increase in fluorescence by 6%±10%). These results imply a novel perspective where bone matrix acts as an intermediary mechanochemical transducer by converting mechanical strain into a chemical signal (pericellular calcium) to which cells respond. Such a mechanism may be responsible for triggering repair at locations of bone matrix undergoing critical deformation levels. PMID:22227434

Sun, Xuanhao; McLamore, Eric; Kishore, Vipuil; Fites, Kateri; Slipchenko, Mikhail; Porterfield, D Marshall; Akkus, Ozan



Nell-1-induced bone regeneration in calvarial defects.  


Many craniofacial birth defects contain skeletal components requiring bone grafting. We previously identified the novel secreted osteogenic molecule NELL-1, first noted to be overexpressed during premature bone formation in calvarial sutures of craniosynostosis patients. Nell-1 overexpression significantly increases differentiation and mineralization selectively in osteoblasts, while newborn Nell-1 transgenic mice significantly increase premature bone formation in calvarial sutures. In the current study, cultured calvarial explants isolated from Nell-1 transgenic newborn mice (with mild sagittal synostosis) demonstrated continuous bone growth and overlapping sagittal sutures. Further investigation into gene expression cascades revealed that fibroblast growth factor-2 and transforming growth factor-beta1 stimulated Nell-1 expression, whereas bone morphogenetic protein (BMP)-2 had no direct effect. Additionally, Nell-1-induced osteogenesis in MC3T3-E1 osteoblasts through reduction in the expression of early up-regulated osteogenic regulators (OSX and ALP) but induction of later markers (OPN and OCN). Grafting Nell-1 protein-coated PLGA scaffolds into rat calvarial defects revealed the osteogenic potential of Nell-1 to induce bone regeneration equivalent to BMP-2, whereas immunohistochemistry indicated that Nell-1 reduced osterix-producing cells and increased bone sialoprotein, osteocalcin, and BMP-7 expression. Insights into Nell-1-regulated osteogenesis coupled with its ability to stimulate bone regeneration revealed a potential therapeutic role and an alternative to the currently accepted techniques for bone regeneration. PMID:16936265

Aghaloo, Tara; Cowan, Catherine M; Chou, Yu-Fen; Zhang, Xinli; Lee, Haofu; Miao, Steve; Hong, Nichole; Kuroda, Shun'ichi; Wu, Benjamin; Ting, Kang; Soo, Chia



Pathobiology and prevention of cancer chemotherapy-induced bone growth arrest, bone loss, and osteonecrosis.  


Cancer chemotherapy has been recognized as one severe risk factor that influences bone growth and bone mass accumulation during childhood and adolescence. This article reviews on the importance of this clinical issue, current understanding of the underlying mechanisms for the skeletal defects and potential preventative strategies. Both clinical and basic studies that appeared from 1990 to 2010 were reviewed for bone defects (growth arrest, bone loss, osteonecrosis, and/or fractures) caused by paediatric cancer chemotherapy. As chemotherapy has become more intensive and achieved greater success in treating paediatric malignancies, skeletal complications such as bone growth arrest, low bone mass, osteonecrosis, and fractures during and/or after chemotherapy have become a problem for some cancer patients and survivors particularly those that have received high dose glucocorticoids and methotrexate. While chemotherapy-induced skeletal defects are likely multi-factorial, recent studies suggest that different chemotherapeutic agents can directly impair the activity of the growth plate and metaphysis (the two major components of the bone growth unit) through different mechanisms, and can alter bone modeling/remodeling processes via their actions on bone formation cells (osteoblasts), bone resorption cells (osteoclasts) and bone "maintenance" cells (osteocytes). Intensive use of multi-agent chemotherapy can cause growth arrest, low bone mass, fractures, and/or osteonecrosis in some paediatric patients. While there are currently no specific strategies for protecting bone growth during childhood cancer chemotherapy, regular BMD monitoring and exercise are have been recommended, and possible adjuvant treatments could include calcium/vitamin D, antioxidants, bisphosphonates, resveratrol, and/or folinic acid. PMID:21342129

Fan, C; Foster, B K; Wallace, W H; Xian, C J



Effects of Inactivity and Exercise on Bone.  

ERIC Educational Resources Information Center

|Research has shown that bone tissue responds to the forces of gravity and muscle contraction. The benefits of weight-bearing exercise in preventing or reversing bone mass loss related to osteoporosis is reviewed. The effects of weightlessness and immobilization, and the possible effects of athletic amenorrhea, on bone mineral density are…

Smith, Everett L.; Gilligan, Catherine



Effects of Inactivity and Exercise on Bone.  

ERIC Educational Resources Information Center

Research has shown that bone tissue responds to the forces of gravity and muscle contraction. The benefits of weight-bearing exercise in preventing or reversing bone mass loss related to osteoporosis is reviewed. The effects of weightlessness and immobilization, and the possible effects of athletic amenorrhea, on bone mineral density are…

Smith, Everett L.; Gilligan, Catherine



Nck1 deficiency accelerates unloading-induced bone loss.  


Mechanical stress is an important signal to determine the levels of bone mass. Unloading-induced osteoporosis is a critical issue in bed-ridden patients and astronauts. Many molecules have been suggested to be involved in sensing mechanical stress in bone, though the mechanisms involved in this phenomenon are not fully understood. Nck1 is an adaptor protein known to mediate signaling from plasma membrane-activated receptors to cytosolic effectors regulating actin cytoskeleton remodeling. Nck1 has also been implicated in cellular responses to endoplasmic reticulum stress. In vitro, in case of cell stress the actin cytoskeleton is disrupted and in such cases Nck1 has been reported to enter the nucleus of the cells to mediate the nuclear actin polymerization. However, the role of Nck1 in vivo during the bone response to mechanical stimuli is unknown. The purpose of this study is to examine the role of Nck1 in unloading-induced bone loss in vivo. Sciatic and femoral nerve resection was conducted. Neurectomy-based unloading enhanced Nck1 gene expression in bone about twofold. Using the Nck1 deficient mice and control Nck1+/+, effects of neurectomy-based unloading on bone structure were examined. Unloading reduced bone volume in wild type mice by 30% whereas the levels in bone loss were exacerbated to 50% in Nck1 deficient mice due to neurectomy after 4 weeks. These data demonstrate that Nck1 gene deficiency accelerates the mechanical unloading-induced bone loss suggesting Nck1 to be a crucial molecule in mechanical stress mediated regulation in bone metabolism. PMID:23280595

Aryal, A C Smriti; Miyai, Kentaro; Hayata, Tadayoshi; Notomi, Takuya; Nakamoto, Tetsuya; Pawson, Tony; Ezura, Yoichi; Noda, Masaki



Potent Ectopic Bone-Inducing Activity of Bone Morphogenetic Protein4\\/7 Heterodimer  

Microsoft Academic Search

We have purified and characterized recombinant Xenopus bone morphogenetic proteins (xBMPs): homodimers of xBMP-4, 7 and heterodimers (xBMP-4\\/7) produced by a baculovirus expression system. Highly purified xBMPs had homogeneous NH2-termini predicted from a consensus motif, Arg-X-X-Arg, while they possessed diverse sugar chains. Implantation of xBMPs together with pure collagen carrier in rats induced new bone formation in a dose-dependent manner.

A. Aono; M. Hazama; K. Notoya; S. Taketomi; H. Yamasaki; R. Tsukuda; S. Sasaki; Y. Fujisawa



Effects of mental stress on autonomic cardiac modulation during weightlessness.  


Sustained weightlessness affects all body functions, among these also cardiac autonomic control mechanisms. How this may influence neural response to central stimulation by a mental arithmetic task remains an open question. The hypothesis was tested that microgravity alters cardiovascular neural response to standardized cognitive load stimuli. Beat-to-beat heart rate, brachial blood pressure, and respiratory frequency were collected in five astronauts, taking part in three different short-duration (10 to 11 days) space missions to the International Space Station. Data recording was performed in supine position 1 mo before launch; at days 5 or 8 in space; and on days 1, 4, and 25 after landing. Heart rate variability (HRV) parameters were obtained in the frequency domain. Measurements were performed in the control condition for 10 min and during a 5-min mental arithmetic stress task, consisting of deducting 17 from a four-digit number, read by a colleague, and orally announcing the result. Our results show that over all sessions (pre-, in-, and postflight), mental stress induced an average increase in mean heart rate (Delta7 +/- 1 beats/min; P = 0.03) and mean arterial pressure (Delta7 +/- 1 mmHg; P = 0.006). A sympathetic excitation during mental stress was shown from HRV parameters: increase of low frequency expressed in normalized units (Delta8.3 +/- 1.4; P = 0.004) and low frequency/high frequency (Delta1.6 +/- 0.3; P = 0.001) and decrease of high frequency expressed in normalized units (Delta8.9 +/- 1.4; P = 0.004). The total power was not influenced by mental stress. No effect of spaceflight was found on baseline heart rate, mean arterial pressure, and HRV parameters. No differences in response to mental stress were found between pre-, in-, and postflight. Our findings confirm that a mental arithmetic task in astronauts elicits sympathovagal shifts toward enhanced sympathetic modulation and reduced vagal modulation. However, these responses are not changed in space during microgravity or after spaceflight. PMID:19897707

Aubert, André E; Verheyden, Bart; d'Ydewalle, Constantin; Beckers, Frank; Van den Bergh, Omer



Inducible Nitric Oxide Synthase Mediates Bone Loss in Ovariectomized Mice  

Microsoft Academic Search

Several clinical studies have shown that bone loss may be attributed to osteoclast recruitment induced by mediators of inflammation. In different experimental paradigms we have recently demonstrated that estrogen exhibits antiinflamma- tory activity by preventing the induction of inducible nitric oxide synthase (iNOS) and other components of the inflam- matory reaction. To verify whether this could explain the estrogen-dependent blockade




Bone formation induced by BMP-2 in human osteosarcoma cells.  


Our previous studies demonstrated that BMP-2 inhibits the tumorigenicity of cancer stem cells identified as cells with high aldehyde dehydrogenase activity (ALDH(br) cells) from the human osteosarcoma cell line OS99-1. We further investigated whether BMP-2 is capable of inducing bone formation in OS99-1 cells. Flow cytometry sorting was used to isolate tumorigenic ALDH(br) and non-tumorigenic ALDH(lo) cells. qRT-PCR was used to quantify the gene expression. A xenograft model was used to verify the bone formation in vivo. There was significantly higher mRNA expression of BMPR1B and BMPR2 in ALDH(lo) cells compared with that in ALDH(br) cells and the BMPR1B expression in ALDH(lo) cells was ~8-fold higher compared to that in ALDHbr cells. BMP-2 was also found to induce higher transcription of osteogenic markers Runx-2, Osterix (Osx), alkaline phosphatase (ALP) and collagen type I in ALDH(lo) cells compared to ALDH(br) cells, which were mediated by the canonical Smad signaling pathway. In vivo, BMP-2 was identified to induce bone formation in both ALDH(br) and ALDH(lo) cells. All animals receiving 1 x 10()4 ALDH(lo) cells treated with 30 µg of BMP-2 per animal showed bone formation within 1-2 weeks after injection in mice. Bone formation induced by BMP-2 in ALDH(lo) cells showed significantly more bone mineral content compared to that in ALDH(br) cells. BMP-2 induces bone formation in heterogeneous osteosarcoma cells and BMP-2 may have a promising therapeutic role for treating human osteosarcoma by inducing differentiation along an osteogenic pathway. PMID:23900689

Wang, Lin; Park, Paul; La Marca, Frank; Than, Khoi; Rahman, Shayan; Lin, Chia-Ying



Engineering bone tissue substitutes from human induced pluripotent stem cells.  


Congenital defects, trauma, and disease can compromise the integrity and functionality of the skeletal system to the extent requiring implantation of bone grafts. Engineering of viable bone substitutes that can be personalized to meet specific clinical needs represents a promising therapeutic alternative. The aim of our study was to evaluate the utility of human-induced pluripotent stem cells (hiPSCs) for bone tissue engineering. We first induced three hiPSC lines with different tissue and reprogramming backgrounds into the mesenchymal lineages and used a combination of differentiation assays, surface antigen profiling, and global gene expression analysis to identify the lines exhibiting strong osteogenic differentiation potential. We then engineered functional bone substitutes by culturing hiPSC-derived mesenchymal progenitors on osteoconductive scaffolds in perfusion bioreactors and confirmed their phenotype stability in a subcutaneous implantation model for 12 wk. Molecular analysis confirmed that the maturation of bone substitutes in perfusion bioreactors results in global repression of cell proliferation and an increased expression of lineage-specific genes. These results pave the way for growing patient-specific bone substitutes for reconstructive treatments of the skeletal system and for constructing qualified experimental models of development and disease. PMID:23653480

de Peppo, Giuseppe Maria; Marcos-Campos, Iván; Kahler, David John; Alsalman, Dana; Shang, Linshan; Vunjak-Novakovic, Gordana; Marolt, Darja



General remarks on the role of the vestibular system in weightlessness  

Microsoft Academic Search

Different methods are described to experimentally achieve weightlessness. Since the function of the otolith system depends on the presence of contact forces opposing gravity, it is disabled in weightlessness and may send misleading positional information to the brain. Without the contributions of the otolith system it is difficult in space to distinguish self-motion from object motion. Furthermore, the disintegration of

R. J. von Baumgarten



The Simulation of Weightlessness Using Water Immersion Techniques: An Annotated Bibliography  

Microsoft Academic Search

This bibliography contains 283 selected references pertaining to behavioral and biomedical research using water immersion techniques. References are organized under three topics: (I) physiological responses to weightlessness, (II) human performance under weightless conditions, and (III) simulation techniques, equipment, and facilities. A brief overview of each topic is presented, and the contents are selectively annotated.

John H. Duddy



Effect of 5E Teaching Model on Student Teachers' Understanding of Weightlessness  

ERIC Educational Resources Information Center

Weight is one of the basic concepts of physics. Its gravitational definition accommodates difficulties for students to understand the state of weightlessness. The aim of this study is to investigate the effect of materials based on 5E teaching model and related to weightlessness on science student teachers' learning. The sample of the study was 9…

Tural, Guner; Akdeniz, Ali Riza; Alev, Nedim



Maximal Oxygen Consumption and the Functional State of the Circulatory System Following Simulated Weightlessness.  

National Technical Information Service (NTIS)

The effects of simulated weightlessness on oxygen consumption and the functional state of the cardiovascular system were studied in four healthy male subjects aged 22-25 yrs. Weightlessness was simulated by 20 days of rigorous bed rest (the horizontal pos...

V. S. Georgievskii L. I. Kakurin B. S. Katkovskii Y. A. Senkevich



Induced membrane technique for reconstruction to manage bone loss.  


Multiple surgeries are often required to manage segmental bone loss because of the complex mechanics and biology involved in reconstruction. These procedures can lead to prolonged recovery times, poor patient outcomes, and even delayed amputation. A two-stage technique uses induced biologic membranes with delayed placement of bone graft to manage this clinical challenge. In the first stage, a polymethyl methacrylate spacer is placed in the defect to produce a bioactive membrane, which appears to mature biochemically and physically 4 to 8 weeks after spacer placement. In the second, cancellous autograft is placed within this membrane and, via elution of several growth factors, the membrane appears to prevent graft resorption and promote revascularization and consolidation of new bone. Excellent clinical results have been reported, with successful reconstruction of segmental bone defects >20 cm. PMID:22382286

Taylor, Benjamin C; French, Bruce G; Fowler, T Ty; Russell, Jeremy; Poka, Attila



Treatment of Streptozotocin-Induced Diabetes Mellitus in Mice by Intra-Bone Marrow Bone Marrow Transplantation plus Portal Vein Injection of ? Cells Induced from Bone Marrow Cells  

Microsoft Academic Search

Curative therapy for diabetes mellitus mainly involves pancreas or islet transplantation to recruit insulin-producing cells. This approach is limited, however, because of both the shortage of donor organs and allograft rejection. Intra-bone marrow bone marrow transplantation (IBM-BMT) has recently been shown to be effective in inducing donor-specific tolerance in mice and rats without the use of immunosuppressants. After induction of

M. Li; M. Inaba; K. Q. Guo; H. Hisha; N. G. Abraham; S. Ikehara



Periosteal response in translation-induced bone remodelling.  

PubMed Central

Translation of transplanted bones induces strain in the periosteum and subsequent bone remodelling. This study examines the periosteal response on the leading and trailing sides of translated bones using an in vivo model where internal bone strain is virtually eliminated. Caudal vertebrae from 4 days old rats were threaded onto the arms of pre-stressed helical torsion springs and transplanted subcutaneously. In the experimental rats, the appliances were activated seven days later causing the bones to translate. Tissues were examined both optically and by transmission electron microscopy. A connective tissue sheath or capsule forms around the bones and, as the arms of the appliance move apart, traction on the enveloping soft tissues produces compression of the periosteum on the leading side and tension on the trailing side with remodelling occurring in a direction opposite to translation. The control periosteum has an ordered structure with well-delineated osteogenic, mid- and fibrous zones. During translation the periosteum on the leading side is consistently narrower than on the trailing side and shows a gradual reduction in formative activity followed by resorption in select areas. Cells and fibres are aligned predominantly parallel to the bone surface. Accelerated formation characterises the trailing side during the translation phase with increased activity and widening of all three periosteal layers. The fibrous layer merges with the connective tissue sheath which frequently is oriented approximately perpendicular to the bone surface. The direction of remodelling is reversed when translation ceases with corresponding changes visible in the periosteum, the osteoblastic layer being the last to show changes. A normal periosteal structure and remodelling pattern is regained when equilibrium of the bones within the soft tissues is attained. This study shows that the enveloping soft tissues profoundly influence the nature and rate of bone remodelling. The changes are reflected in the periosteum which functions as an integrated unit modulating the signal transmitted to the osteoblasts which play a key role in events occurring at the bone surface. Changes are not attributable to internal bone strain. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13

Feik, S A; Ellender, G; Crowe, D M; Ramm-Anderson, S M



Porphyromonas gingivalis infection-induced tissue and bone transcriptional profiles.  


Porphyromonas gingivalis has been associated with subgingival biofilms in adult periodontitis. However, the molecular mechanisms of its contribution to chronic gingival inflammation and loss of periodontal structural integrity remain unclear. This investigation aimed to examine changes in the host transcriptional profiles during a P. gingivalis infection using a murine calvarial model of inflammation and bone resorption. P. gingivalis FDC 381 was injected into the subcutaneous soft tissue over the calvaria of BALB/c mice for 3 days, after which the soft tissues and calvarial bones were excised. RNA was isolated from infected soft tissues and calvarial bones and was analysed for transcript profiles using Murine GeneChip((R)) arrays to provide a molecular profile of the events that occur following infection of these tissues. After P. gingivalis infection, 6452 and 2341 probe sets in the infected soft tissues and calvarial bone, respectively, were differentially expressed (P bone included cell adhesion (immune system) molecules, Toll-like receptors, B-cell receptor signaling, transforming growth factor-beta cytokine family receptor signaling, and major histocompatibility complex class II antigen processing pathways resulting in proinflammatory, chemotactic effects, T-cell stimulation, and downregulation of antiviral and T-cell chemotactic effects. P. gingivalis-induced inflammation activated osteoclasts, leading to local bone resorption. This is the first in vivo evidence that localized P. gingivalis infection differentially induces transcription of a broad array of host genes, the profiles of which differed between inflamed soft tissues and calvarial bone. PMID:20331794

Meka, A; Bakthavatchalu, V; Sathishkumar, S; Lopez, M C; Verma, R K; Wallet, S M; Bhattacharyya, I; Boyce, B F; Handfield, M; Lamont, R J; Baker, H V; Ebersole, J L; Kesavalu, L



Expression of bone matrix proteins during dexamethasone-induced mineralization of human bone marrow stromal cells.  


Glucocorticoids have been shown to induce the differentiation of bone marrow stromal osteoprogenitor cells into osteoblasts and the mineralization of the matrix. Since the expression of bone matrix proteins is closely related to the differentiation status of osteoblasts and because matrix proteins may play important roles in the mineralization process, we investigated the effects of dexamethasone (Dex) on the expression of bone matrix proteins in cultured normal human bone marrow stromal cells (HBMSC). Treatment of HBMSC with Dex for 23 days resulted in a significant increase in alkaline phosphatase activity with maximum values attained on day 20 at which time the cell matrix was mineralized. Northern blot analysis revealed an increase in the steady-state mRNA level of alkaline phosphatase over 4 weeks of Dex exposure period. The observed increase in the alkaline phosphatase mRNA was effective at a Dex concentration as low as 10(-10) M with maximum values achieved at 10(-8)M. In contrast, Dex decreased the steady-state mRNA levels of both bone sialoprotein (BSP) and osteopontin (OPN) over a 4 week observation period when compared to the corresponding control values. The relative BSP and OPN mRNA levels among the Dex treated cultures, however, showed a steady increase after more than 1 week exposure. The expression of osteocalcin mRNA which was decreased after 1 day Dex exposure was undetectable 4 days later. Neither control nor Dex-treated HBMSC secreted osteocalcin into the conditioned media in the absence of 1 ,25(OH)(2)D(3) during a 25-day observation period. The accumulated data indicate that Dex has profound and varied effects on the expression of matrix proteins produced by human bone marrow stromal cells. With the induced increment in alkaline phosphatase correlating with the mineralization effects of Dex, the observed concomitant decrease in osteopontin and bone sialoprotein mRNA levels and the associated decline of osteocalcin are consistent with the hypothesis that the regulation of the expression of these highly negatively charged proteins is essential in order to maximize the Dex-induced mineralization process conditioned by normal human bone marrow stromal osteoprogenitor cells. PMID:9173083

Cheng, S L; Zhang, S F; Avioli, L V



Glucocorticoid-Induced Avascular Bone Necrosis: Diagnosis and Management  

PubMed Central

Glucocorticoid use is one of the most important causes of avascular bone necrosis (AVN). The pathogenesis of glucocorticoid-induced AVN is not fully understood but postulated mechanisms include fat hypertrophy, fat emboli and intravascular coagulation that cause impedance of blood supply to the bones. Data regarding the relationship between AVN and dosage, route of administration and treatment duration of glucocorticoids are conflicting, with some studies demonstrating the cumulative dose of glucocorticoid being the most important determining factor. Early recognition of this complication is essential as the prognosis is affected by the stage of the disease. Currently, there is no consensus on whether universal screening of asymptomatic AVN should be performed for long-term glucocorticoid users. A high index of suspicion should be exhibited for bone and joint pain at typical sites. Magnetic resonance imaging (MRI) or bone scintigraphy is more sensitive than plain radiograph for diagnosing early-stage AVN. Conservative management of AVN includes rest and reduction of weight bearing. Minimization of glucocorticoid dose or a complete withdrawal of the drug should be considered if the underlying conditions allow. The efficacy of bisphosphonates in reducing the rate of collapse of femoral head in AVN is controversial. Surgical therapy of AVN includes core decompression, osteotomy, bone grafting and joint replacement. Recent advances in the treatment of AVN include the use of tantalum rod and the development of more wear resistant bearing surface in hip arthroplasty.

Chan, KL; Mok, CC



Predicting Bone Mechanical State During Recovery After Long-Duration Skeletal Unloading Using QCT and Finite Element Modeling.  

National Technical Information Service (NTIS)

During long-duration missions at the International Space Station, astronauts experience weightlessness leading to skeletal unloading. Unloading causes a lack of a mechanical stimulus that triggers bone cellular units to remove mass from the skeleton. A ma...

J. A. Pennline K. L. Chang



Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration.  


Anticancer chemotherapy drugs challenge hematopoietic tissues to regenerate but commonly produce long-term sequelae. Chemotherapy-induced deficits in hematopoietic stem or stromal cell function have been described, but the mechanisms mediating hematopoietic dysfunction remain unclear. Administration of multiple cycles of cisplatin chemotherapy causes substantial sensory neuropathy. Here we demonstrate that chemotherapy-induced nerve injury in the bone marrow of mice is a crucial lesion impairing hematopoietic regeneration. Using pharmacological and genetic models, we show that the selective loss of adrenergic innervation in the bone marrow alters its regeneration after genotoxic insult. Sympathetic nerves in the marrow promote the survival of constituents of the stem cell niche that initiate recovery. Neuroprotection by deletion of Trp53 in sympathetic neurons or neuroregeneration by administration of 4-methylcatechol or glial-derived neurotrophic factor (GDNF) promotes hematopoietic recovery. These results demonstrate the potential benefit of adrenergic nerve protection for shielding hematopoietic niches from injury. PMID:23644514

Lucas, Daniel; Scheiermann, Christoph; Chow, Andrew; Kunisaki, Yuya; Bruns, Ingmar; Barrick, Colleen; Tessarollo, Lino; Frenette, Paul S



ACTH protects against glucocorticoid-induced osteonecrosis of bone.  


We report that adrenocorticotropic hormone (ACTH) protects against osteonecrosis of the femoral head induced by depot methylprednisolone acetate (depomedrol). This therapeutic response likely arises from enhanced osteoblastic support and the stimulation of VEGF by ACTH; the latter is largely responsible for maintaining the fine vascular network that surrounds highly remodeling bone. We suggest examining the efficacy of ACTH in preventing human osteonecrosis, a devastating complication of glucocorticoid therapy. PMID:20421485

Zaidi, Mone; Sun, Li; Robinson, Lisa J; Tourkova, Irina L; Liu, Li; Wang, Yujuan; Zhu, Ling-Ling; Liu, Xuan; Li, Jianhua; Peng, Yuanzhen; Yang, Guozhe; Shi, Xingming; Levine, Alice; Iqbal, Jameel; Yaroslavskiy, Beatrice B; Isales, Carlos; Blair, Harry C



Characterization of cancer-induced bone pain: an exploratory study  

Microsoft Academic Search

Purpose  Cancer-induced bone pain (CIBP) is the commonest cause of pain in patients with cancer. Its association with increased morbidity\\u000a combined with limitations of currently available therapies makes it a clinical challenge. Clinical characterization of this\\u000a complex pain syndrome is essential in underpinning clinical management and informing future research. The aim of this exploratory\\u000a study was to characterise CIBP using self-rating

Barry J. A. Laird; John Walley; Gordon D. Murray; Eleanor Clausen; Lesley A. Colvin; Marie T. Fallon



ACTH protects against glucocorticoid-induced osteonecrosis of bone  

PubMed Central

We report that adrenocorticotropic hormone (ACTH) protects against osteonecrosis of the femoral head induced by depot methylprednisolone acetate (depomedrol). This therapeutic response likely arises from enhanced osteoblastic support and the stimulation of VEGF by ACTH; the latter is largely responsible for maintaining the fine vascular network that surrounds highly remodeling bone. We suggest examining the efficacy of ACTH in preventing human osteonecrosis, a devastating complication of glucocorticoid therapy.

Zaidi, Mone; Sun, Li; Robinson, Lisa J.; Tourkova, Irina L.; Liu, Li; Wang, Yujuan; Zhu, Ling-Ling; Liu, Xuan; Peng, Yuanzhen; Yang, Guozhe; Shi, Xingming; Levine, Alice; Iqbal, Jameel; Yaroslavskiy, Beatrice B.; Isales, Carlos; Blair, Harry C.



Experimental and Theoretical Challenges of Creating Electrostatic Orbits in Weightlessness  

NASA Astrophysics Data System (ADS)

In January 2006, a team of students from Rhodes College was awarded flight time aboard NASA’s specialized C-9B aircraft known as the “Weightless Wonder” to perform an experiment in microgravity. This experiment demonstrated a prediction of Coulomb’s Law that two oppositely charged spheres should orbit each other under certain conditions. However a number of issues complicate this demonstration such as polarization effects (which affect the nature of the inverse square law and thus the stability of orbits), fluctuations in the microgravity conditions, and the effects of air pressure and humidity on charge leakage. This poster will discuss how we resolved these issues to successfully perform our experiment under the mentoring of Brent Hoffmeister and Shubho Banerjee.

Andring, Kevin W.; Hoffmeister, B.; Banerjee, S.; Janeski, J.; Quinn, S.; Keedy, D.; Campbell, D.



Early periosteal changes in translation-induced bone modelling.  

PubMed Central

This primarily ultrastructural study examines the effects of strain induced in the periosteum using an in vivo translation model with minimal internal bone strain. Caudal vertebrae (CV 7, 8, 9) from 4 d rats were threaded onto the arms of prestressed helical torsion springs and transplanted subcutaneously into 50 g hosts of the same inbred strain. After 7 d the appliances were activated in the experimental rats causing the bones to translate, i.e. to move through the soft tissues. Tissues for histology were obtained at this time (0) and at 1, 3, 5, 7, 10 and 14 d; for electron microscopy, experimental tissues were obtained at 0 time, 30 min, 1, 2, 6, 12, 18 and 24 h and at 0 time and 12 h for the controls. As the arms of the appliance move apart, traction on the enveloping soft tissues produces compression of the periosteum on the leading side and tension on the trailing side with resultant eccentric remodelling of the bones, generally opposite to the direction of movement. A rapid and differential structural response occurs, characterised by accelerated formation on the trailing side with the reverse on the leading, where changes are not as marked initially. Long thin trabeculae oriented in the line of tension form on the trailing side whereas the shaft on the leading side becomes thinner and flatter. Ultrastructural examination of the early stages shows that the fibrous periosteum is first affected, with alterations in collagen packing preceding cellular changes. The midzone shows the greatest change and events here presage those which finally occur at the bone surface and are reflected in altered osteoblastic activity. This study shows that translation-induced stress produces rapid morphological changes in the periosteum which, by acting as an integrated unit, has the capacity to modulate the adaptive bone modelling response. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13

Feik, S A



Motion Sickness Precipitated in the Weightless Phase of Parabolic Flight by Coriolis Accelerations.  

National Technical Information Service (NTIS)

Nineteen normal persons and three deaf subjects with bilateral loss of labyrinthine function (L-D subjects) were exposed to Coriolis accelerations during the brief periods of weightlessness in parabolic flighy by having them move their heads while rotatin...

A. Graybiel R. S. Kennedy R. S. Kellogg



Cardiovascular Deconditioning Effects of Long-Term Simulated Weightlessness in Rats.  

National Technical Information Service (NTIS)

We investigated the cardiovascular deconditioning effect of long-term simulated weightlessness to elucidate its mechanisms. Our research goal was established for the following three reasons. First, even after several decades of extensive research, there s...

L. Zhang J. Chen Z. Ding J. Ma



Preadaptation to the Stimulus Rearrangement of Weightlessness: Preliminary Studies and Concepts for Trainer Designs.  

National Technical Information Service (NTIS)

An effort to develop preflight adaptation training (PAT) apparatus and procedures to adapt astronauts to the stimulus rearrangement of weightless spaceflight is being pursued. Based on the otolith tilt-translation reinterpretation model of sensory adaptat...

D. E. Parker M. F. Reschke





Sections Bone, Joint, and Muscle Disorders Chapters Biology of the Musculoskeletal System Bones Bone, although strong, is a constantly changing tissue that has several functions. Bones serve as rigid structures to ...


[Vestibular apparatus study of the toad, Xenopus laevis, and rats under prolonged weightlessness].  


Fertilized eggs of the clawed toad Xenopus laevis were placed aboard of orbital laboratory of "Salut-6" spacecraft where they developed for 20 days at temperature 15 degrees C. The larvae were fixed in weightlessness. Light and electronmicroscopic studies revealed undisturbed structure on the saccular and utricular maculae and otolith membranes. Some ultrastructural abnormalities were found in the inner ear of adult rats after 20 days of weightlessness ("Kosmos-936"). PMID:6970471

Vinnikov, Ia A; Lychakov, D V; Pal'mbakh, L R; Govardovski?, V I; Adanina, V O


Oral Glucocorticoid-Induced Fall in Cortical Bone Volume and Density in Postmenopausal Asthmatic Patients  

Microsoft Academic Search

:   Despite a deepening understanding of the influence of glucocorticoids (GC) on trabecular bone, little is known about GC-induced\\u000a cortical bone loss. To elucidate the mechanism of GC-induced loss of cortical bone strength with particular reference to cortical\\u000a bone loss, changes in cortical density, relative cortical volume, and the Strength Strain Index (SSI) based on biomechanical\\u000a analyses of the geographic

H. Tsugeno; B. Goto; T. Fujita; M. Okamoto; T. Mifune; F. Mitsunobu; K. Ashida; Y. Hosaki; T. Tsuji; Y. Tanizaki



The homing of bone marrow MSCs to non-osseous sites for ectopic bone formation induced by osteoinductive calcium phosphate.  


Osteoinductive biomaterials are promising for bone repair. There is no direct proof that bone marrow mesenchymal stem cells (BMSCs) home to non-osseous sites and participate in ectopic bone formation induced by osteoinductive bioceramics. The objective of this study was to use a sex-mismatched beagle dog model to investigate BMSC homing via blood circulation to participate in ectopic bone formation via osteoinductive biomaterial. BMSCs of male dogs were injected into female femoral marrow cavity. The survival and stable chimerism of donor BMSCs in recipients were confirmed with polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH). Biphasic calcium phosphate (BCP) granules were implanted in dorsal muscles of female dogs. Y chromosomes were detected in samples harvested from female dogs which had received male BMSCs. At 4 weeks, cells with Y-chromosomes were distributed in the new bone matrix throughout the BCP granule implant. At 6 weeks, cells with Y chromosomes were present in newly mineralized woven bone. TRAP positive osteoclast-like cells were observed in 4-week implants, and the number of such cells decreased from 4 to 6 weeks. These results show that osteoprogenitors were recruited from bone marrow and homed to ectopic site to serve as a cell source for calcium phosphate-induced bone formation. In conclusion, BMSCs were demonstrated to migrate from bone marrow through blood circulation to non-osseous bioceramic implant site to contribute to ectopic bone formation in a canine model. BCP induced new bone in muscles without growth factor delivery, showing excellent osteoinductivity that could be useful for bone tissue engineering. PMID:23298780

Song, Guodong; Habibovic, Pamela; Bao, Chongyun; Hu, Jing; van Blitterswijk, Clemens A; Yuan, Huipin; Chen, Wenchuan; Xu, Hockin H K



Maternal perinatal diet induces developmental programming of bone architecture.  


Maternal high-fat (HF) diet can alter offspring metabolism via perinatal developmental programming. This study tests the hypothesis that maternal HF diet also induces perinatal programming of offspring bone mass and strength. We compared skeletal acquisition in pups from C57Bl/6J mice fed HF or normal diet from preconception through lactation. Three-week-old male and female pups from HF (HF-N) and normal mothers (N-N) were weaned onto normal diet. Outcomes at 14 and 26 weeks of age included body mass, body composition, whole-body bone mineral content (WBBMC) via peripheral dual-energy X-ray absorptiometry, femoral cortical and trabecular architecture via microcomputed tomography, and glucose tolerance. Female HF-N had normal body mass and glucose tolerance, with lower body fat (%) but higher serum leptin at 14 weeks vs. N-N (P<0.05 for both). WBBMC was 12% lower at 14 weeks and 5% lower at 26 weeks, but trabecular bone volume fraction was 20% higher at 14 weeks in female HF-N vs. N-N (P<0.05 for all). Male HF-N had normal body mass and mildly impaired glucose tolerance, with lower body fat (%) at 14 weeks and lower serum leptin at 26 weeks vs. N-N (P<0.05 for both). Serum insulin was higher at 14 weeks and lower at 26 weeks in HF-N vs. N-N (P<0.05). Trabecular BV/TV was 34% higher and cortical bone area was 6% higher at 14 weeks vs. N-N (P<0.05 for both). These data suggest that maternal HF diet has complex effects on offspring bone, supporting the hypothesis that maternal diet alters postnatal skeletal homeostasis. PMID:23503967

Devlin, M J; Grasemann, C; Cloutier, A M; Louis, L; Alm, C; Palmert, M R; Bouxsein, M L



Lysophosphatidic acid-induced chemotaxis of bone cells.  

SciTech Connect

Lysophosphatidic acid (LPA) is a platelet-derived bioactive lipid that is postulated to regulate wound healing. LPA activates G protein-coupled receptors to induce Ca2+ signaling in MC3T3-E1 pre-osteoblasts, and is a potent chemotactic stimulus for these cells. Since bone fracture healing requires the migration of osteoblast progenitors, we postulate that LPA is among the factors that stimulate bone repair. UMR 106-01 cells, which express a more mature osteoblastic phenotype than MC3T3-E1 cells, did not migrate in response to LPA, although they express LPA receptors and exhibit LPA-induced Ca2+ signals. This suggests that LPA differentially induces pre-osteoblast chemotaxis, consistent with our hypothesis that LPA stimulates the motility of osteoblast progenitors during bone healing. LPA-stimulated MC3T3-E1 cells exhibit striking changes in morphology and F-actin architecture, and phosphatidylinositol-3 kinase (PI3K) is required for motility-associated cytoskeletal rearrangements in many cell types. We found a dose-dependent reduction in LPA-induced osteoblast migration when cells also were treated with the PI3K inhibitor, LY294002. Treatment of many cell types with LPA is associated with an autocrine/paracrine transactivation of the EGF receptor (EGFR) via shedding of surface-tethered EGFR ligands, a phenomenon often required for LPA-induced chemotaxis. MC3T3-E1 cells express multiple EGFR ligands (epigen, epiregulin, HB-EGF and amphiregulin) and migrated in response to EGF. However, while EGF-stimulated motility in MC3T3-E1 cells was blocked by an EGFR inhibitor, there was no significant effect on LPA-induced chemotaxis. Activation of MAP kinases is a hallmark of EGFR-mediated signaling, and EGF treatment of MC3T3-E1 cells led to a strong stimulation of ERK1/2 kinase. In contrast, LPA induced only a minor elevation in ERK activity. Thus, it is likely that the increase in ERK activity by LPA is related to cell proliferation associated with lipid treatment. We conclude that LPA-induced MC3T3-E1 cell chemotaxis requires PI3K-associated cytoskeletal changes, but not transactivation of the EGF receptor.

Karagiosis, Sue A.; Masiello, Lisa M.; Bollinger, Nikki; Karin, Norm J.



Yeast-incorporated gallium attenuates glucocorticoid-induced bone loss in rats by inhibition of bone resorption.  


Glucocorticoids (GC) are potent anti-inflammatory agents and widely used for the treatment of many immune-mediated and inflammatory diseases, whereas GC-induced osteoporosis (GIOP) is the most common cause of secondary osteoporosis and significantly increases the patients' morbidity and mortality. GIOP is characterized as diminished osteogenesis and accelerated bone resorption. Yeast-incorporated gallium (YG) as an organic compound not only reduces elements-associated toxicity, but also maintains its therapeutic effect on improving bone loss or promoting fracture healing in ovariectomized female rats. The aim of this study was to examine whether YG could prevent GC-induced bone loss. Five-month-old male Sprague-Dawley rats were randomly divided into three groups (n?=?6): two groups were administered dexamethasone (0.1 mg/kg/day) or vehicle (PBS) subcutaneously for 5 weeks; one other group was received dexamethasone subcutaneously and YG (120 ?g/kg/day) orally. Trabecular bone microarchitectural parameters, bone mineral density (BMD), bone strength, body weight, and serum biochemical markers of bone resorption and formation were examined. Compared to the GC alone group, treatment with YG not only prevented microarchitectural deterioration of trabecular bone volume relative to tissue volume, trabecular number, and trabecular separation, but also significantly improved BMD, mechanical strength, and body weight in GC-treated rats. Moreover, YG decreased tartrate-resistant acid phosphatase 5b level but failed to change alkaline phosphatase level in GC-treated rats. This is the first study to show that YG prominently attenuates bone loss and microarchitectural deterioration and inhibits the increased bone resorption in GIOP. It implies that YG might be an alternative therapy for prevention of GC-induced bone loss in humans. PMID:23532566

Ren, Zhaozhou; Yang, Liqing; Xue, Feng; Meng, Qingjie; Wang, Kejia; Wu, Xian; Ji, Chao; Jiang, Teng; Liu, Da; Zhou, Long; Zhang, Jing; Fu, Qin



[Temporal bone histopathology of noise-induced hearing loss].  


To examine the relationship between hearing and changes in the inner ear, we investigated human temporal bone specimens from 2 patients with noise-induced hearing loss and prepared audio-cytocochleograms as described by Schuknecht et al. Patient 1 was a 50-year-old male who died of thyroid cancer and had worked at a printing house for 38 years. Patient 2 was a 58-year old male who died of maxillary sinus cancer and had worked in construction for 22 years. A pure-tone audiogram showed high-tone sensorineural hearing loss with c5-dip-type hearing disorder in both ears in Patient 1, and a high-tone abrupt form of sensorineural hearing loss in Patient 2. Pathological examination of the temporal bone revealed degeneration and disappearance of the organ of Corti at the basal turn and disappearance of cochlear neurons in both patients. Audio-cytocochleograms revealed hearing disorder consistent with the changes in the inner ear in both patients. Marked degeneration and disappearance of the organ of Corti and stria vascularis were present in patient 1. It is generally known that disorders of the organ of Corti for a long period is involved in the etiology of noise-induced hearing loss. This degeneration of the organ of Corti is produced at a basilar membrane with the maximum amplitude related to exposure to noise according to a physical and mechanical factors. Moreover, animal experiments have shown that exposure to noise decrease cochlear blood flow. In Patient 1 both the organ of Corti and the stria vascularis exhibited degeneration, suggesting that not only physical and mechanical factors but a cochlear circulatory disorder related to exposure to noise was involved in the etiology of the pathological changes in the temporal bone related to noise-induced hearing loss. PMID:15765731

Nakamoto, Yoshinori; Iino, Yukiko; Kodera, Kazuoki



Drug-induced liver injury after allogeneic bone marrow transplantation.  


A 23-year-old woman developed acute severe hepatitis and jaundice on day 183 after bone marrow transplantation from HLA-B antigen mismatched-related donor. The administration of prednisolone and cessation of the prescribed drugs resolved the liver injury. Drug lymphocyte stimulation test was positive for acyclovir, and liver biopsy indicated the characteristics of drug-induced liver injury (DILI) rather than graft-versus-host disease. Physicians should keep DILI in mind when considering differential diagnosis for liver complications after allogeneic cell transplantation. PMID:24037455

Tachibana, Takayoshi; Nozaki, Akito; Enaka, Makiko; Yamamoto, Eri; Kawasaki, Rika; Koharazawa, Hideyuki; Hagihara, Maki; Ishibashi, Daisuke; Nakajima, Yuki; Kuwabara, Hideyuki; Tomita, Naoto; Ishigatsubo, Yoshiaki; Fujisawa, Shin



Bacterial-responsive B lymphocytes induce periodontal bone resorption.  


Host immune responses play a key role in periodontal diseases. We have found that B lymphocytes in human periodontal lesions bear abundant receptor activator of NF-kappaB ligand (RANKL), a major factor in the regulation of osteoclast differentiation. The purpose of this study was to evaluate Actinobacillus actinomycetemcomitans-responsive B lymphocytes in their level of RANKL expression and their effects on periodontal bone resorption. Congenitally athymic Rowett rats received injections of formalin-fixed A. actinomycetemcomitans into the gingival papillae, and donor B cells from normal rats immunized with A. actinomycetemcomitans were transferred via tail vein injection. We demonstrated that B cells from A. actinomycetemcomitans-immunized animals had greater levels of RANKL expression and induced a significantly higher level of osteoclast differentiation from RAW 264.7 cells than did nonimmune B cells that were not Ag specific. This activity was eliminated by incubation with the RANKL decoy receptor osteoprotegerin fusion protein. A. actinomycetemcomitans-binding B cell (ABB) and RANKL-expressing B cells were recovered from the gingival tissues of recipient rats transferred with ABB, but not from recipients of PBS nonimmune B cells or A. actinomycetemcomitans nonbinding B cells. Also, recipients of ABB exhibited increased osteoclast formation on the alveolar bone surface and significant periodontal bone resorption. This effect was antagonized by injection of osteoprotegerin fusion protein into the local gingival tissues. In summary, this study suggests that B lymphocytes can contribute to increased periodontal bone resorption in the absence of T lymphocytes. This effect is associated with the up-regulation of RANKL expression. PMID:16365458

Han, Xiaozhe; Kawai, Toshihisa; Eastcott, Jean W; Taubman, Martin A




Technology Transfer Automated Retrieval System (TEKTRAN)

Clinical surveys indicate that heavy drinking is a risk factor for the development of osteoporosis. However, the molecular mechanisms underlying ethanol-induced bone loss remain the subject of dispute with some studies showing ethanol effects on bone formation and others on bone breakdown. In thes...


Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-?  

PubMed Central

Estrogen deficiency induces bone loss by upregulating osteoclastogenesis by mechanisms not completely defined. We found that ovariectomy-enhanced T-cell production of TNF-?, which, acting through the TNF-? receptor p55, augments macrophage colony-stimulating factor–induced (M-CSF–induced) and RANKL-induced osteoclastogenesis. Ovariectomy failed to induce bone loss, stimulate bone resorption, or increase M-CSF– and RANKL-dependent osteoclastogenesis in T-cell deficient mice, establishing T cells as essential mediators of the bone-wasting effects of estrogen deficiency in vivo. These findings demonstrate that the ability of estrogen to target T cells, suppressing their production of TNF-?, is a key mechanism by which estrogen prevents osteoclastic bone resorption and bone loss.

Cenci, Simone; Weitzmann, M. Neale; Roggia, Cristiana; Namba, Noriyuki; Novack, Deborah; Woodring, Jessica; Pacifici, Roberto



Electrical potentials in bone induced by ultrasound irradiation in the megahertz range  

NASA Astrophysics Data System (ADS)

Low frequency mechanical studies have reported the contribution of stress-induced electrical potentials to bone metabolism. However, the healing mechanism of bone fractures by low intensity ultrasound is not yet clear. We demonstrate that bone can generate electrical potentials by ultrasound irradiation in the MHz range. Electrical potentials were obtained from the output of bovine cortical bone transducers. In the range of 0.7-2.5 MHz, sensitivities of bone transducers were around 1/1000 of a poly (vinylidene fluoride) ultrasonic transducer and did not depend on magnitude and alignment of hydroxyapatite crystallites in bone.

Okino, M.; Coutelou, S.; Mizuno, K.; Yanagitani, T.; Matsukawa, M.



Relationships between orientation, movement and posture in weightlessness: preliminary ethological observations.  


Weightlessness in man induces changes in astronaut orientations and consequently in his patterns of movements and postures. An ethological method has been used to describe the "overall" spontaneous behaviour of astronauts as seen from video recordings made during Space Flights. The work has consisted in analysing the relationships between orientation, movement and posture as an indication of a motor adaptative reorganization in such a situation. The results obtained lead us to consider three different aspects: (1) Orientation references. The astronaut orientates himself with reference to the Space Shuttle's internal structure; the increase of visual activity confirms the choice of the retinal vertical as frame of reference. (2) Motor coordination. The main data reveals a decrease in motor stereotypes by the diversity of motor acts observed and the importance of the link between orientation and posture described as follows: slightly inclined forward position, with legs flexed at about 135 degrees. (3) Cognitive references. There appears to be a new organization of the cognitive image of the body scheme, the missing vestibular information being supplied by peripheral vision instead which could play a role in the astronaut's perception of his own movement. PMID:11540652

Tafforin, C



Trabecular and cortical bone changes in vertebral and peripheral skeletons induced by surgical menopause  

Microsoft Academic Search

Using dual x-ray absorptiometry (DXA), quantitative computed tomography (QCT), and microdensitometry (MD) methods, we performed\\u000a a 3-year longitudinal study of bone changes induced by surgical menopause, i.e., hysterectomy with unilateral or bilateral\\u000a oophorectomy (OVX), in 52 nonmenopausal women. In the trabecular spine, bone mineral content (Dc) and bone mineral density (Dd) were determined by DXA, and bone mineral density (L2

Sigeharu Dokou; Yuzuru Satou; Youko Soeda



Effect of 5E Teaching Model on Student Teachers' Understanding of Weightlessness  

NASA Astrophysics Data System (ADS)

Weight is one of the basic concepts of physics. Its gravitational definition accommodates difficulties for students to understand the state of weightlessness. The aim of this study is to investigate the effect of materials based on 5E teaching model and related to weightlessness on science student teachers' learning. The sample of the study was 9 volunteer student teachers who were in their first grade in Science Teaching Program in Fatih Faculty of Education, Karadeniz Technical University. Both qualitative and quantitative data were gathered to find answers to the research questions. Findings revealed that all physics textbooks reviewed gave gravitational definition of weight. Also the concept of weightlessness hasn't been covered in high school and some university textbooks. It was determined that before the implementation student teachers had non-scientific explanations about weightlessness. The implementation of the 5E teaching model and materials developed are effective on learning the weightlessness. It is suggested that similar applications can also be used in other physics subjects or in other fields of science.

Tural, Güner; Akdeniz, Ali R?za; Alev, Nedim



Expressions of integrin subunits in osteoblasts during weightlessness simulation using clionstat  

NASA Astrophysics Data System (ADS)

Space flight experiments and studies carried out in altered gravity environments have revealed that exposure to altered gravity conditions results in (mal)adaptation of cellular function. In the present study, we used a clinostat to generate a vector-averaged gravity to simulate weightlessness environment. We then observed the responses of rat calvarial osteoblasts subsequent to rotation at 30 revolutions per minute (rpm) for 72 h. We found that the gene expressions of three integrin subunits started to change from 24 h of rotation in clinostat but not in stationary cultures. The decreased percent changes of integrin a5 mRNA at 24, 48 and 72 h were 11.3 +/- 2.6%, 18.7 +/- 4.2% and 9.8 +/ - 2.1%, respectively. The same trend was saw in the expression of integrin av mRNA as 23.0 +/- 4.7%, 12.3 +/- 1.6% and 16.7 +/- 3.2%, respectively. Moreover, the expressions of integrin ß1 mRNA in different periods were also declined with the percent changes of 15.3 +/- 1.3%, 11.4 +/- 1.2% and 26.4 +/- 5.5%, respectively. All cells contain membrane-anchored attachment proteins able to recognize specific chemical motifs in the extracellular macromolecules forming the supporting scaffold, made of various types of collagen, adhesive glycoproteins, elastin, proteoglycans, etc. These cell-matrix interactions are mainly mediated by receptors of the integrins family, heterodimeric molecules made of an extracellular domain connected through a transmembrane sequence to an intracytoplasmic tail. Our results suggest that vector-averaged gravity causes alterations of signal transduction and integrin-mediated cell adhesion in osteoblasts by altering the gene expressions of several crucial integrin subunits. These alterations might contribute to the pathogenesis of osteoporotic bone loss as observed in actual space flights.

Zhang, S.; Wang, B.; Zhao, D.; Nie, J.; Li, Y.


Effects of microgravity on bone and calcium homeostasis  

NASA Astrophysics Data System (ADS)

Mechanical function is known to be of crucial importance for the maintenance of bone tissue. Gravity on one hand and muscular effort on the other hand are required for normal skeletal structure. It has been shown by numerous experimental studies that loss of total-body calcium, and marked skeletal changes occur in people who have flown in space. However, most of the pertinent investigations have been conducted on animal models, including rats and non-human primates, and a reasonably clear picture of bone response to spaceflight has emerged during the past few years. Osteopenia induced by microgravity was found to be associated with reduction in both cortical and trabecular bone formation, alteration in mineralization patterns, and disorganization of collagen, and non-collagenous protein metabolism. Recently, cell-culture techniques have offered a direct approach of altered gravity effects at the osteoblastic-cell level. But the fundamental mechanisms by which bone and calcium are lost during spaceflight are not yet fully known. Infrequenccy and high financial cost of flights have created the necessity to develop on-Earth models designed to mimic weightlessness effects. Antiorthostatic suspension devices are now commonly used to obtain hindlimb unloading in rats, with skeletal effects similar to those observed after spaceflight. Therefore, actual and ``simulated'' spaceflights, with investigations conducted at whole body and cellular levels, are needed to elucidate pathogeny of bone loss in space, to develop effective countermeasures, and to study recovery processes of bone changes after return to Earth.

Zérath, E.


MR imaging of therapy-induced changes of bone marrow  

Microsoft Academic Search

MR imaging of bone marrow infiltration by hematologic malignancies provides non-invasive assays of bone marrow cellularity\\u000a and vascularity to supplement the information provided by bone marrow biopsies. This article will review the MR imaging findings\\u000a of bone marrow infiltration by hematologic malignancies with special focus on treatment effects. MR imaging findings of the\\u000a bone marrow after radiation therapy and chemotherapy

Heike E. Daldrup-Link; Tobias Henning; Thomas M. Link



Vertebral Fracture and Cortical Bone Changes in Corticosteroid-Induced Osteoporosis  

Microsoft Academic Search

:   Despite an intriguing understanding of trabecular bone dynamics, little is known about corticosteroid-induced cortical bone\\u000a loss and fractures. Recently, we verified a steroid-induced decrease in cortical bone volume and density using peripheral\\u000a quantitative computed tomography (pQCT) in adult asthmatic patients given oral corticosteroids. Subsequently, the pQCT parameters\\u000a and presence of vertebral fractures were investigated to further clarify the role

H. Tsugeno; T. Fujita; B. Goto; T. Sugishita; Y. Hosaki; K. Ashida; Y. Tanizaki; Y. Shiratori



Alterations in dorsal horn neurones in a rat model of cancer-induced bone pain  

Microsoft Academic Search

Cancer-induced bone pain is a major clinical problem. A rat model based on intra-tibial injection of MRMT-1 mammary tumour cells was used to mimic progressive cancer-induced bone pain. At the time of stable behavioural changes (decreased thresholds to mechanical and cold stimuli) and bone destruction, in vivo electrophysiology was used to characterize natural (mechanical, thermal, and cold) and electrical-evoked responses

C. E Urch; T Donovan-Rodriguez; A. H Dickenson



New bone formation in nude mouse calvaria induced by canine prostate tissue.  


Osteoblastic metastases are common in patients with advanced prostate cancer. The pathophysiology of the new bone formation at metastatic sites is not currently known, but it is hypothesized that growth factors secreted by the prostate may be involved. Unfortunately, most rodent models of prostate cancer with metastasis to bone are osteolytic and not osteoblastic. Significant osteolysis by tumor cells at metastatic sites also may lead to fractures or bone instability. Misinterpretation of new periosteal bone due to bone instability as tumor-cell osteo-induction is another disadvantage of the osteolytic models. To circumvent these problems, we have developed a model system of new bone formation in the calvaria of nude mice stimulated by normal canine prostate tissue. Collagenase-digested normal prostate tissue was implanted adjacent to the calvaria of nude mice. Calvaria were examined at 2 weeks post-implantation for changes in the bone microenvironment by histology, calcein uptake at sites of bone mineralization, and tartrate-resistant acid phosphatase staining for osteoclasts. The prostate tissue remained viable and induced abundant new woven bone formation on the adjacent periosteal surface. In some cases new bone formation also was induced on the distant or concave calvarial periosteum. The new bone stained intensely with calcein, which demonstrated mineralization of the bone matrix. The new bone formation on prostate-implanted calvaria significantly increased (1.7-fold) the thickness of the calvaria compared with control calvaria. New bone formation was not induced in calvaria of mice implanted with normal canine kidney, urinary bladder, spleen, or skeletal muscle tissue, or mice with surgically-induced disruption of the periosteum. Osteoclast numbers in the medullary spaces and periosteum of calvaria were mildly increased (61%) in mice with implanted prostate tissue. In conclusion, this animal model will be useful for investigating the roles of prostate-derived growth factors on new bone formation in vivo. PMID:12431820

LeRoy, Bruce E; Bahnson, Robert R; Rosol, Thomas J



Use of electronic speckle pattern interferometers for the analysis of convective states of liquids in weightlessness  

NASA Astrophysics Data System (ADS)

Interferometry has always been a powerful tool to diagnose the response of liquids, when changes of status parameters induce modifications in their optical properties. Interferometric measurements are based on the ability to measure variations, around a reference configuration, in the optical path length or the refractive index. Investigations done so far on heat convection driven by capillary forces, indicate that the observation of both the bulk phase and of the free surface, is instrumental for the understanding of the physical mechanisms steering the heat transfer phenomena in 'weightless liquids'. When used in space application, conventional interferometers suffer of some fundamental drawbacks, because of the severe requirements in terms of mechanical stability of the optical elements. Holographic interferometry removes the most stringent limitations of classical interferometry, but requires precise positioning of the recording plate, with accuracy better than half a wavelength. The superior feature of an electronic speckle pattern interferometer (ESPI) is that it enables real time correlation fringes to be recorded by a video camera and displayed on a television monitor, without recourse to any form of photographic processing or plate relocation. This comparative ease of operation allows the technique of ESPI to be extended to considerably more complex problems of deformation analysis and measurement of refractive index modulation. Since it basically works as a time differential interferometer, measurements can always be referred to a well known configuration and condition of the test sample, reducing or even eliminating the requirements on mechanical stability. This paper describes how double-path ESPI are accommodated within the optical diagnostics of a microgravity payload, fluid physics facility, due to launch in 1998 on the Russian retrievable capsule FOTON. The two- ESPI layout permits one to observe and quantify the deformation of the free surface of a liquid subjected to a thermal gradient.Motions induced by the convective flows in the bulk phase can be monitored at the same time. The main features of the ESPI are presented together with design outlines and optical performances.

Verga, Antonio; Baglioni, Pietro; Dupont, Olivier; Dewandel, J. L.; Beuselinck, Tom; Bouwen, J.



Use of eletronic speckle pattern interferometers for the analysis of convective states of liquids in weightlessness  

NASA Astrophysics Data System (ADS)

Interferometry has always been a powerful tool to diagnose the response of liquids when changes of status parameters induce modifications in their optical properties. Interferometric measurements are based on the ability to measure variations in the optical path length around a reference configuration. Investigations done so far on heat convention driven by capillary forces indicate that the observation of both the bulk phase and of the free surface is instrumental for understanding the physical mechanisms steering the heat transfer phenomena in 'weightless liquids.' When used in space applications, conventional interferometers suffer some fundamental drawbacks because of the severe requirements in terms of the mechanical stability of the optical elements. Holographic interferometry removes the most stringent limitations of classical interferometry, but requires precise positioning of the recording plate, with accuracy better than half a wavelength. The superior feature of an electronic speckle pattern interferometer (ESPI) is that it enables real time correlation fringes to be recorded by a video camera and displayed on a television monitor, without recourse to any form of photographic processing or plate relocation. This comparative ease of operation enables the technique of electronic speckle pattern interferometry to be extended to considerably more complex problems of deformation analysis and measurement of refractive index modulation. Since it basically works as a time differential interferometer, measurements can always be referred to a well known configuration and condition of the test sample, reducing or even eliminating the requirements on mechanical stability. We describe how a double-path ESPI is accommodated within the optical diagnostics of a microgravity payload, fluid physics facility, due for launch in 1999 on the Russian retrievable capsule Foton. The ESPI here described enables one to observe and quantify the deformation of the free surface of a liquid subjected to a thermal gradient. Motions induced by the convective flows in the bulk phase can be monitored at the same time. The main features of the ESPI are presented together with design outlines and optical performances.

Verga, Antonio; Baglioni, Pietro; Dupont, Olivier; Dewandel, Jean-Luc; Beuselinck, Tom; Bouwen, Jan



Morphine treatment accelerates sarcoma-induced bone pain, bone loss, and spontaneous fracture in a murine model of bone cancer  

Microsoft Academic Search

Metastatic bone cancer causes severe pain that is primarily treated with opioids. A model of bone cancer pain in which the progression of cancer pain and bone destruction is tightly controlled was used to evaluate the effects of sustained morphine treatment. In cancer-treated mice, morphine enhanced, rather than diminished, spontaneous, and evoked pain; these effects were dose-dependent and naloxone-sensitive. SP

Tamara King; Anna Vardanyan; Lisa Majuta; Ohannes Melemedjian; Ray Nagle; Anne E. Cress; Todd W. Vanderah; Josephine Lai; Frank Porreca



A TNF receptor loop peptide mimic blocks RANK ligand-induced signaling, bone resorption, and bone loss  

PubMed Central

Activating receptor activator of NF-?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 showed that a peptide (WP9QY) that mimics this TNFR contact site and inhibits TNF-?–induced activity bound to RANK ligand (RANKL). Changing a single residue predicted to play an important role in the interaction reduced the binding significantly. WP9QY, but not the altered control peptide, inhibited the RANKL-induced activation of RANK-dependent signaling in RAW 264.7 cells but had no effect on M-CSF–induced activation of some of the same signaling events. WP9QY but not the control peptide also prevented RANKL-induced bone resorption and osteoclastogenesis, even when TNFRs were absent or blocked. In vivo, where both RANKL and TNF-? promote osteoclastogenesis, osteoclast activity, and bone loss, WP9QY prevented the increased osteoclastogenesis and bone loss induced in mice by ovariectomy or low dietary calcium, in the latter case in both wild-type and TNFR double-knockout mice. These results suggest that a peptide that mimics a TNFR ligand contact site blocks bone resorption by interfering with recruitment and activation of osteoclasts by both RANKL and TNF.

Aoki, Kazuhiro; Saito, Hiroaki; Itzstein, Cecile; Ishiguro, Masaji; Shibata, Tatsuya; Blanque, Roland; Mian, Anower Hussain; Takahashi, Mariko; Suzuki, Yoshifumi; Yoshimatsu, Masako; Yamaguchi, Akira; Deprez, Pierre; Mollat, Patrick; Murali, Ramachandran; Ohya, Keiichi; Horne, William C.; Baron, Roland



Bone tumours induced in rats with radioactive cerium.  


A technique is described for the induction of metastasizing bone tumours in rats by local inoculation of 144cerium. Bone sarcomas develop in 90% of the animals and 74% of these had lung metastases. The tumours can be easily cultured and maintained by serial transplantations. Preliminary data of clinical, histological and kinetic characteristics of these bone tumours are given. PMID:6932906

Delbrück, H G; Allouche, M; Jasmin, C; Morin, M; Deml, F; Anghileri, L; Masse, R; Lafuma, J



MR imaging of therapy-induced changes of bone marrow  

PubMed Central

MR imaging of bone marrow infiltration by hematologic malignancies provides non-invasive assays of bone marrow cellularity and vascularity to supplement the information provided by bone marrow biopsies. This article will review the MR imaging findings of bone marrow infiltration by hematologic malignancies with special focus on treatment effects. MR imaging findings of the bone marrow after radiation therapy and chemotherapy will be described. In addition, changes in bone marrow microcirculation and metabolism after anti-angiogenesis treatment will be reviewed. Finally, new specific imaging techniques for the depiction of regulatory events that control blood vessel growth and cell proliferation will be discussed. Future developments are directed to yield comprehensive information about bone marrow structure, function and microenvironment.

Henning, Tobias; Link, Thomas M.



Some Results from Studies on the Effects of Weightlessness on the Growth of Epiphytic Orchids.  

National Technical Information Service (NTIS)

Epidendrum orchids were placed in a Malakhit-2 micro-greenhouse aboard the Soyuz-36-Salyut-6 space station to test their growth under weightless conditions. Growth occurred but was less than in control plants left on Earth; cells were smaller and parenchy...

T. M. Cherevchenko T. K. Mayko



Effect of Weightlessness Conditions on the Somatic Embryogenesis in the Culture of Carrot Cells.  

National Technical Information Service (NTIS)

A carrot cell culture seeded in Petri dishes in the United States and transported to the USSR was subjected to weightlessness for 20 days during the flight of Kosmos 782. The controls were cultures placed on a centrifuge (1 g) inside the satellite and cul...

R. G. Butenko N. N. Dmitriyeva V. Ongko L. V. Basyrova



Solar energy collector including a weightless balloon with sun tracking means  

Microsoft Academic Search

A solar energy collector having a weightless balloon, the balloon including a transparent polyvinylfluoride hemisphere reinforced with a mesh of ropes secured to its outside surface, and a laminated reflector hemisphere, the inner layer being clear and aluminized on its outside surface and the outer layer being opaque, the balloon being inflated with lighter-than-air gas. A heat collection probe extends

Hall; Frederick F



Solar energy collector including a weightless balloon with sun tracking means  

Microsoft Academic Search

A solar energy collector is described having a weightless balloon, the balloon including a transparent polyvinylfluoride hemisphere reinforced with a mesh of ropes secured to its outside surface, and a laminated reflector hemisphere, the inner layer being clear and aluminized on its outside surface and the outer layer being opaque, the balloon being inflated with lighter-than-air gas. A heat collection




Physiologic mechanisms effecting circulatory and body fluid losses in weightlessness as shown by mathematical modeling.  


The mechanisms causing large body water losses in weightlessness are not clear. It has long been considered that a central volume expansion drives the physiologic adaptation to a reduced total blood volume, with normal blood composition eventually regained. However, inflight venous pressure measures suggest that central volume expansion in weightlessness may be very transient, or that considerable cardiovascular adaptation to fluid shifts occurs on the ground while astronauts wait in the semi-supine pre-launch position. If a central volume stimulus does not persist, other mechanisms must drive the adaptation of circulation to a reduced blood volume and account for body fluid losses. Recent results from the SLS-1 mission suggest that body fluid volumes do not simply decline to new equilibria but that they decrease to a low point, then undergo some recovery. Similar "under-shoots" of body fluid volumes have also been shown in computer simulations, providing confidence in the validity of the model. The purpose of this study was to examine the mechanisms which could explain the loss of body fluids in weightlessness and how a cardiovascular preadaptation countermeasure we previously tested ameliorated body fluid losses. It is assumed that the physiology of head down tilt (HDT) provides a reasonably accurate analog of weightless exposure. PMID:11537415

Simanonok, K E; Srinivasan, R S; Charles, J B



Ultrasound Enhances Recombinant Human BMP2 Induced Ectopic Bone Formation in a Rat Model  

Microsoft Academic Search

Two methods to improve bone repair include the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) and low-intensity pulsed ultrasound (LIPUS). The present study was designed to determine if LIPUS enhances the effect of rhBMP-2–induced bone formation in a well characterized ectopic implant model. Absorbable collagen sponges loaded with 0-, 1-, 2.5- or 5-?g doses of rhBMP-2 were implanted subcutaneously

Coen A. Wijdicks; Amarjit S. Virdi; Kotaro Sena; Dale R. Sumner; Robert M. Leven



Bone tumours induced in rats with radioactive cerium.  

PubMed Central

A technique is described for the induction of metastasizing bone tumours in rats by local inoculation of 144cerium. Bone sarcomas develop in 90% of the animals and 74% of these had lung metastases. The tumours can be easily cultured and maintained by serial transplantations. Preliminary data of clinical, histological and kinetic characteristics of these bone tumours are given. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7

Delbruck, H. G.; Allouche, M.; Jasmin, C.; Morin, M.; Deml, F.; Anghileri, L.; Masse, R.; Lafuma, J.



Age-dependent microdamage removal following mechanically induced microdamage in trabecular bone in vivo.  


In order to examine the potential age-related response of trabecular bone to microdamage, a novel animal model utilizing a bone chamber to load existing distal femoral trabecular bone of rats was developed. Fifteen 8-month-old (mature) and fifteen 24-month-old (old) Fischer Brown Norway rats underwent bilateral insertion of the bone chamber. After a 3-week recovery period, one leg per animal underwent damage-inducing loading. Double fluorochrome labeling was used to identify microcracks induced by loading. A greater crack density was found in loaded trabecular bone than in corresponding unloaded control bone at day 0 in both age groups (mature n=5, old n=4). At day 35 post loading, older rats (n=3) had greater crack density (suggesting little removal of microcracks), whereas younger rats (n=5) had no difference between loaded and unloaded limbs, suggesting induced microcracks were removed. The difference in bone volume fraction between the loaded and unloaded limb were significantly different at 21 and 35 days post loading when comparing the old with the mature rats. The data suggest a reduced ability of bone to recover after damage in the older rats. The damage-inducing capabilities of the animal model were demonstrated using double fluorochrome labeling in vivo for detection of microcracks. The results indicate that removal of microdamage is altered with age. PMID:17055351

Waldorff, Erik I; Goldstein, Steven A; McCreadie, Barbara R



Bone Marrow Histological Modifications Induced by Alpha Interferon in Hairy Cell Leukemia  

Microsoft Academic Search

This paper reports the bone marrow histological picture in 7 patients with hairy cell leukemia treated with recombinant interferon. Bone marrow biopsies were performed at diagnosis, after 1, 3 and 7 months from the beginning of treatment and at 12 months at treatment suspension. The main modifications observed were a conspicuous reduction of hairy cell infiltrate, profound hypoplasia induced by

G. Lambertenghi-Deliliers; E. Benazzi; A. Cortelezzi; E. E. Polli




Technology Transfer Automated Retrieval System (TEKTRAN)

Lactation-induced bone loss is promptly restored in the post-weaning period by a process of anabolic rebuilding, the endocrine and molecular basis of which still remains enigmatic. Ethanol (EtOH) consumption during this post-weaning period prevents the recovery of bone density and may be a significa...


Simvastatin-loaded ?-TCP drug delivery system induces bone formation and prevents rhabdomyolysis in OVX mice.  


Bone formation and regeneration is a prolonged process that requires a slow drug release system to assist in the long-term recovery. A drug-delivery system is developed that allows for the controlled release of simvastin, without exhibiting the side effects associated with high concentrations of simvastatin, and is still capable of inducing constant bone formation. PMID:23184712

Chou, Joshua; Ito, Tomoko; Otsuka, Makoto; Ben-Nissan, Besim; Milthorpe, Bruce




Microsoft Academic Search

Fatigue induced microdamage in bone accumulates with age and in osteoporosis, compromising bone strength and leading to fracture failure. Such microdamage must be visualised and quantified in order to understand its role and aid in the prediction and prevention of fractures. Histological dyes have been used singly and in sequence to achieve this. Basic fuchsin, detected using transmitted light and

T. C. Lee; F. J. O'Brien; D. Taylor; R. Parkesh; T. Gunnlaugsson


Modulation of Doxorubicin-Induced Genotoxicity by Aegle marmelos in Mouse Bone Marrow: A Micronucleus Study  

Microsoft Academic Search

The effect of various concentrations of Aegle marmelos (AME) on the doxorubicin (DOX)-induced genotoxic effects in mice bone marrow was studied. Treatment of mice with different concentrations of DOX resulted in a dose-dependent elevation in the frequency of micronucleated polychromatic (MPCE) as well as normochromatic (MNCE) erythrocytes in mouse bone marrow. The frequencies of MPCE and MNCE increased with scoring

Ponemone Venkatesh; Bellary Shantala; Ganesh Chandra Jagetia; K. Koteshwer Rao; Manjeshwar Shrinath Baliga



Osteogenesis induced by a bone forming peptide from the prodomain region of BMP-7.  


Osteoporosis is a reduction in skeletal mass due to an imbalance between bone formation and bone resorption. Many researchers have tried to develop adjuvants as specific suppressors of bone resorption and stimulators of bone formation for therapeutic purposes in patients with osteoporosis. Therefore, specific stimulators on bone formation are one of therapeutic significance in the treatment of osteoporosis. Until now, the regulation of bone generation has been the focus of bone morphogenetic protein-7 (BMP-7) investigation from mature form. However, new peptides from immature form which has osteogenic activity has not been reported and developments of these proteins are still remained. In this study, we found a new peptide sequence, called bone forming peptide-1 (BFP-1) and have more high activities of osteogenic differentiation compared with BMP-7. BFP-1-treated multipotent bone marrow stromal stem cells (MBSCs) induced the expression levels and activity of alkaline phosphatase (ALP). Moreover, BFP-1 enhanced the levels of CD44, CD47 and CD51 expression as well as increased Ca(2+) content in MBSCs. In current study, radiography at 8 weeks revealed that BFP-1 pretreated-MBSC transplanted animals had strongly increased bone formation compared to that in the BMP-7 pretreated MBSC transplanted animals. Our finding indicates a new insight into peptides from the immature region of BMP-7 can also be useful in the development of adjuvant therapies for bone-related diseases. PMID:22795855

Kim, Hyung Keun; Kim, Ji Hyun; Park, Dae Sung; Park, Kyung Soon; Kang, Seong Soo; Lee, Jun Sik; Jeong, Myung Ho; Yoon, Taek Rim



Disruption of PTH Receptor 1 in T Cells Protects against PTH-Induced Bone Loss  

PubMed Central

Background Hyperparathyroidism in humans and continuous parathyroid hormone (cPTH) treatment in mice cause bone loss by regulating the production of RANKL and OPG by stromal cells (SCs) and osteoblasts (OBs). Recently, it has been reported that T cells are required for cPTH to induce bone loss as the binding of the T cell costimulatory molecule CD40L to SC receptor CD40 augments SC sensitivity to cPTH. However it is unknown whether direct PTH stimulation of T cells is required for cPTH to induce bone loss, and whether T cells contribute to the bone catabolic activity of PTH with mechanisms other than induction of CD40 signaling in SCs. Methodology/Principal Findings Here we show that silencing of PTH receptor 1 (PPR) in T cells blocks the bone loss and the osteoclastic expansion induced by cPTH, thus demonstrating that PPR signaling in T cells is central for PTH-induced reduction of bone mass. Mechanistic studies revealed that PTH activation of the T cell PPR stimulates T cell production of the osteoclastogenic cytokine tumor necrosis factor ? (TNF). Attesting to the relevance of this effect, disruption of T cell TNF production prevents PTH-induced bone loss. We also show that a novel mechanism by which TNF mediates PTH induced osteoclast formation is upregulation of CD40 expression in SCs, which increases their RANKL/OPG production ratio. Conclusions/Significance These findings demonstrate that PPR signaling in T cells plays an essential role in PTH induced bone loss by promoting T cell production of TNF. A previously unknown effect of TNF is to increase SC expression of CD40, which in turn increases SC osteoclastogenic activity by upregulating their RANKL/OPG production ratio. PPR-dependent stimulation of TNF production by T cells and the resulting TNF regulation of CD40 signaling in SCs are potential new therapeutic targets for the bone loss of hyperparathyroidism.

Tawfeek, Hesham; Bedi, Brahmchetna; Li, Jau-Yi; Adams, Jonathan; Kobayashi, Tatsuya; Weitzmann, M. Neale; Kronenberg, Henry M.; Pacifici, Roberto



Pharmacological inhibition of intracellular calcium release blocks acid-induced bone resorption  

PubMed Central

In vivo chronic metabolic acidosis induces net Ca2+ efflux from bone, and incubation of neonatal mouse calvariae in medium simulating physiological metabolic acidosis induces bone resorption. It appears that activation of the proton (H+) receptor OGR1 in the osteoblast leads to an increase in intracellular Ca2+, which is associated with an increase in cyclooxygenase 2 (COX2) and PGE2-induced receptor activator of NF-?B ligand (RANKL) and H+-induced osteoclastic bone resorption. To support this hypothesis, we tested whether intracellular Ca2+ signaling was integral to H+-induced bone resorption by determining whether 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) and 2-aminoethoxydiphenyl borate (2-APB), inhibitors of inositol trisphosphate-mediated Ca2+ signaling, would block H+-induced bone resorption in cultured neonatal calvariae and, if so, would do so by inhibiting H+-induced stimulation of COX2 and RANKL in osteoblastic cells. We found that H+-induced bone resorption is significantly inhibited by TMB-8 and 2-APB. Both compounds also inhibit H+-induced stimulation of COX2 protein in calvariae and COX2 mRNA and protein levels in primary osteoblasts. H+-induced stimulation of RANKL in calvarial cultures, as well as primary cells, is also completely inhibited by TMB-8 and 2-APB. These results support the hypothesis that H+ stimulation of net Ca2+ efflux from bone, mediated by COX2- and subsequent PGE2-induced RANKL production, is initiated in the osteoblast via activation of Ca2+ signaling.

Bushinsky, David A.



Leptin Reduces Ovariectomy-Induced Bone Loss in Rats  

Microsoft Academic Search

Bone mineral density increases with fat body mass, and obe- sity has a protective effect against osteoporosis. However, the relationship between fat body mass and bone mineral density is only partially explained by a combination of hormonal and mechanical factors. Serum leptin levels are strongly and di- rectly related to fat body mass. We report here the effects of leptin




Gelatinous Bone Marrow Transformation Complicated by Self-Induced Malnutrition  

Microsoft Academic Search

A 48-year-old woman with a history of anorexia nervosa was admitted to our hospital because of malaise, anorexia and edema in the face and legs. She was diagnosed with gelatinous bone marrow and iron deficiency anemia due to severe malnutrition. She was intravenously treated by saccharated ferric oxide and her anemia was improved, but her bone marrow still showed much

Daisuke Nonaka; Minoru Tanaka; Kouichi Takaki; Morio Umeno; Takashi Okamura; Hirohisa Taketa



Blast-induced electromagnetic fields in the brain from bone piezoelectricity  

Microsoft Academic Search

In this paper, we show that bone piezoelectricity—a phenomenon in which bone polarizes electrically in response to an applied mechanical stress and produces a short-range electric field—may be a source of intense blast-induced electric fields in the brain, with magnitudes and timescales comparable to fields with known neurological effects. We compute the induced charge density in the skull from stress

Ka Yan Karen Lee; Michelle K. Nyein; David F. Moore; J. D. Joannopoulos; Simona Socrate; Timothy Imholt; Raul Radovitzky; Steven G. Johnson



Fluid and Solute Transport in Bone: Flow-Induced Mechanotransduction  

PubMed Central

Much recent evidence suggests that bone cells sense their mechanical environment via interstitial fluid flow. In this review, we summarize theoretical and experimental approaches to quantify fluid and solute transport in bone, starting with the early investigations of fluid shear stress applied to bone cells. The pathways of bone interstitial fluid and solute movement are high-lighted based on recent theoretical models, as well as a new generation of tracer experiments that have clarified and refined the structure and function of the osteocyte pericellular matrix. Then we trace how the fluid-flow models for mechanotransduction have evolved as new ultrastructural features of the osteocyte lacunar-canalicular porosity have been identified and how more recent in vitro fluid-flow and cell-stretch experiments have helped elucidate at the molecular level the possible pathways for cellular excitation in bone.

Fritton, Susannah P.; Weinbaum, Sheldon



IKKss as a target for treatment of inflammation induced bone loss  

PubMed Central

The transcription factor nuclear factor (NF)-?B is well recognised as a pivotal player in osteoclastogenesis and inflammation induced bone loss. Here, the authors discuss their recent results, obtained using a genetic approach in mice, that indicate the importance of IKKß, and not IKK?, as a transducer of signals from receptor activator of NF-?B (RANK) to NF-?B. Ablation of IKKß results in lack of osteoclastogenesis and unresponsiveness of IKKß deficient mice to inflammation induced bone loss. In the need of a more effective therapy for the treatment of inflammatory diseases causing bone resorption, specific inhibition of IKKß represents a logical alternative strategy to the current therapies.

Ruocco, M; Karin, M



Prostate Cancer Metastases to Bone: Role of High Bone Turnover Induced by Androgen Deprivation.  

National Technical Information Service (NTIS)

Most patients with advanced prostate cancer have bone metastases. These metastases contribute significantly to the morbidity and mortality associated with advanced prostate cancer. Unfortunately, our knowledge of how and why prostate cancer metastasizes t...

S. S. Padalecki



Influence of bone osteocalcin levels on bone loss induced by ovariectomy in rats  

Microsoft Academic Search

To investigate the role of osteocalcin (OC) in bones, bone parameters in warfarin (WF)-treated rats after ovariectomy (OVX)\\u000a were compared with those in intact rats. Rats were divided into an intact group and WF-treated group. Warfarin was orally\\u000a given to rats for 16 weeks, and then OVX was performed and rats in the WF-treated groups continued receiving WF. Twelve weeks

Kuniko Hara; Masatoshi Kobayashi; Yasuhiro Akiyama



Imatimid-induced bone marrow necrosis detected on MRI examination and mimicking bone metastases  

Microsoft Academic Search

Imatinib has revolutionized the treatment and prognosis of patients with gastrointestinal stromal tumors (GIST). In contrast\\u000a to liver and\\/or abdominal involvement, bone metastases are an uncommon event in GIST. We report here two patients with metastatic\\u000a GIST who developed pelvic bone marrow focal lesions visible on MRI examinations, while Imatinib dramatically improved other\\u000a tumor sites. A biopsy in one patient

D. Vanel; S. Bonvalot; C. Le Pechoux; A. Cioffi; J. Domont; A. Le Cesne



Natriuretic peptide-sensitive guanylyl cyclase expression is down-regulated in human melanoma cells at simulated weightlessness  

Microsoft Academic Search

The membrane-bound guanylyl cyclases A and B (GC-A\\/B), which are receptors for natriuretic peptides, are expressed in cancer cells including melanomas and may represent new anticancer targets. Here, we report down-regulation of GC-A\\/B expression in human metastatic melanoma cells at simulated weightlessness in comparison to 1g conditions, suggesting attenuation of metastatic potential in weightlessness.

Krassimira Ivanova; Peter Eiermann; Wasiliki Tsiockas; Jens Hauslage; Ruth Hemmersbach; Rupert Gerzer



The Role of Purinergic Receptors in Cancer-Induced Bone Pain  

PubMed Central

Cancer-induced bone pain severely compromises the quality of life of many patients suffering from bone metastasis, as current therapies leave some patients with inadequate pain relief. The recent development of specific animal models has increased the understanding of the molecular and cellular mechanisms underlying cancer-induced bone pain including the involvement of ATP and the purinergic receptors in the progression of the pain state. In nociception, ATP acts as an extracellular messenger to transmit sensory information both at the peripheral site of tissue damage and in the spinal cord. Several of the purinergic receptors have been shown to be important for the development and maintenance of neuropathic and inflammatory pain, and studies have demonstrated the importance of both peripheral and central mechanisms. We here provide an overview of the current literature on the role of purinergic receptors in cancer-induced bone pain with emphasis on some of the difficulties related to studying this complex pain state.

Falk, Sarah; Uldall, Maria; Heegaard, Anne-Marie



Alendronate as an Effective Countermeasure to Disuse Induced Bone loss.  

National Technical Information Service (NTIS)

Microgravity, similar to diuse immobilization on earth, causes rapid bone loss. This loss is believed to be an adaptive response to the reduced musculoskelatal forces in space and occurs gradually enough that changes occurring during short duration space ...

A. D. LeBlanc D. Lai H. J. Evans L. C. Shackelford N. J. Rianon S. M. Smith T. B. Driscol



Chemical and morphologic alterations of rabbit bone induced by adriamycin  

Microsoft Academic Search

Long term, low dose administration of adriamycin (ADR) to young growing rabbits resulted in significant alterations in bone\\u000a structure and chemistry. Morphologic changes were most pronounced at epiphyseal and metaphyseal areas of long bones. Epiphyseal\\u000a cartilage plates were thin and there was derangement of growth zones. Areas of primary and secondary spongiosa were deficient\\u000a in trabeculae, osteoblasts and osteoclasts. Analysis

D. M. Young; J. L. Fioravanti; H. M. Olson; D. J. Prieur



Exercise induced mechano-sensing and substance P mediated bone modeling in Atlantic salmon.  


Mechanical stress plays a vital role in maintaining bone architecture. The process by which osteogenic cells convert the mechanical signal into a biochemical response governing bone modeling is not clear, however. In this study, we investigated how Atlantic salmon (Salmo salar) vertebra responds to exercise-induced mechanical loading. Bone formation in the vertebrae was favored through increased expression of genes involved in osteoid production. Fourier transform infrared spectroscopy (FT-IR) showed that bone matrix secreted both before and during sustained swimming had different properties after increased load compared to control, suggesting that both new and old bones are affected. Concomitantly, both osteoblasts and osteocytes in exercised salmon showed increased expression of the receptor nk-1 and its ligand substance P (SP), both known to be involved in osteogenesis. Moreover, in situ hybridization disclosed SP mRNA in osteoblasts and osteocytes, supporting an autocrine function. The functional role of SP was investigated in vitro using osteoblasts depleted for SP. The cells showed severely reduced transcription of genes involved in mineralization, demonstrating a regulatory role for SP in salmon osteoblasts. Investigation of ?-tubulin stained osteocytes revealed cilia-like structures. Together with SP, cilia may link mechanical responses to osteogenic processes in the absence of a canaliculi network. Our results imply that salmon vertebral bone responds to mechanical load through a highly interconnected and complex signal and detection system, with SP as a key factor for initializing mechanically-induced bone formation in bone lacking the canaliculi system. PMID:23219942

Ytteborg, Elisabeth; Torgersen, Jacob Seilø; Pedersen, Mona Elisabeth; Helland, Ståle J; Grisdale-Helland, Barbara; Takle, Harald



Human stem cell osteoblastogenesis mediated by novel glycogen synthase kinase 3 inhibitors induces bone formation and a unique bone turnover biomarker profile in rats.  


Wnt activation by inhibiting glycogen synthase kinase 3 (GSK-3) causes bone anabolism in rodents making GSK-3 a potential therapeutic target for osteoporotic and osteolytic metastatic bone disease. To understand the wnt pathway related to human disease translation, the ability of 3 potent inhibitors of GSK-3 (AZD2858, AR79, AZ13282107) to 1) drive osteoblast differentiation and mineralisation using human adipose-derived stem cells (hADSC) in vitro; and 2) stimulate rat bone formation in vivo was investigated. Bone anabolism/resorption was determined using clinically relevant serum biomarkers as indicators of bone turnover and bone formation assessed in femurs by histopathology and pQCT/?CT imaging. GSK-3 inhibitors caused ?-catenin stabilisation in human and rat mesenchymal stem cells, stimulated hADSC commitment towards osteoblasts and osteogenic mineralisation in vitro. AZD2858 produced time-dependent changes in serum bone turnover biomarkers and increased bone mass over 28days exposure in rats. After 7days, AZD2858, AR79 or AZ13282107 exposure increased the bone formation biomarker P1NP, and reduced the resorption biomarker TRAcP-5b, indicating increased bone anabolism and reduced resorption in rats. This biomarker profile was differentiated from anabolic agent PTH1-34 or the anti-resorptive Alendronate-induced changes. Increased bone formation in cortical and cancellous bone as assessed by femur histopathology supported biomarker changes. 14 day AR79 treatment increased bone mineral density and trabecular thickness, and decreased trabecular number and connectivity assessed by pQCT/?CT. GSK-3 inhibition caused hADSC osteoblastogenesis and mineralisation in vitro. Increased femur bone mass associated with changes in bone turnover biomarkers confirmed in vivo bone formation and indicated uncoupling of bone formation and resorption. PMID:23872097

Gilmour, Peter S; O'Shea, Patrick J; Fagura, Malbinder; Pilling, James E; Sanganee, Hitesh; Wada, Hiroki; Courtney, Paul F; Kavanagh, Stefan; Hall, Peter A; Escott, K Jane



Disease modification of breast cancer-induced bone remodeling by cannabinoid 2 receptor agonists.  


Most commonly originating from breast malignancies, metastatic bone cancer causes bone destruction and severe pain. Although novel chemotherapeutic agents have increased life expectancy, patients are experiencing higher incidences of fracture, pain, and drug-induced side effects; furthermore, recent findings suggest that patients are severely undertreated for their cancer pain. Strong analgesics, namely opiates, are first-line therapy in alleviating cancer-related pain despite the severe side effects, including enhanced bone destruction with sustained administration. Bone resorption is primarily treated with bisphosphonates, which are associated with highly undesirable side effects, including nephrotoxicity and osteonecrosis of the jaw. In contrast, cannabinoid receptor 2 (CB(2) ) receptor-specific agonists have been shown to reduce bone loss and stimulate bone formation in a model of osteoporosis. CB(2) agonists produce analgesia in both inflammatory and neuropathic pain models. Notably, mixed CB(1) /CB(2) agonists also demonstrate a reduction in ErbB2-driven breast cancer progression. Here we demonstrate for the first time that CB(2) agonists reduce breast cancer-induced bone pain, bone loss, and breast cancer proliferation via cytokine/chemokine suppression. Studies used the spontaneously-occurring murine mammary cell line (66.1) implanted into the femur intramedullary space; measurements of spontaneous pain, bone loss, and cancer proliferation were made. The systemic administration of a CB(2) agonist, JWH015, for 7 days significantly attenuated bone remodeling, assuaged spontaneous pain, and decreased primary tumor burden. CB(2) -mediated effects in vivo were reversed by concurrent treatment with a CB(2) antagonist/inverse agonist but not with a CB(1) antagonist/inverse agonist. In vitro, JWH015 reduced cancer cell proliferation and inflammatory mediators that have been shown to promote pain, bone loss, and proliferation. Taken together, these results suggest CB(2) agonists as a novel treatment for breast cancer-induced bone pain, in which disease modifications include a reduction in bone loss, suppression of cancer growth, attenuation of severe bone pain, and increased survival without the major side effects of current therapeutic options. PMID:22903605

Lozano-Ondoua, Alysia N; Hanlon, Katherine E; Symons-Liguori, Ashley M; Largent-Milnes, Tally M; Havelin, Josh J; Ferland, Henry L; Chandramouli, Anupama; Owusu-Ankomah, Mabel; Nikolich-Zugich, Tijana; Bloom, Aaron P; Jimenez-Andrade, Juan Miguel; King, Tamara; Porreca, Frank; Nelson, Mark A; Mantyh, Patrick W; Vanderah, Todd W



Potential benefits of maximal exercise just prior to return from weightlessness  

SciTech Connect

The purpose of this study was to determine whether performance of a single maximal bout of exercise during weightlessness within hours of return to earth would enhance recovery of aerobic fitness and physical work capacities under a 1G environment. Ten healthy men were subjected to a 10-d bedrest period in the 6-deg headdown position. A graded maximal supine cycle ergometer test was performed before and at the end of bedrest to simulate exercise during weightlessness. Following 3 h of resumption of the upright posture, a second maximal exercise test was performed on a treadmill to measure work capacity under conditions of 1G. Compared to before bedrest, peak oxygen consumption, V(O/sub 2/), decreased by 8.7 percent and peak heart rate (HR) increased by 5.6 percent in the supine cycle test at the end of bedrest. However, there were no significant changes in peak V(O/sub 2/) and peak HR in the upright treadmill test following bedrest. These data suggest that one bout of maximal leg exercise prior to return from 10 d of weightlessness may be adequate to restore preflight aerobic fitness and physical work capacity. 26 references.

Convertino, V.A.



Simulated weightlessness in the design and exploitation of a NMR-compatible bioreactor.  


Mammalian cells cultured in simulated weightlessness take advantage of a favorable environment, experiencing low shear stress and reduced turbulence. NMR spectroscopy allows the on-line noninvasive monitoring of cell growth and metabolism. With this in mind, we developed a novel bioreactor that fits into a NMR instrument and in which the simulated weightlessness conditions are obtained by a suitable medium and a flow-lift suspension. In detail, the gravitational vector acting on cells is counterbalanced by the hydrodynamic thrusts created by a bottom-up spiral flow of a fluid having increased density. We validate its efficiency (a) by calculating the main physical parameters as relative velocity, shear stress, and oxygen transport, and (b) by comparing the experimental results of growing a cell culture in the proposed bioreactor with those obtained using an established simulated weightlessness system (rotating wall vessel, NASA). As a test study we focused on the proliferation of human umbilical vein endothelial cells (HUVEC) in terms of cell viability and organization of their cytoskeleton. PMID:15458330

Bradamante, Silvia; Barenghi, Livia; Villa, Alessandro


RAGE supports parathyroid hormone-induced gains in femoral trabecular bone  

PubMed Central

Parathyroid hormone (PTH) restores bone mass to the osteopenic skeleton, but significant questions remain as to the underlying mechanisms. The receptor for advanced glycation end products (RAGE) is a multiligand receptor of the immunoglobulin superfamily; however, recent studies indicate a role in bone physiology. We investigated the significance of RAGE to hormone-induced increases in bone by treating 10-wk-old female Rage-knockout (KO) and wild-type (WT) mice with human PTH-(1–34) at 30 ?g·kg?1·day?1 or vehicle control, 7 days/wk, for 7 wk. PTH produced equivalent relative gains in bone mineral density (BMD) and bone mineral content (BMC) throughout the skeleton in both genotypes. PTH-mediated relative increases in cortical area of the midshaft femur were not compromised in the null mice. However, the hormone-induced gain in femoral cancellous bone was significantly attenuated in Rage-KO mice. The loss of RAGE impaired PTH-mediated increases in femoral cancellous bone volume, connectivity density, and trabecular number but did not impact increases in trabecular thickness or decreases in trabecular spacing. Disabling RAGE reduced femoral expression of bone formation genes, but their relative PTH-responsiveness was not impaired. Neutralizing RAGE did not attenuate vertebral cancellous bone response to hormone. Rage-null mice exhibited an attenuated accrual rate of bone mass, with the exception of the spine, and an enhanced accrual rate of fat mass. We conclude that RAGE is necessary for key aspects of the skeleton's response to anabolic PTH. Specifically, RAGE is required for hormone-mediated improvement of femoral trabecular architecture but not intrinsically necessary for increasing cortical thickness.

Philip, Binu K.; Childress, Paul J.; Robling, Alexander G.; Heller, Aaron; Nawroth, Peter P.; Bierhaus, Angelika



Pathological role of osteoclast costimulation in arthritis-induced bone loss  

PubMed Central

Abnormal T cell immune responses induce aberrant expression of inflammatory cytokines such as TNF-?, leading to osteoclastmediated bone erosion and osteoporosis in autoimmune arthritis. However, the mechanism underlying enhanced osteoclastogenesis in arthritis is not completely understood. Here we show that TNF-? contributes to inflammatory bone loss by enhancing the osteoclastogenic potential of osteoclast precursor cells through inducing paired Ig-like receptor-A (PIR-A), a costimulatory receptor for receptor activator of NF-?B (RANK). In fact, bone erosion and osteoporosis, but not inflammation, caused by aberrant TNF-? expression were ameliorated in mice deficient in Fc receptor common ? subunit or ?2-microglobulin, in which the expression of PIR-As and PIR-A ligands is impaired, respectively. These results establish the pathological role of costimulatory receptors for RANK in bone loss in arthritis and may provide a molecular basis for the future therapy of inflammatory diseases.

Ochi, Sae; Shinohara, Masahiro; Sato, Kojiro; Gober, Hans-Jurgen; Koga, Takako; Kodama, Tatsuhiko; Takai, Toshiyuki; Miyasaka, Nobuyuki; Takayanagi, Hiroshi



Usefulness of daily +2Gz load as a countermeasure against physiological problems during weightlessness  

NASA Astrophysics Data System (ADS)

Adaptation to head-down-tilt bed rest as a simulated microgravity leads to an abnormality of reflex control of circulation, hypovolemia and reduction of exercise capacity. We hypothesized that this cardiovascular deconditioning and reduction of exercise capacity could be prevented by a daily 1 hr centrifugation at +2Gz. To test this hypothesis, twenty healthy male subjects underwent 4 day of 6° head-down-tilt bed rest. Ten of them were exposed to a +2Gz load for up to 30 min twice per day (the Gz group). The remaining 10 were not exposed to a Gz load (the no-Gz group). We estimated autonomic cardiovascular control by power spectral analysis of blood pressure and R-R interval variability, and baroreflex regulation by the transfer function analysis and the sequence method, before and after bed rest. Further, we measured hematocrit as an index of changes in plasma volume and maximal oxygen consumption as an index of exercise capacity, before and after bed rest. Result: In the no-Gz group, heart rate increased after bed rest. The high frequency power of R-R interval variability as an index of cardiac parasympathetic nervous activity, baroreflex gains estimated by transfer function analysis and the sequence method as index of the integrated arterial-cardiac baroreflex function decreased significantly. Associated with these changes, the ratio of low to high frequency power of R-R as an indicator of cardiac sympathovagal balance tended to increase after bed rest in the no-Gz group. However, those showed no significant changes after bed rest in the Gz group. Hematocrit increased after bed rest in the no-Gz group. It also tended to increase in the Gz group, however it did not achieve statistical significance. Maximal oxygen consumption decreased significantly to similar extent in both the groups. Conclusion: This result suggested that 1) a daily 1hr +2Gz load produced by a centrifuge might eliminate the changes in autonomic cardiovascular control during simulated weightlessness; 2) furthermore, it might partly reverse hypovolemia induced by bed rest; 3) however, it could not prevent the decreases in exercise capacity.

Iwasaki, Ken-ichi; Sasaki, Tsuyoshi; Hirayanagi, Kaname; Yajima, Kazuyoshi


Compactin and Simvastatin, but Not Pravastatin, Induce Bone Morphogenetic Protein2 in Human Osteosarcoma Cells  

Microsoft Academic Search

Bone morphogenetic protein (BMP)-2, a member of the BMP family, plays an important role in osteoblast differentiation and bone formation. To discover small molecules that induce BMP-2, a luciferase reporter vector containing the 5?-flanking promoter region of the human BMP-2 gene was constructed and transfected into human osteosarcoma (HOS) cells. By the screening of an in-house natural product library with

Masako Sugiyama; Tohru Kodama; Kyoko Konishi; Keiichi Abe; Sumio Asami; Shinzo Oikawa



Severe hyperparathyroidism with bone abnormalities and metastatic calcification in rats with adenine-induced uraemia  

Microsoft Academic Search

Background. Marked parathyroid hyperplasia with bone diseases and vascular calcification are unsolved issues in dialysis patients. In this study, we made azotemic model rats by adenine feeding and analyzed the development and progression of the abnormalities. Methods. Renal failure was induced in 8-week-old male Wistar rats by feeding 0.75% adenine-containing diet for 6 weeks. Serum parameters, parathyroid hyperplasia, bone changes

Keiichi Tamagaki; Qunsheng Yuan; Hiroyuki Ohkawa; Ikuo Imazeki; Yoshiyuki Moriguchi; Nobuo Imai; Susumu Sasaki; Kazuo Takeda; Masafumi Fukagawa



A high-fat diet induces obesity and impairs bone acquisition in young male mice.  


The postnatal development of obesity is highly associated with the excessive consumption of a high-calorie, high-fat diet (HFD). However, the correlation between HFD-induced pediatric obesity and skeletal development remains to be elucidated. In the present study, postnatal day 17 (PND17) mice were weaned on a HFD for eight weeks ad libitum to induce obesity. The HFD mice showed a significant increase in the total body weight and gonadal and abdominal fat mass compared with the control animals. Peripheral quantitative (pQ) CT scans of the tibial bone revealed that the bone mineral density (BMD), including the total, trabecular and cortical BMD, was unchanged between the HFD and control diet groups, but that it was inversely associated with body fat. By contrast, the bone mineral content (BMC) and trabecular area were significantly decreased in the HFD group compared with the control. RNA and protein were isolated from the femur. qPCR and western blot analyses showed a significant downregulation in the gene expression of the key canonical Wnt signaling molecule ?-catenin, the osteoblastic cell differentiation marker Runt-related transcription factor 2 (Runx2) and also in the ?-catenin gene encoded protein levels of the HFD mice when compared with the controls. Consistent with the increased fat mass in the HFD-induced obese animals, the expression of the adipogenic genes and aP2 was increased compared with the controls. Bone marrow cells were aspirated and the ex vivo bone marrow cell cultures showed that the number of colony-forming unit osteoblasts (CFU-OBs) per bone was significantly decreased in the samples from the HFD mice compared with those from the controls. These observations suggested that HFD-induced obesity in growing animals may affect the total available osteoblastic cell differentiation progenitors in the bone, while increasing adipogenesis. This may result in negative consequences for the bone later on in adult life. PMID:23444006

Lu, Xiao-Mei; Zhao, Hong; Wang, En-Hua



Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction  

Microsoft Academic Search

To confirm whether human cancer-induced stromal cells are derived from bone marrow, bone marrow (BM) cells obtained from ?-galactosidase transgenic and recombination activating gene 1 (RAG-1) deficient double-mutant mice (H-2b) were transplanted into sublethally irradiated severe combined immunodeficient (SCID) mice (H-2d). The human pancreatic cancer cell line Capan-1 was subcutaneously xenotransplanted into SCID recipients and stromal formation was analyzed on

Genichiro Ishii; Takafumi Sangai; Tatsuya Oda; Yasuyuki Aoyagi; Takahiro Hasebe; Naoki Kanomata; Yasushi Endoh; Chie Okumura; Yoko Okuhara; Junji Magae; Makito Emura; Takahiro Ochiya; Atsushi Ochiai



Effects of physical activities that induce moderate external loading on bone metabolism in male athletes  

Microsoft Academic Search

Sports characterized by little or moderate weight bearing or impact have a low osteogenic effect. However, the action of such sports on bone turnover remains unclear. The objective of this study was to determine the effect on bone remodelling of physical activities that induce moderate external loading on the skeleton. Thirty-eight male athletes aged 18–39 years (cyclists, n?=?11; swimmers, n?=?13;

L Maïmoun; D Mariano-Goulart; I Couret; J Manetta; E Peruchon; JP Micallef; R Verdier; M Rossi; JL Leroux



Cell-induced response by tetracyclines on human bone marrow colonized hydroxyapatite and Bonelike ®  

Microsoft Academic Search

Semi-synthetic tetracyclines are commonly used antibiotics that also seem to play an important role in the modulation of the immuno-inflammatory imbalance, verified in several bone diseases. The association of a therapeutic agent (that prevents bacterial infection and induces tissue formation) to a biomaterial aiming to repair\\/regenerate bone defects could contribute to a more predictable clinical outcome. The present study intends

P. S. Gomes; J. D. Santos; M. H. Fernandes



Repression of Osteoblast Maturation by ERR? Accounts for Bone Loss Induced by Estrogen Deficiency  

PubMed Central

ERR? is an orphan member of the nuclear receptor family, the complete inactivation of which confers resistance to bone loss induced by ageing and estrogen withdrawal to female mice in correlation with increased bone formation in vivo. Furthermore ERR? negatively regulates the commitment of mesenchymal cells to the osteoblast lineage ex vivo as well as later steps of osteoblast maturation. We searched to determine whether the activities of ERR? on osteoblast maturation are responsible for one or both types of in vivo induced bone loss. To this end we have generated conditional knock out mice in which the receptor is normally present during early osteoblast differentiation but inactivated upon osteoblast maturation. Bone ageing in these animals was similar to that observed for control animals. In contrast conditional ERR?KO mice were completely resistant to bone loss induced by ovariectomy. We conclude that the late (maturation), but not early (commitment), negative effects of ERR? on the osteoblast lineage contribute to the reduced bone mineral density observed upon estrogen deficiency.

Gallet, Marlene; Saidi, Soraya; Hay, Eric; Photsavang, Johann; Marty, Caroline; Sailland, Juliette; Carnesecchi, Julie; Tribollet, Violaine; Barenton, Bruno; Forcet, Christelle; Birling, Marie-Christine; Sorg, Tania; Chassande, Olivier; Cohen-Solal, Martine; Vanacker, Jean-Marc



Tumor Tissue-Derived Formaldehyde and Acidic Microenvironment Synergistically Induce Bone Cancer Pain  

PubMed Central

Background There is current interest in understanding the molecular mechanisms of tumor-induced bone pain. Accumulated evidence shows that endogenous formaldehyde concentrations are elevated in the blood or urine of patients with breast, prostate or bladder cancer. These cancers are frequently associated with cancer pain especially after bone metastasis. It is well known that transient receptor potential vanilloid receptor 1 (TRPV1) participates in cancer pain. The present study aims to demonstrate that the tumor tissue-derived endogenous formaldehyde induces bone cancer pain via TRPV1 activation under tumor acidic environment. Methodology/Principal Findings Endogenous formaldehyde concentration increased significantly in the cultured breast cancer cell lines in vitro, in the bone marrow of breast MRMT-1 bone cancer pain model in rats and in tissues from breast cancer and lung cancer patients in vivo. Low concentrations (1?5 mM) of formaldehyde induced pain responses in rat via TRPV1 and this pain response could be significantly enhanced by pH 6.0 (mimicking the acidic tumor microenvironment). Formaldehyde at low concentrations (1 mM to 100 mM) induced a concentration-dependent increase of [Ca2+]i in the freshly isolated rat dorsal root ganglion neurons and TRPV1-transfected CHO cells. Furthermore, electrophysiological experiments showed that low concentration formaldehyde-elicited TRPV1 currents could be significantly potentiated by low pH (6.0). TRPV1 antagonists and formaldehyde scavengers attenuated bone cancer pain responses. Conclusions/Significance Our data suggest that cancer tissues directly secrete endogenous formaldehyde, and this formaldehyde at low concentration induces metastatic bone cancer pain through TRPV1 activation especially under tumor acidic environment.

Yang, Fei; Han, Ying; Li, Hui; Luo, Hongjun; Duan, Bo; Xu, Tianle; Maoying, Qiliang; Tan, Huangying; Wang, Jun; Zhao, Hongmei; Liu, Fengyu; Wan, You



Subtle shake-up in bone-loss research.  


Recent research in the prevention of bone loss during weightlessness is described. Scientists are studying the effects of vibration on bone loss in laboratory animals and humans. Research is focused on determining how bone formation is triggered, the effects of stimulation of the stress response in bones, and the mechanisms behind the effects. Clinton Rubin at the State University of New York at Stony Brook is experimenting with 90 Hz vibration frequencies in rats. Other researchers are studying the effects of vibration plates in the treatment of osteoporosis in postmenopausal women and in children with low bone density. Tests among astronauts have been proposed, but none are scheduled. PMID:11898823

Flinn, Edward D



Fusobacterium nucleatum and Tannerella forsythia induce synergistic alveolar bone loss in a mouse periodontitis model.  


Tannerella forsythia is strongly associated with chronic periodontitis, an inflammatory disease of the tooth-supporting tissues, leading to tooth loss. Fusobacterium nucleatum, an opportunistic pathogen, is thought to promote dental plaque formation by serving as a bridge bacterium between early- and late-colonizing species of the oral cavity. Previous studies have shown that F. nucleatum species synergize with T. forsythia during biofilm formation and pathogenesis. In the present study, we showed that coinfection of F. nucleatum and T. forsythia is more potent than infection with either species alone in inducing NF-?B activity and proinflammatory cytokine secretion in monocytic cells and primary murine macrophages. Moreover, in a murine model of periodontitis, mixed infection with the two species induces synergistic alveolar bone loss, characterized by bone loss which is greater than the additive alveolar bone losses induced by each species alone. Further, in comparison to the single-species infection, mixed infection caused significantly increased inflammatory cell infiltration in the gingivae and osteoclastic activity in the jaw bones. These data show that F. nucleatum subspecies and T. forsythia synergistically stimulate the host immune response and induce alveolar bone loss in a murine experimental periodontitis model. PMID:22547549

Settem, Rajendra P; El-Hassan, Ahmed Taher; Honma, Kiyonobu; Stafford, Graham P; Sharma, Ashu



Similarities and discrepancies in subchondral bone structure in two differently induced canine models of osteoarthritis.  


In osteoarthritis (OA), cartilage degradation is accompanied by subchondral bone changes. The pathogenesis and physiology of bone changes in OA are still unclear. The changes in subchondral bone architecture and cartilage damage were compared in differently induced experimental models of OA. Experimental OA was induced bilaterally by anterior cruciate ligament transection (ACLT) or by cartilage trauma (Groove model); bilateral sham surgery served as control. Lysylpyridinoline (LP, bone resorption) and C-telopeptide of type II collagen (CTX-II, cartilage breakdown) were measured over time. At 20 weeks after surgery, the subchondral cortical plate and trabecular bone of the tibia were analyzed by micro-computed tomography (microCT) and cartilage degeneration was analyzed histologically and biochemically. In both models, cartilage degeneration and cortical subchondral plate thinning were present. CTX-II levels were elevated over time in both models. Subchondral trabecular bone changes were observed only in the ACLT model, not in the Groove model. Correspondingly, LP levels were elevated over time in the ACLT model and not in the Groove model. Interestingly, the trabecular bone changes in the ACLT model were extended to the metaphyseal area. The early decrease in plate thickness, present in both models, as was cartilage damage, suggests that plate thinning is a phenomenon that is intrinsic to the process of OA independent of the cause/induction of OA. On the other hand, trabecular changes in subchondral and metaphyseal bone are not part of a common pathway of OA development and may be induced biomechanically in the destabilized and less loaded ACLT joint. PMID:20200954

Intema, Femke; Sniekers, Yvonne H; Weinans, Harrie; Vianen, Marieke E; Yocum, Sue A; Zuurmond, Anne-Marie M; DeGroot, Jeroen; Lafeber, Floris P; Mastbergen, Simon C



Fish bone-induced hepatic abscess: medical treatment.  


We report a case of a 59-year-old man admitted for acute myocardial infarction. He subsequently spiked a high-grade fever on the second day after percutaneous coronary intervention. Computed tomography imaging of the abdomen revealed a hepatic abscess secondary to gastrointestinal perforation by a fish bone. Medical therapy with antibiotics was preferred over surgical drainage of the hepatic abscess in view of the fact that the patient was on dual antiplatelet agents. The hepatic abscess was completely resolved with conservative antimicrobial therapy. Antimicrobial therapy appears to be a viable option in selected patients with hepatic abscess secondary to fish bone perforation, especially if they have contraindications to surgery. PMID:21451917

Ng, C T; Htoo, A; Tan, S Y



Management of cancer treatment-induced bone loss in early breast and prostate cancer - a consensus paper of the Belgian Bone Club  

Microsoft Academic Search

Cancer treatment-induced bone loss (CTIBL) is one of the most important side effects of adjuvant antineoplastic treatment\\u000a in hormone-dependent neoplasms. Chemotherapy, GnRH analogs and tamoxifen can induce marked bone loss in premenopausal women\\u000a with early breast cancer. Aromatase inhibitors (AIs) are replacing tamoxifen as the preferred treatment for postmenopausal\\u000a women. As a class effect, steroidal (exemestane) and non-steroidal (anastrozole and

J. J. Body; P. Bergmann; S. Boonen; Y. Boutsen; J. P. Devogelaer; S. Goemaere; J. Y. Reginster; S. Rozenberg; J. M. Kaufman



Granulocyte-Macrophage Colony-Stimulating Factor-Induced Antibody-Dependent Cellular Cytotoxicity in Bone Marrow Macrophages: Application in Bone Marrow Transplantation  

Microsoft Academic Search

Granulocyte-macrophage colony-stimulating factor (GM- CSF) has been reported to induce antitumor activity in pe- ripheral blood monocytes. We examined the role of GM- CSF on bone marrow (BM) macrophages in inducing antibody-dependent cellular cytotoxicity (ADCC) against murine and human tumor cells in vitro and in vivo with the aim of applying this approach in an autologous bone marrow transplantation (BMT)

Bishan S. Charak; Ravin Agah; Amitabha Mazumder



2-Nitropropane-induced DNA damage in rat bone marrow  

Microsoft Academic Search

DNA damage detected by the comet assay (single cell gel electrophoresis) and 8-oxo-7,8-dihydro-2?-deoxyguanosine (8-oxodG) formation in DNA in the bone marrow has been studied in groups of 6 male Wistar rats treated with a single i.p. injection of the carcinogen 2-nitropropane (2-NP, 100 mg\\/kg body weight) or vehicle. Twenty-four hours after 2-NP the average tail length in the comet assay

Xin-sheng Deng; Jinsheng Tuo; Henrik E Poulsen; Steffen Loft



Bone marrow non-mesenchymal mononuclear cells induce functional differentiation of neuroblastoma cells.  


Less is known about the non-mesenchymal mononuclear cell fraction of human bone marrow on functional adaptation of neuroblastoma cells. Using immunocytochemistry, we showed that bone-marrow mononuclear cell (BMMC)-conditioned medium can induce tyrosine hydroxylase expression in neuroblastoma cells, which is similar to the effect of retinoic acid. Using quantitative RT-PCR, we showed that NGF, CNTF, and BDNF mRNAs were detected in unfractionated BMMC populations from all human donors at different expression levels. Our results suggest that cells of the non-mesenchymal mononuclear cell fraction can induce functional adaptation of neuroblastoma cells, probably via their secreted trophic factors. PMID:23551916

Phruksaniyom, Chareerut; Dharmasaroja, Permphan; Issaragrisil, Surapol



Chronic alcohol ingestion induces osteoclastogenesis and bone loss through IL-6 in mice  

PubMed Central

To investigate the role of IL-6 in alcohol-mediated osteoporosis, we measured a variety of bone remodeling parameters in wild-type (il6+/+) or IL-6 gene knockout (il6–/–) mice that were fed either control or ethanol liquid diets for 4 months. In the il6+/+ mice, ethanol ingestion decreased bone mineral density, as determined by dual-energy densitometry; decreased cancellous bone volume and trabecular width and increased trabecular spacing and osteoclast surface, as determined by histomorphometry of the femur; increased urinary deoxypyridinolines, as determined by ELISA; and increased CFU-GM formation and osteoclastogenesis as determined ex vivo in bone marrow cell cultures. In contrast, ethanol ingestion did not alter any of these parameters in the il6–/– mice. Ethanol increased receptor activator of NF-?B ligand (RANKL) mRNA expression in the bone marrow of il6+/+ but not il6–/– mice. Additionally, ethanol decreased several osteoblastic parameters including osteoblast perimeter and osteoblast culture calcium retention in both il6+/+ and il6–/– mice. These findings demonstrate that ethanol induces bone loss through IL-6. Furthermore, they suggest that IL-6 achieves this effect by inducing RANKL and promoting CFU-GM formation and osteoclastogenesis.

Dai, Jinlu; Lin, Dinlii; Zhang, Jian; Habib, Paula; Smith, Peter; Murtha, Jill; Fu, Zheng; Yao, Zhi; Qi, Yinghua; Keller, Evan T.



Morphological differences in BMP-2-induced ectopic bone between solid and crushed hyaluronan hydrogel templates.  


The possibility to affect bone formation by using crushed versus solid hydrogels as carriers for bone morphogenetic protein 2 (BMP-2) was studied. Hydrogels, based on chemical crosslinking between hyaluronic acid and poly(vinyl alcohol) derivatives, were loaded with BMP-2 and hydroxyapatite. Crushed and solid forms of the gels were analyzed both in vitro via a release study using ¹²?I radioactive labeling of BMP-2, and in vivo in a subcutaneous ectopic bone model in rats. Dramatically different morphologies were observed for the ectopic bone formed in vivo in the two types of gels, even though virtually identical release profiles were observed in vitro. Solid hydrogels induced formation of a dense bone shell around non-degraded hydrogel, while crushed hydrogels demonstrated a uniform bone formation throughout the entire sample. These results suggest that by crushing the hydrogel, the construct's three-dimensional network becomes disrupted. This could expose unreacted functional groups, making the fragment's surfaces reactive and enable limited chemical fusion between the crushed hydrogel fragments, leading to similar in vitro release profiles. However, in vivo these interactions could be broken by enzymatic activity, creating a macroporous structure that allows easier cell infiltration, thus, facilitating bone formation. PMID:23392969

Hulsart-Billström, Gry; Piskounova, Sonya; Gedda, Lars; Andersson, Britt-Marie; Bergman, Kristoffer; Hilborn, Jöns; Larsson, Sune; Bowden, Tim



Oxidative stress induced by chromium (VI) in bone of suckling rats.  


Exposure to hexavalent chromium Cr(VI) compounds is of concern in many Cr-related industries and their surrounding environments. K(2)Cr(2)O(7) is widely recognized as an animal and human carcinogen, mutagen, and teratogen. The present study investigated the bone maturity of suckling rats whose mothers were treated with K(2)Cr(2)O(7). Experiments were carried out on female Wistar rats given 700 ppm of K(2)Cr(2)O(7) in their drinking water from the 14th day of pregnancy until day 14 after delivery. Exposing dams to K(2)Cr(2)O(7) caused disorders in the bone of their progeny. As corollary to this, malondialdehyde levels increased, while glutathione, a non-protein thiol and vitamin C decreased. Alteration of the antioxidant system in the treated group was also confirmed by the significant decline of superoxide dismutase, catalase, and glutathione peroxidase activities. Furthermore, K(2)Cr(2)O(7) induced changes in bone mineralization, especially calcium and phosphorus levels, which decreased. Whereas, in plasma and urine, they increased and decreased inversely. These results suggest that K(2)Cr(2)O(7) accelerated bone resorption activity. In fact, in treated pups, total tartrate-resistant acid phosphatase, which reflected bone resorption, was enhanced while total alkaline phosphatase, which reflected bone formation, was reduced. The impairment of bone function was corresponded histologically. PMID:21543464

Soudani, Nejla; Ibtissem Ben Amara; Troudi, Afef; Bouaziz, Hanen; Boudawara, Tahia; Zeghal, Najiba



Murine bone cell lines as models for spaceflight induced effects on differentiation and gene expression  

NASA Astrophysics Data System (ADS)

Critical health factors for space crews especially on long-term missions are radiation exposure and the absence of gravity DNA double strand breaks DSB are presumed to be the most deleterious DNA lesions after radiation as they disrupt both DNA strands in close proximity Besides radiation risk the absence of gravity influences the complex skeletal apparatus concerning muscle and especially bone remodelling which results from mechanical forces exerting on the body Bone is a dynamic tissue which is life-long remodelled by cells from the osteoblast and osteoclast lineage Any imbalance of this system leads to pathological conditions such as osteoporosis or osteopetrosis Osteoblastic cells play a crucial role in bone matrix synthesis and differentiate either into bone-lining cells or into osteocytes Premature terminal differentiation has been reported to be induced by a number of DNA damaging or cell stress inducing agents including ionising and ultraviolet radiation as well as treatment with mitomycin C In the present study we compare the effects of sequential differentiation by adding osteoinductive substances ss -glycerophosphate and ascorbic acid Radiation-induced premature differentiation was investigated regarding the biosynthesis of specific osteogenic marker molecules and the differentiation dependent expression of marker genes The bone cell model established in our laboratory consists of the osteocyte cell line MLO-Y4 the osteoblast cell line OCT-1 and the subclones 4 and 24 of the osteoblast cell line MC3T3-E1 expressing several

Lau, P.; Hellweg, C. E.; Baumstark-Khan, C.; Reitz, G.


Mechanically-induced osteogenesis in the cortical bone of pre- to peripubertal stage and peri- to postpubertal stage mice  

Microsoft Academic Search

BACKGROUND: Exercise during postnatal development plays a key role in determining adult bone mass and reducing the risk of fracture and osteoporosis later in life. However, the relationship between mechanically-induced osteogenesis and age is unclear. Elevated levels of estrogen during puberty may inhibit periosteal bone formation. Thus, magnitudes of mechanically-induced osteogenesis may be vary with pubertal state. METHODS: The present

Jeffrey H Plochocki



The relationship between bone marrow characteristics and the clinical prognosis of antithyroid drug-induced agranulocytosis.  


This study is aimed to explore the relationship between bone marrow characteristics and clinical prognosis of antithyroid drug (ATD) induced agranulocytosis. A retrospective study was conducted in the first affiliated hospital of the University of South China. A total of 33 hospitalized patients diagnosed with ATD-induced agranulocytosis were analyzed. The bone marrow characteristics were classified into two types. Type I was characterized by reduction or absence of granulocytic precursors and type II was recognized as hypercellular bone marrow with dysmaturity of granulocytic cells. Bone marrow of 20 cases (61%) were characterized with type I whereas 13 cases (39%) with type II. The median duration of neutrophil recovery and high-grade fever were 4.7 ± 1.0 days and 3.6 ± 2.5 days respectively for type II, compared to 8.0 ± 2.8 days and 8.6 ± 3.1 days for type I (p < 0.01 in both compared groups). However, there was no significant difference between the two types in terms of age, median duration of drug administration before the diagnosis of agranulocytosis, the amount of neutrophil count on admission and the total administration dose of granulocyte-colony stimulating factor (G-CSF) before bone marrow examination. Two cases of type I died of complications from infection. This study showed that the bone marrow characteristics of ATD-induced agranulocytosis could be classifed into two types. Also, the clinical prognosis was closely related to the bone marrow features. Type I is the dominant type which is usually associated with worse clinical prognosis compared to type II. PMID:23117149

Yang, Jing; Zhong, Jing; Xiao, Xin-Hua; Zhou, Ling-Zhi; Chen, Ya-Jun; Liu, Jiang-Hua; Cao, Ren-Xian; Wen, Ge-Bo



Carbon monoxide protects against ovariectomy-induced bone loss by inhibiting osteoclastogenesis.  


Carbon monoxide (CO) has been shown to have remarkable therapeutic value at low dosage by suppressing inflammation via inhibitory effects on macrophages, which are also precursors of osteoclasts (OC). The objective of the present study was to determine whether CO limits bone loss through its effects on osteoclastogenesis. Intraperitoneal injection of CO-releasing molecule 2 (CORM2) into mice with reduced bone mass due to ovariectomy (OVX) resulted in significantly elevated bone mass. Increased serum levels of collagen-type I fragments, tartrate-resistant acid phosphatase 5b, and reactive oxygen species (ROS) due to OVX were also decreased when treated with CORM2. In vitro, CORM2 inhibited receptor activator of nuclear factor-?B ligand (RANKL)-induced OC formation without affecting bone resorption. CORM2 reduced long-lasting ROS levels and nuclear factor-?B (NF-?B) activation in response to RANKL. Inhibition of NADPH oxidase partially reduced the inhibitory effect of CO. CO induced increase of peroxiredoxin 1 (PRX1) in BMM. Down-regulation of PRX1 reduced the inhibitory effect of CO on OC formation and sustained the ROS levels induced by RANKL, suggesting that CO reduces generation of ROS and scavenges ROS to inhibit osteoclastogenesis. These data suggest that the inhibitory effect of CO on osteoclastogenesis is caused by impaired RANKL signaling through defective NF-?B activation and reduced levels of long-lasting ROS. These changes result in decreased bone loss. Our data highlight the potential utility of CO for ameliorating bone loss induced by loss of ovarian function. PMID:23380478

Van Phan, Tien; Sul, Ok-Joo; Ke, Ke; Lee, Mi-Hyun; Kim, Woon-Ki; Cho, Yeon-Soo; Kim, Hyun-Ju; Kim, Shin-Yoon; Chung, Hun-Taeg; Choi, Hye-Seon



Potent inhibitory effect of Foeniculum vulgare Miller extract on osteoclast differentiation and ovariectomy-induced bone loss.  


Inhibition of osteoclast differentiation and bone resorption is considered an effective therapeutic approach to the treatment of postmenopausal bone loss. To find natural compounds that may inhibit osteoclastogenesis, we screened herbal extracts on bone marrow cultures. In this study, we found that an aqueous extract of Foeniculum vulgare Miller seed (FvMs) at low concentration, which has traditionally been used as a treatment for a variety of ailments, inhibits the osteoclast differentiation and bone resorptive activity of mature osteoclasts. We further investigated the effects of FvMs on ovariectomy (OVX)-induced bone loss using microcomputed tomography, biomechanical tests and serum marker assays for bone remodeling. Oral administration of FvMs (30 mg or 100 mg/kg/day) for 6 weeks had an intermediary effect on the prevention of femoral bone mineral density (BMD), bone mineral content (BMC), and other parameters compared to OVX controls. In addition, FvMs slightly decreased bone turnover markers that were accelerated by OVX. The bone-protective effects of FvMs may be due to suppression of an OVX-induced increase in bone turnover. Collectively, our findings indicate that FvMs have potential in preventing bone loss in postmenopausal osteoporosis by reducing both osteoclast differentiation and function. PMID:22447109

Kim, Tae-Ho; Kim, Hyun-Ju; Lee, Sang-Han; Kim, Shin-Yoon



The bone inducing capacity of syngeneic thyroid tissue in guinea-pig muscle.  


Syngeneic thyroid extract injected into the rectus femoris muscle of guinea-pigs resulted in the appearance within the muscle of osteoblasts and the formation of bone. Injection of irritant failed to do so. It is thought that thyroid extracts exert their effect by inducing osteoblast transporation in muscle fibroblasts. PMID:102746

Zarrin, K



Chemoprotective effects of carnosine against genotoxicity induced by cyclophosphamide in mice bone marrow cells.  


The protective effects of carnosine as a natural dipeptide were investigated in mouse bone marrow cells against genotoxicity induced by cyclophosphamide. Mice were injected with solutions of carnosine at three different doses (10, 50 and 100 mg kg(-1) bw) for five consecutive days. On the fifth day of treatment, mice were injected cyclophosphamide and killed after 24 h. The frequency of micronuclei in polychromatic erythrocytes and the ratio of polychromatic erythrocyte/polychromatic erythrocyte + normochromatic erythrocyte [PCE/(PCE + NCE)] were evaluated by May-Grunwald/Giemsa staining. Histopathology of bone marrow was examined in mice treated with cyclophosphamide and carnosine. Carnosine significantly reduced micronucleated polychromatic erythrocytes (MnPCEs) induced by cyclophosphamide at all three doses. Carnosine at dose of 100 mg kg(-1) bw reduced MnPCEs 3.76-fold and completely normalized the PCE/(PCE + NCE) ratio. Administration of carnosine inhibited bone marrow toxicity induced by cyclophosphamide. It appeared that carnosine with protective activity reduced the oxidative stress and genotoxicity induced by cyclophosphamide in bone marrow cells of mice. PMID:22535690

Naghshvar, Farshad; Abianeh, Shahrzad Mohseni; Ahmadashrafi, Saeb; Hosseinimehr, Seyed Jalal



Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival  

PubMed Central

Estrogen deficiency in menopause is a major cause of osteoporosis in women. Estrogen acts to maintain the appropriate ratio between bone-forming osteoblasts and bone-resorbing osteoclasts in part through the induction of osteoclast apoptosis. Recent studies have suggested a role for Fas ligand (FasL) in estrogen-induced osteoclast apoptosis by an autocrine mechanism involving osteoclasts alone. In contrast, we describe a paracrine mechanism in which estrogen affects osteoclast survival through the upregulation of FasL in osteoblasts (and not osteoclasts) leading to the apoptosis of pre-osteoclasts. We have characterized a cell-type-specific hormone-inducible enhancer located 86 kb downstream of the FasL gene as the target of estrogen receptor-alpha induction of FasL expression in osteoblasts. In addition, tamoxifen and raloxifene, two selective estrogen receptor modulators that have protective effects in bone, induce apoptosis in pre-osteoclasts by the same osteoblast-dependent mechanism. These results demonstrate that estrogen protects bone by inducing a paracrine signal originating in osteoblasts leading to the death of pre-osteoclasts and offer an important new target for the prevention and treatment of osteoporosis.

Krum, Susan A; Miranda-Carboni, Gustavo A; Hauschka, Peter V; Carroll, Jason S; Lane, Timothy F; Freedman, Leonard P; Brown, Myles



Pre-receptorial regulation of steroid hormones in bone cells: Insights on glucocorticoid-induced osteoporosis  

Microsoft Academic Search

In the past decades, concern on glucocorticoid-induced osteoporosis has increased with the widespread use of exogenous glucocorticoids (GC). Mature bone-forming cells (osteoblasts) are considered to be the principal site of action of GC in the skeleton. More likely, it is the entire cellular and molecular network surrounding these cells that is targeted by pharmacological doses of GC. Not only osteoblast

Silvia Pierotti; Loredana Gandini; Andrea Lenzi; Andrea M. Isidori



The synergistic effect of SaOS-2 cell extract and other bone-inducing agents on human bone cell cultivation.  


Human osteosarcoma cell line SaOS-2 is an osteoblastic cell model that contains factors like bone morphogenetic proteins necessary for initiating bone formation. The cell line also expresses high levels of osteoinductive activity. In contrast to highly complicated and expensive ways to identify, purify, and separate specific bone-inducing agents from SaOS-2 cells, lysate can be used as an alternative to isolated bone-stimulating factors. Lysates of SaOS-2 stimulate the activity of the alkaline phosphatase of human osteoblastic cells HOS 58 in vitro. In other words, they probably possess osteoinductive activity. Different serial concentrations of substances like dexamethasone and insulin were tested with and without a lysate of SaOS-2 cells to assay their synergistic action. Results showed that a lysate of the SaOS-2 cell line acts as a synergistic agent and increases the osteoinductive activity of known bone-inducing agents. SaOS-2 cell lysate could be used in the future as a clinical agent to promote bone repair and possibly enhance osteointegration. Using SaOS-2 total cellular extract offers the possibility of lowering the effective dose of other bone-inducing agents. PMID:23337819

Saif, Ashraf; Wende, Kristian; Lindequist, Ulrike



Proton-induced prompt gamma-ray emission for determination of light elements in human bone  

Microsoft Academic Search

Proton-induced prompt gamma-ray emission (PIGE) analysis has been used for the determination of light elements in human dense\\u000a bone samples. Li, B, N, O, F, Na, Mg, Al, P and Ca peaks were detected. Smoothed, freeze-dried samples were irradiated in\\u000a vacuo by 2.4 MeV protons and the induced prompt gamma rays recorded with a 110 cm3 Ge(Li) detector. Absolute concentrations

M. Hyvönen-Dabek



Effect of anti-osteoporotic agents on the prevention of bone loss in unloaded bone.  


Pharmaceutical countermeasures to treat disuse osteoporosis are rarely studied. Pharmaceutical studies for the treatment and prevention of osteoporosis depend on the ovariectomized rat model, which is a suitable model for the disease in women. Disuse osteoporosis affects men and women, but there is lack of awareness and relevant pharmaceutical studies for this condition. The objectives of this study were to verify the validity of an unusual tail-suspension rat model in the induction of disuse osteoporosis and subsequent pharmaceutical treatments. This model was created by unloading the hind limbs of the rats in order to create a state of weightlessness in their hindlimb bones. Validation of the model was performed with non-suspended rats. This study included five groups of suspended rats fed with different agents, such as distilled water (control), high-, medium- and low-dose raloxifene and a bisphosphonate (alendronate). The experiment lasted for 28 days. Comparisons were made between the suspended control and treatment groups. Ovariectomized and sham?operated rats were also included as a reference for bone changes during osteoporosis. Changes in bone mineral density (BMD) at the distal femur and proximal tibia, microarchitecture at the distal femur and biomechanical strength at the diaphyseal femur were studied. Reduction of BMD and deterioration of trabeculae were similar between the suspended control and ovariectomized rats. Loss of BMD induced by tail suspension was reduced most effectively by medium-dose raloxifene. Deterioration of trabecular microarchitecture was also prevented by raloxifene. The tail-suspension rat model is suitable for the study of disuse osteoporosis under the effects of various therapeutic agents. The preventive effects of raloxifene against bone loss under disuse conditions have been demonstrated using this model. PMID:23970373

Siu, Wing Sum; Ko, Chun Hay; Hung, Leung Kim; Lau, Ching Po; Lau, Clara Bik San; Fung, Kwok Pui; Leung, Ping Chung



Is bone formation induced by high-frequency mechanical signals modulated by muscle activity?  


Bone formation and resorption are sensitive to both external loads arising from gravitational loading as well to internal loads generated by muscular activity. The question as to which of the two sources provides the dominant stimulus for bone homeostasis and new bone accretion is arguably tied to the specific type of activity and anatomical site but it is often assumed that, because of their purportedly greater magnitude, muscle loads modulate changes in bone morphology. High-frequency mechanical signals may provide benefits at low- (<1g) and high- (>1g) acceleration magnitudes. While the mechanisms by which cells perceive high-frequency signals are largely unknown, higher magnitude vibrations can cause large muscle loads and may therefore be sensed by pathways similar to those associated with exercise. Here, we review experimental data to examine whether vibrations applied at very low magnitudes may be sensed directly by transmittance of the signal through the skeleton or whether muscle activity modulates, and perhaps amplifies, the externally applied mechanical stimulus. Current data indicate that the anabolic and anti-catabolic effects of whole body vibrations on the skeleton are unlikely to require muscular activity to become effective. Even high-frequency signals that induce bone matrix deformations of far less than five microstrain can promote bone formation in the absence of muscular activity. This independence of cells on large strains suggests that mechanical interventions can be designed that are both safe and effective. PMID:20190375

Judex, S; Rubin, C T



[Effects of ipriflavone on bone loss induced by GnRH analog].  


The aim of this study is to evaluate the association between GnRH analogues and ipriflavone, drug modulating the bone turnover limiting the negative bone effects of analogue. Thirty patients (33 +/- 5.4 years, mean +/- SD) affect by benign gynecological conditions in which there was an indication to use GnRH analogs have been treated with leuprolide acetate at the monthly intramuscular dose of 3.75 mg, for six months. Fifteen of these patients also received 600 mg/day per os of ipriflavone (group A), while the other 15 patients have been treated exclusively with leuprolide acetate (group B). Before and after treatment, radial bone mineral density (BMD) and main markers of bone turnover were measured in all patients. Before treatment no difference in the considered parameters could be detected between the two groups. In group A, after 6 months of treatment no significant decrease in BMD and no variations in the bone turnover parameters. On the contrary, in group B, after six months of treatment, a significant decrease (p < 0.05) in BMD was observed in comparison to basal and group A values. In the same group alkaline phosphatase, osteocalcin and urinary calcium/creatinine and hydroxyproline/creatinine ratio proved significantly increased in comparison to basal and group A values (both with p < 0.05). Ipriflavone, therefore, seems to be effective in counteracting the negative effects of GnRH-a induced on bone. PMID:9005368

Pellicano, M; Morgera, R; Affinito, P; Di Carlo, C; Napolitano, V; Merlino, P; Tremolaterra, F; Palomba, S; Nappi, C



Improved conditions to induce hepatocytes from rat bone marrow cells in culture.  


Recent studies have revealed that bone marrow cells can develop into hepatocytes by in vivo transplantation under certain circumstances. However, little is known about the mechanism of bone marrow cell differentiation into hepatocytes. It is important to determine suitable culture conditions in which bone marrow cells will be differentiated into hepatocytes not only for understanding differentiation mechanisms but also for efficient amplification of hepatocyte-progenitor cells of bone marrow origin, this being a prerequisite for potential therapeutic use. In the present study, we found that hepatocyte growth factor (HGF) receptor (c-Met)- and alpha-fetoprotein-expressing cells were present in adult rat bone marrow. We also found that these cells also express hematopoietic stem cell markers, such as CD34, Thy-1, and c-Kit. Using an HGM medium with HGF and EGF, we succeeded in propagating hepatocyte-like cells induced from adult rat bone marrow in culture. These cells were immunocytochemically stained for albumin. By RT-PCR analysis of cultures containing the hepatocyte-like cells, we detected mRNAs of tryptophan-2,3-dioxygenase and tyrosine aminotransferase, markers of hepatocytes at a terminal differentiation stage. The present culture therefore can be a useful resource for cell transplantation therapy for liver diseases. PMID:12379214

Miyazaki, Masahiro; Akiyama, Ichiro; Sakaguchi, Masakiyo; Nakashima, Emiko; Okada, Mayumi; Kataoka, Ken; Huh, Nam-ho



Tannerella forsythia infection-induced calvarial bone and soft tissue transcriptional profiles  

PubMed Central

SUMMARY Tannerella forsythia is associated with subgingival biofilms in adult periodontitis, although the molecular mechanisms contributing to chronic inflammation and loss of periodontal bone remain unclear. We examined changes in the host transcriptional profiles during a T. forsythia infection using a murine calvarial model of inflammation and bone resorption. Tannerella forsythia was injected into the subcutaneous soft tissue over calvariae of BALB/c mice for 3 days, after which, the soft tissues and calvarial bones were excised. RNA was isolated and Murine GeneChip® array analysis of transcript profiles showed that 3226 genes were differentially expressed in the infected soft tissues (P < 0.05) and 2586 genes were differentially transcribed in calvarial bones after infection. Quantitative real-time reverse transcription-polymerase chain reaction analysis of transcription levels of selected genes corresponded well with the microarray results. Biological pathways significantly impacted by T. forsythia infection in calvarial bone and soft tissue included leukocyte transendothelial migration, cell adhesion molecules (immune system), extracellular matrix–receptor interaction, adherens junction, and antigen processing and presentation. Histologic examination revealed intense inflammation and increased osteoclasts in calvarias compared with controls. In conclusion, localized T. forsythia infection differentially induces transcription of a broad array of host genes, and the profiles differ between inflamed soft tissues and calvarial bone.

Bakthavatchalu, V.; Meka, A.; Sathishkumar, S.; Lopez, M. C.; Bhattacharyya, I.; Boyce, B. F.; Mans, J. J.; Lamont, R. J.; Baker, H. V.; Ebersole, J. L.; Kesavalu, L.



Prevention of bone loss by Panax ginseng in a rat model of inflammation-induced bone loss.  


This study evaluated the protective effect of Panax Ginseng (PG) on bone metabolism in an experimental ovariectomy (OVX) model of osteoporosis in which inflammation was induced by subcutaneous magnesium silicate. The groups were: sham control (Group1, SH), sham+inflammation (Group2, SHinf), OVX (Group3), OVX+inflammation (Group4, OVXinf), OVX+inflammation+PG 100 mg/kg (Group5, OVXinf+PG1), OVX+inflammation+PG 200 mg/kg (Group6, OVXinf+PG2), OVX+PG 100 mg/kg (Group7, OVX+PG1), OVX+PG 200 mg/kg (Group8, OVX+PG1). After the OVX surgery, all the groups were allowed to recover for two months. On the 59th day after the OVX, inflammation was induced in Groups 2, 4, 5, and 6 by subcutaneous injections of magnesium silicate in the back of the animals. Groups 5 and 7 were administered oral PG 100 mg/kg, and Groups 6 and 8 were administered oral PG 200 mg/kg from the 60th to the 80th day. PG 200 mg/kg was able to restore BMD, up to values measured in both the OVX and the SH animals. The levels of OC and OP decreased in OVXinf+PG1 and OVXinf+PG2 groups. The serum levels of TNF—?, IL—1?, and IL—6 were increased significantly in the OVXinf rats compared with the SH group. The present data showed that PG protected against in the OVX model and in inflammation-induced bone loss rat model. PMID:23374453

Avsar, U; Karakus, E; Halici, Z; Bayir, Y; Bilen, H; Aydin, A; Avsar, U Z; Ayan, A; Aydin, S; Karadeniz, A



Altered canonical hedgehog-gli signalling axis in pesticide-induced bone marrow aplasia mouse model.  


The mechanistic interplay between pesticide exposure and development of marrow aplasia is not yet well established but there are indices that chronic pesticide exposure in some instances causes marrow aplasia like haematopoietic degenerative condition in human beings. Canonical Hedgehog (Hh) signalling has multiple roles in a wide range of developmental processes, including haematopoiesis. The present study was designed to explore the status of four important components of the canonical Hedgehog signalling cascade, the Sonic Hedgehog (Shh), Ptch1, Smo, and Gli1, in a mouse model of chronic pesticide-induced bone marrow aplasia. We used 5 % aqueous mixture of pesticides (chlorpyriphos, prophenophos, cypermethrin, alpha-methrin, and hexaconazole) for inhalation and dermal exposure of 6 hours per day and 5 days a week up to 90 days. Murine bone marrow aplasia related to chronic pesticide treatment was confirmed primarily by haemogram, bone marrow cellularity, short term bone marrow explant culture for cellular kinetics, bone marrow smear, and fl ow cytometric Lin-Sca-1+C-kit+ extracellular receptor expression pattern. Later, components of hedgehog signalling were analysed in the bone marrow of both control and pesticide-treated aplastic groups of animals. The results depicted pancytopenic feature of peripheral blood, developmental anomaly of neutrophils, depression of primitive stem and progenitor population along with Shh, Ptch1, Smo and Gli1 expression in aplasia group. This investigation suggests that pesticide-induced downregulation of two critically important proteins--Ptch1 and Gli1--inside the haematopoietic stem and progenitor cell population impairs haematopoietic homeostasis and regeneration mechanism in vivo concurrent with bone marrow aplasia. PMID:23152377

Chaklader, Malay; Das, Prosun; Pereira, Jacintha Archana; Chaudhuri, Samaresh; Law, Sujata



Properties of bisphosphonates in the 13762 rat mammary carcinoma model of tumor-induced bone resorption.  


Bone metastasis from primary tumors is a clinically important complication of neoplastic progression. The role of parathyroid hormone-related protein (PTHrP) and transforming growth factor (TGF)-beta1 in this process has been clearly established. The current study describes an in vivo model of 13762 rat mammary carcinoma tumor cell-induced osteolysis in which PTHrP and TGF-beta1 expression is observed. Exposure of in vitro-cultured 13762 cells to doxorubicin, cis-platinum, carboplatin, methotrexate, 5-fluorouracil, paclitaxel, alendronate, risedronate, or pamidronate for 72 h resulted in varying effects on cell proliferation (IC(50) values of 0.005, 0.4, 1.9, >40, 17.9, 0.003, >40, >40, and 33.6 micro M, respectively). Tumor cells were implanted into the intramedullary space of the proximal tibia of rats, and the time course of tumor progression was evaluated using radiographic and microcomputed tomography scanning techniques. Trabecular bone mineral density, cortical bone mineral density, and whole bone mineral density were measured (in mg/cm(3)). In untreated animals, radiographic evidence of osteolysis was evident 7 days after implantation. Trabecular bone mineral density and whole bone mineral density were significantly decreased by 21 days after implantation (48% and 26%, respectively). Bisphosphonates showed broad protective activity against tumor-driven osteolysis, Immunohistochemical evaluation of s.c. and intratibially implanted cells demonstrated the expression of PTHrP and TGF-beta1. The results of this study demonstrate the ability of 13762 rat mammary carcinoma cells to elicit a measurable osteolysis and that bisphosphonates inhibit the tumor-induced bone resorption in this model. PMID:14654555

Alvarez, Enrique; Westmore, Michael; Galvin, Rachelle J Sells; Clapp, Crystal L; Considine, Eileen L; Smith, Shawn J; Keyes, Kristan; Iversen, Philip W; Delafuente, Dawn M; Sulaimon, Shola; Zambrano, Carmen; Ma, Linda; Sato, Masahiko; Martin, T John; Teicher, Beverly A; Galbreath, Elizabeth J



Response Kinetics of Radiation-induced Micronucleated Reticulocytes in Human Bone Marrow Culture  

PubMed Central

The frequency of micronucleated reticulocytes (MN-RETs) in the bone marrow or peripheral blood is a sensitive indicator of cytogenetic damage. While the kinetics of MN-RET induction in rodent models following irradiation have been investigated and reported, information about MN-RET induction of human bone marrow after radiation exposure is sparse. In this report, we describe a human long-term bone marrow culture (LTBMC), established in three-dimensional (3D) bioreactors, which sustains long-term erythropoiesis. Using this system, we measured the kinetics of human bone marrow red blood cell (RBC) and reticulocyte (RET) production, as well as the kinetics of human MN-RET induction following radiation exposure up to 6 Gy. Human bone marrow established in the 3D bioreactor demonstrated an average percentage of RBCs among total viable cells peaking at 21% on day 21. The average percentage of RETs among total viable cells reached a maximum of 11% on day 14, and remained above 5% by day 28, suggesting that terminal erythroid differentiation was still active. Time- and dose-dependent induction of MN-RET by gamma radiation was observed in the human 3D LTBMC, with peak values occurring at approximately 3 days following 1 Gy irradiation. A trend towards delayed peak to 3–5 days post-radiation was observed with radiation doses ? 2 Gy. Our data reveal valuable information on the kinetics of radiation-induced MN-RET of human bone marrow cultured in the 3D bioreactor, a synthetic bioculture system, and suggest that this model may serve as a promising tool for studying MN-RET formation in human bone marrow, thereby providing opportunities to study bone marrow genotoxicity testing, mitigating agent effects, and other conditions that are not ordinarily feasible to experimental manipulation in vivo.

Sun, Hongliang; Tsai, Ying; Nowak, Irena; Dertinger, Stephen D.; David Wu, J. H.; Chen, Yuhchyau



Effect of methylprednisolone on bone mineral density in rats with ovariectomy-induced bone loss and suppressed endogenous adrenaline levels by metyrosine  

PubMed Central

Objectives: In this study, effect of methylprednisolone on bone mineral density (BMD) was investigated in rats with overiectomy induced bone lose and suppressed endogenous adrenalin levels, and compared to alendronate. Materials and Methods: Severity of bone loss in the examined material (femur bones) was evaluated by BMD measurement. Results: The group with the highest BMD value was metyrosinemetyrosine + methylprednisolone combination (0.151 g/cm2), while that with the lowest BMD was methylprednisolone (0.123 g/cm2). Alendronate was effective only when used alone in ovariectomized rats (0.144 g/cm2), but not when used in combination with methylprednisolone (0.124 g/cm2). In the ovariectomized rat group which received only metyrosine, BMD value was statistically indifferent from ovariectomized control group. Conclusions: Methylprednisolone protected bone loss in rats with suppressed adrenaline levels because of metyrosinemetyrosine.

Yilmaz, Mehmet; Isaoglu, Unal; Uslu, Turan; Yildirim, Kadir; Seven, Bedri; Akcay, Fatih; Hacimuftuoglu, Ahmet



Leishmania donovani infection induces anemia in hamsters by differentially altering erythropoiesis in bone marrow and spleen.  


Leishmania donovani is a parasite that causes visceral leishmaniasis by infecting and replicating in macrophages of the bone marrow, spleen, and liver. Severe anemia and leucopenia is associated with the disease. Although immune defense mechanisms against the parasite have been studied, we have a limited understanding of how L. donovani alters hematopoiesis. In this study, we used Syrian golden hamsters to investigate effects of L. donovani infection on erythropoiesis. Infection resulted in severe anemia and leucopenia by 8 weeks post-infection. Anemia was associated with increased levels of serum erythropoietin, which indicates the hamsters respond to the anemia by producing erythropoietin. We found that infection also increased numbers of BFU-E and CFU-E progenitor populations in the spleen and bone marrow and differentially altered erythroid gene expression in these organs. In the bone marrow, the mRNA expression of erythroid differentiation genes (?-globin, ?-globin, ALAS2) were inhibited by 50%, but mRNA levels of erythroid receptor (c-kit, EpoR) and transcription factors (GATA1, GATA2, FOG1) were not affected by the infection. This suggests that infection has a negative effect on differentiation of erythroblasts. In the spleen, erythroid gene expression was enhanced by infection, indicating that the anemia activates a stress erythropoiesis response in the spleen. Analysis of cytokine mRNA levels in spleen and bone marrow found that IFN-? mRNA is highly increased by L. donovani infection. Expression of the IFN-? inducible cytokine, TNF-related apoptosis-inducing ligand (TRAIL), was also up-regulated. Since TRAIL induces erythroblasts apoptosis, apoptosis of bone marrow erythroblasts from infected hamsters was examined by flow cytometry. Percentage of erythroblasts that were apoptotic was significantly increased by L. donovani infection. Together, our results suggest that L. donovani infection inhibits erythropoiesis in the bone marrow by cytokine-mediated apoptosis of erythroblasts. PMID:23533629

Lafuse, William P; Story, Ryan; Mahylis, Jocelyn; Gupta, Gaurav; Varikuti, Sanjay; Steinkamp, Heidi; Oghumu, Steve; Satoskar, Abhay R



Overexpressed LIM mineralization proteins do not require LIM domains to induce bone.  


Rat LIM mineralization protein 1 (LMP-1, an LIM domain protein) mediates bone morphogenetic protein 6 (BMP-6) induction of bone nodule formation in fetal rat calvarial osteoblast (ROB) cultures. We have isolated the complementary DNA (cDNA) for the human homologue of LMP-1 from an adult human heart cDNA library and showed that when overexpressed it is osteoinductive in the same culture system. The recently revised cDNA sequence of Enigma, the protein product of which binds to the insulin receptor and the tyrosine kinase receptor ret, now matches the nucleotide sequence of human LMP-1 (hLMP-1). A truncated, 223 amino acid (AA) LMP-1(t) protein has identical effects as the full-length protein, despite the deletion of the LIM domains. Two splice variants of human LMP-1 have been detected. Human LMP-2 has a 119-base pair (bp) deletion between bp 325 and 444 and a 17-bp insertion at bp 444. The resulting derived protein contains 423 AA with the LIM domains intact and does not induce bone formation when overexpressed in ROB cultures. Human LMP-3 has the same 17 nucleotide insertion at bp 444, resulting in a shift in the reading frame that causes a stop codon to occur at bp 505-507. The resulting 153 AA protein does not have the LIM domains, but overexpression of hLMP-3 induces bone formation in osteoblast cultures. These findings suggest that the LIM domains are not required for LMPs to induce bone formation. In addition, a small region (36 AA) of the LMP-1 protein may be required for bone formation. PMID:11874232

Liu, Yunshan; Hair, Gregory A; Boden, Scott D; Viggeswarapu, Manjula; Titus, Louisa



Bone marrow edema induced by a bullet after a self-inflicted accidental firing.  


We present a case of a postmortem finding of bone marrow edema in postmortem magnetic resonance imaging (PMMR) indirectly induced by a bullet, which barely missed the bone of a 92year old man found kneeling in front of his bed of a tidy apartment. Additionally, a selective postmortem computed tomography angiography (PMCTA) of the left leg was performed, visualizing a laceration of the left femoral vein by the bullet with consecutive contrast media extravasation. A vast pulmonary fat embolism was diagnosed and together with the blood loss found to be the cause of death. PMID:24112989

Berger, Nicole; Paula, Pia; Gascho, Dominic; Flach, Patricia M; Thali, Michael J; Ross, Steffen G; Ampanozi, Garyfalia



Fluorine determination in human and animal bones by particle-induced gamma-ray emission.  


Fluorine was determined in the iliac crest bones of patients and in ribs collected from post-mortem investigations by particle-induced gamma-ray emission based on the 19F(p,p'gamma)19F reaction, using 2.0/2.5 MeV protons. The results indicate that for 68% of the human samples the F concentration is in the range 500-1999 microg g(-1). For comparison purposes fluorine was also determined in some animal bones; in some animal tissues lateral profiles of fluorine were measured. PMID:11569877

Sastri, C S; Iyengar, V; Blondiaux, G; Tessier, Y; Petri, H; Hoffmann, P; Aras, N K; Zaichick, V; Ortner, H M



Bone marrow transplantation in a patient with drug-induced aplastic anemia  

PubMed Central

A 23-year-old woman gravely ill with Pseudomonas septicemia secondary to presumed drug-induced bone marrow aplasia received marrow transplantation from two male HL-A identical sibling donors. She had a successful engraftment with excellent but temporary clinical improvement. Subsequently she succumbed to graft-versus-host disease manifested by Pseudomonas and Candida albicans septicemia, cytomegalovirus pneumonitis, three phases of dermatitis, nausea, vomiting, dysphagia, diarrhea, fever, edema and bone pain, with gradual but complete graft suppression by the 74th day after the transplantation. A second marrow transplant on the 70th day was unsuccessful.

Banerjee, T. K.; Band, P. R.; Pabst, H.; Goldsand, G.; Armstrong, W. D.; Brown, J.; Hill, J. R.; Dossetor, J. B.



The calcium-sensing receptor complements parathyroid hormone-induced bone turnover in discrete skeletal compartments in mice.  


Although the calcium-sensing receptor (CaSR) and parathyroid hormone (PTH) may each exert skeletal effects, it is uncertain how CaSR and PTH interact at the level of bone in primary hyperparathyroidism (PHPT). Therefore, we simulated PHPT with 2 wk of continuous PTH infusion in adult mice with deletion of the PTH gene (Pth(-/-) mice) and with deletion of both PTH and CaSR genes (Pth(-/-)-Casr (-/-) mice) and compared skeletal phenotypes. PTH infusion in Pth(-/-) mice increased cortical bone turnover, augmented cortical porosity, and reduced cortical bone volume, femoral bone mineral density (BMD), and bone mineral content (BMC); these effects were markedly attenuated in PTH-infused Pth(-/-)-Casr(-/-) mice. In the absence of CaSR, the PTH-stimulated expression of receptor activator of nuclear factor-?B ligand and tartrate-resistant acid phosphatase and PTH-stimulated osteoclastogenesis was also reduced. In trabecular bone, PTH-induced increases in bone turnover, trabecular bone volume, and trabecular number were lower in Pth(-/-)-Casr(-/-) mice than in Pth(-/-) mice. PTH-stimulated genetic markers of osteoblast activity were also lower. These results are consistent with a role for CaSR in modulating both PTH-induced bone resorption and PTH-induced bone formation in discrete skeletal compartments. PMID:22275754

Xue, Yingben; Xiao, Yongjun; Liu, Jingning; Karaplis, Andrew C; Pollak, Martin R; Brown, Edward M; Miao, Dengshun; Goltzman, David



The response of structure and function of the gravireceptor in a vertebrate to near weightlessness.  


The paper sums up results of a 7-day space flight experiment (D-l-Mission-BW-STA 00-STATEX) using growing frog embryos and larvae (Xenopus laevis) as a model system. Evaluation of photographs taken from the surface of sectioned deep-frozen objects, and micrographs using TEM and SEM show no aberrations in the shape, size, position, or respective electron density of the otolith membranes in larvae developed for 154 h under near-zero g. The further evaluation of the "weightless larvae" revealed a probably not yet described otolith-like formation below the dorsal wall of the vestibulum. In the weightless larvae this formation outnumbers, also qualitatively, strongly the 1-g control samples. The swimming behavior of the tadpoles which was observed about one hour after landing of the Space Shuttle showed a typical anomaly (loop swimming), which is known from larvae developed on the clinostat or from fish flown aboard Apollo capsules. An extra result is the lack of striking effects of cosmic radiation on the embryonic development of the flown Xenopus eggs. PMID:11542431

Neubert, J; Briegleb, W; Schatz, A; Hertwig, I; Kruse, B



Neural and humoral controlling mechanisms of cardiovascular functions in man under weightlessness simulated by water immersion  

NASA Astrophysics Data System (ADS)

To clarify how neural and humoral mechanisms operate to control cardiovascular unctions in man under weightlessness, the response of sympathetic nerve activity was observed in healthy human subjects by means of microneurographic technique with the changes of several hemodynamic parameters and hormonal responses during thermoneutral head-out water immersion. Muscle sympathetic nerve activity was markedly suppressed by head-out immersion, concomitantly with a reduction of the leg volume, an increase of the stroke volume and a reduction of total peripheral resistance. At the same time, plasma level of norepinephrine, vasopressive and antidiuretic hormones (ADH, aldosterone, renin activity, angiotensin I·II) were reduced, while vasodepressive and diuretic hormone (ANP) was markedly increased. The systemic blood pressure was maintained almost unchanged during head-out water immersion. The suppressive response of sympathetic nerve activity seemed to be age-dependent. This response was less prominent in the elderly than in young subjects. It is concluded that the suppressive response of muscle sympathetic activity plays an important role to maintain hemodynamic homeostasis under weightlessness to compensate for the cephalad fluid shift and the resultant increase of the stroke volume in cooperation with the hormonal responses.

Mano, T.; Iwase, S.; Saito, M.; Koga, K.; Abe, H.; Inamura, K.; Matsukawa, T.


Possibility of long-distance heat transport in weightlessness using supercritical fluids  

NASA Astrophysics Data System (ADS)

Heat transport over large distances is classically performed with gravity or capillarity driven heat pipes. We investigate here whether the “piston effect,” a thermalization process that is very efficient in weightlessness in compressible fluids, could also be used to perform long-distance heat transfer. Experiments are performed in a modeling heat pipe (16.5 mm long, 3 mm inner diameter closed cylinder), with nearly adiabatic polymethylmethacrylate walls and two copper base plates. The cell is filled with H2 near its gas-liquid critical point (critical temperature: 33 K). Weightlessness is achieved by submitting the fluid to a magnetic force that compensates gravity. Initially the fluid is isothermal. Then heat is sent to one of the bases with an electrical resistance. The instantaneous amount of heat transported by the fluid is measured at the other end. The data are analyzed and compared with a two-dimensional numerical simulation that allows an extrapolation to be made to other fluids (e.g., CO2 , with critical temperature of 300 K). The major result is concerned with the existence of a very fast response at early times that is only limited by the thermal properties of the cell materials. The yield in terms of ratio, injected or transported heat power, does not exceed 10-30% and is limited by the heat capacity of the pipe. These results are valid in a large temperature domain around the critical temperature.

Beysens, D.; Chatain, D.; Nikolayev, V. S.; Ouazzani, J.; Garrabos, Y.



Possibility of long-distance heat transport in weightlessness using supercritical fluids.  


Heat transport over large distances is classically performed with gravity or capillarity driven heat pipes. We investigate here whether the "piston effect," a thermalization process that is very efficient in weightlessness in compressible fluids, could also be used to perform long-distance heat transfer. Experiments are performed in a modeling heat pipe (16.5 mm long, 3 mm inner diameter closed cylinder), with nearly adiabatic polymethylmethacrylate walls and two copper base plates. The cell is filled with H2 near its gas-liquid critical point (critical temperature: 33 K). Weightlessness is achieved by submitting the fluid to a magnetic force that compensates gravity. Initially the fluid is isothermal. Then heat is sent to one of the bases with an electrical resistance. The instantaneous amount of heat transported by the fluid is measured at the other end. The data are analyzed and compared with a two-dimensional numerical simulation that allows an extrapolation to be made to other fluids (e.g., CO2, with critical temperature of 300 K). The major result is concerned with the existence of a very fast response at early times that is only limited by the thermal properties of the cell materials. The yield in terms of ratio, injected or transported heat power, does not exceed 10-30% and is limited by the heat capacity of the pipe. These results are valid in a large temperature domain around the critical temperature. PMID:21230663

Beysens, D; Chatain, D; Nikolayev, V S; Ouazzani, J; Garrabos, Y



Long-term stability of bone tissues induced by an osteoinductive biomaterial, recombinant human bone morphogenetic protein-2 and a biodegradable carrier.  


The long-term stability of bone tissues induced by recombinant human bone morphogenetic protein-2 (rhBMP-2) and poly[L-lactide-co-glycolide] copolymer-coated gelatin sponge (PGS) was examined. In 16 dogs, 2.5 cm unilateral bone defects were created in the left tibial diaphyses. Tibia was fixed with metal plate, and PGS impregnated with (0.4 mg/cm(3)) or without rhBMP-2 was implanted into 15 or one defects, respectively. The metal plates of rhBMP-2-treated limbs were removed 16 weeks after the implantation. The bilateral tibiae of five animals each of the rhBMP-2-treated group were harvested at 32, 52 or 104 weeks, and served for biomechanical testing and histology. Although the defect that received PGS alone resulted in nonunion at 16 weeks, all defects treated with rhBMP-2 achieved radiographic bony union by 8 weeks. Biomechanical properties of the regenerated bones restored to the levels of intact tibiae at 32 weeks, but torsional stiffness was significantly higher. No statistical significances were detected in all parameters between regenerated and intact tibiae at 104 weeks. No radiographic and histological findings suggesting enhanced resorption to the regenerated bones were observed. These results suggest the long-term stability of the bone tissues induced by rhBMP-2, and the usefulness of rhBMP-2-impregnated PGS as a biomaterial for long bone defect filling. PMID:14738843

Kokubo, Satoshi; Mochizuki, Manabu; Fukushima, Shinji; Ito, Teruo; Nozaki, Kazutoshi; Iwai, Takaya; Takahashi, Koichiro; Yokota, Shoji; Miyata, Keiji; Sasaki, Nobuo



Binge Alcohol-Induced Bone Damage is Accompanied by Differential Expression of Bone Remodeling-Related Genes in Rat Vertebral Bone  

Microsoft Academic Search

Binge alcohol-related bone damage is prevented by concurrent administration of bisphosphonates, suggesting an activation of\\u000a bone resorption with patterned alcohol exposure. Although chronic alcohol abuse is known to cause osteopenia, little is known\\u000a about the effects of binge drinking on bone metabolism. We examined the effects of binge alcohol exposure on the relationship\\u000a between bone damage and modulation of bone

John J. Callaci; Ryan Himes; Kristen Lauing; Frederick H. Wezeman; Kirstyn Brownson



Human Cementum Protein 1 induces expression of bone and cementum proteins by human gingival fibroblasts  

SciTech Connect

We recently presented evidence showing that a human cementoblastoma-derived protein, named Cementum Protein 1 (CEMP1) may play a role as a local regulator of cementoblast differentiation and cementum-matrix mineralization. This protein was shown to be expressed by cementoblasts and progenitor cells localized in the periodontal ligament. In this study we demonstrate that transfection of CEMP1 into human gingival fibroblasts (HGF) induces mineralization and expression of bone and cementum-matrix proteins. The transfected HGF cells had higher alkaline phosphatase activity and proliferation rate and they expressed genes for alkaline phosphatase, bone sialoprotein, osteocalcin, osteopontin, the transcription factor Runx2/Cbfa1, and cementum attachment protein (CAP). They also produced biological-type hydroxyapatite. These findings indicate that the CEMP1 might participate in differentiation and mineralization of nonosteogenic cells, and that it might have a potential function in cementum and bone formation.

Carmona-Rodriguez, Bruno [Laboratorio de Biologia Celular y Molecular, Facultad de Odontologia, UNAM, Cd. Universitaria, Coyoacan, Mexico, D.F. 04510 (Mexico); Alvarez-Perez, Marco Antonio [Laboratorio de Biologia Celular y Molecular, Facultad de Odontologia, UNAM, Cd. Universitaria, Coyoacan, Mexico, D.F. 04510 (Mexico); Narayanan, A. Sampath [Department of Pathology, School of Medicine, UW, Seattle (United States); Zeichner-David, Margarita [Center for Craniofacial Molecular Biology, School of Dentistry, USC, Los Angeles (United States); Reyes-Gasga, Jose [Instituto de Fisica, UNAM (Mexico); Molina-Guarneros, Juan [Facultad de Medicina, UNAM (Mexico); Garcia-Hernandez, Ana Lilia [Laboratorio de Biologia Celular y Molecular, Facultad de Odontologia, UNAM, Cd. Universitaria, Coyoacan, Mexico, D.F. 04510 (Mexico); Suarez-Franco, Jose Luis [Laboratorio de Biologia Celular y Molecular, Facultad de Odontologia, UNAM, Cd. Universitaria, Coyoacan, Mexico, D.F. 04510 (Mexico); Chavarria, Ivet Gil [Laboratorio de Biologia Celular y Molecular, Facultad de Odontologia, UNAM, Cd. Universitaria, Coyoacan, Mexico, D.F. 04510 (Mexico); Villarreal-Ramirez, Eduardo [Laboratorio de Biologia Celular y Molecular, Facultad de Odontologia, UNAM, Cd. Universitaria, Coyoacan, Mexico, D.F. 04510 (Mexico); Arzate, Higinio [Laboratorio de Biologia Celular y Molecular, Facultad de Odontologia, UNAM, Cd. Universitaria, Coyoacan, Mexico, D.F. 04510 (Mexico)]. E-mail:



Interferon regulatory factor-2 induces megakaryopoiesis in mouse bone marrow hematopoietic cells.  


Megakaryopoiesis is associated with inflammatory reactions. To investigate the role of interferon regulatory factors (IRFs) in inflammation-associated megakaryopoiesis, mouse bone marrow hematopoietic stem cells (HSCs) were analyzed. IFN-gamma treatment induced IRF-2 expression as well as the expression of CD41 and IRF-1 in HSCs. An in vitro clonogenic assay showed that IRF-2- but not IRF-1-overexpressing cells increased the number of megakaryocytic colonies. IRF-2 transfection up-regulated CD41 promoter activity in hematopoietic cell lines. The number of CD41-positive bone marrow cells increased in mice injected with IRF-2-expressing bone marrow cells. These findings suggest that IRF-2 plays an important role in megakaryopoiesis in inflammatory states. PMID:19818776

Masumi, Atsuko; Hamaguchi, Isao; Kuramitsu, Madoka; Mizukami, Takuo; Takizawa, Kazuya; Momose, Haruka; Naito, Seishiro; Yamaguchi, Kazunari



Quantitative measurement of the stresses induced during polymerisation of bone cement.  


When bone cement cures, residual stresses due to bulk and thermal shrinkage will result. Present finite element (FE) simulations of implanted constructs often do not account for these stresses as an initial condition; this may lead to overestimations of the fatigue life of the cement. In the present study, an instrumented stem equipped with strain gauges and a thermocouple was employed to experimentally quantify the residual stresses induced as a result of bone cement curing within a simulated bone/cement/stem construct. Residual stresses as high as 10 MPa were observed in the cement mantle. Residual stresses of this magnitude are potentially high enough to initiate damage within the cement mantle or at the stem/cement interface immediately post-implantation. The acoustic emission technique has demonstrated that cracking and sliding mechanisms are occurring during curing, resulting in partial relaxation of these stresses. The implications for FE simulations of the implanted construct are discussed. PMID:15046932

Roques, A; Browne, M; Taylor, A; New, A; Baker, D



Application of Laser-Induced Bone Therapy by Carbon Dioxide Laser Irradiation in Implant Therapy  

PubMed Central

This study evaluated the application of laser-induced bone therapy (LIBT) to reduce implant healing time in rat tibia. Twenty 10-week-old female Sprague-Dawlay rats were used. The rats received laser irradiation (laser group) or sham operation (control group) on either side of the tibia. Five days after invasion, titanium implants were inserted in proximal tibia. Five, 10, and 20 days after implant placement, tibiae were collected. After taking micro-CT and performing a torque test, the tibiae were decalcified and 8-?m-thick sections were prepared. Specimens were stained with hematoxylin and eosin. Results. Micro-CT images, removal torque values, and histomorphometric analysis data demonstrated a significantly accelerated bone formation in the laser group earlier in the healing process. Conclusion. The use of laser irradiation was effective in promoting bone formation and acquiring osseointegration of titanium implants inserted in rat tibia. LIBT may be suitable for use in implant therapy.

Naka, Takahiro; Yokose, Satoshi



Zoledronate induces apoptosis in cells from fibro-cellular membrane of unicameral bone cyst (UBC).  


Unicameral bone cyst (UBC) is a benign cystic lesion in children which is prone to fracture. Various treatments are available, but recurrence after different types of percutaneous injection therapy can cause bone destruction and pathologic fracture. The potential therapeutic effects of anti-resorptive agents, such as bisphosphonates, have not been investigated for UBC. The objective of this study was to characterize the cells from the fibro-cellular membrane of unicameral bone cyst (UBC cells) and to determine whether zoledronate, a nitrogen-containing bisphosphonate, could induce apoptosis in UBC cells. Flow cytometry and immunoblotting were performed in order to determine whether zoledronate induced apoptosis. Cells derived from normal human trabecular bones were used as controls against UBC cells to compare the effect of zoledronate in inducing apoptosis. Immunohisto/cytochemistry (IHC/ICC) and mini-array analyses were performed on tissues and cultured cells. Isolated peripheral blood mononuclear cells were incubated with conditioned media from the UBC cells to determine whether they are capable of inducing osteoclastogenesis. UBC membrane is composed of cells staining positively with CD68, SDF-1, STRO-1 and RANKL, but in vitro cells showed no staining with antibodies to CD68 and STRO-1, suggesting that there was a clonal selection of stromal cells during cell culture. UBC cells also express RUNX2 (runt-related transcription factor-2, core binding factor-1), a key transcription factor for osteoblastic differentiation. In addition, media collected from UBC cells induced a generation of multi-nucleated osteoclast-like cells of peripheral blood mononuclear cells. Zoledronate induced apoptosis of UBC cells in a dose-dependent manner. Apoptosis was evidenced by induction of the active cleaved form of caspase-3. The baseline apoptotic fractions were similar in UBC cells and trabecular bone cells. However, in the overall apoptotic fractions in this study, trabecular bone cells showed 17.2% of apoptosis, significantly lower than 24.2% of UBC cells (p-value=0.007). With the various zoledronate concentrations, mean apoptotic fractions of trabecular bone cells was 19.2%, significantly lower than 27.8% of UBC cells (p-value=0.040). With GGOH co-treatment in various zoledronate concentrations, 15.1% apoptosis was shown in trabecular bone cells, which was not significantly lower than 20.6% of UBC cells (p-value=0.076). This data suggests that zoledronate causes apoptosis in both UBC and trabecular bone cells by inhibition of the mevalonate pathway. In addition to the known anti-osteoclastogenic effect of bisphosphonates, the GGOH inhibitory effects of zoledronate were more prominent in UBC cells than trabecular bone cells, indicating their potential therapeutic role in UBC. PMID:15921873

Yu, John; Chang, Seong-Sil; Suratwala, Sanjeev; Chung, Woo-Sik; Abdelmessieh, Peter; Lee, Hahn-Jun; Yang, Jay; Lee, Francis Young-In



Ablation of the Pro-Apoptotic Protein Bax Protects Mice from Glucocorticoid-Induced Bone Growth Impairment  

PubMed Central

Dexamethasone (Dexa) is a widely used glucocorticoid to treat inflammatory diseases; however, a multitude of undesired effects have been reported to arise from this treatment including osteoporosis, obesity, and in children decreased longitudinal bone growth. We and others have previously shown that glucocorticoids induce apoptosis in growth plate chondrocytes. Here, we hypothesized that Bax, a pro-apoptotic member of the Bcl-2 family, plays a key role in Dexa-induced chondrocyte apoptosis and bone growth impairment. Indeed, experiments in the human HCS-2/8 chondrocytic cell line demonstrated that silencing of Bax expression using small-interfering (si) RNA efficiently blocked Dexa-induced apoptosis. Furthermore, ablation of Bax in female mice protected against Dexa-induced bone growth impairment. Finally, Bax activation by Dexa was confirmed in human growth plate cartilage specimens cultured ex vivo. Our findings could therefore open the door for new therapeutic approaches to prevent glucocorticoid-induced bone growth impairment through specific targeting of Bax.

Zaman, Farasat; Chrysis, Dionisios; Huntjens, Kirsten; Fadeel, Bengt; Savendahl, Lars



Regression of Adjuvant-Induced Arthritis in Rats Following Bone Marrow Transplantation  

NASA Astrophysics Data System (ADS)

Total body irradiation followed by bone marrow transplantation was found to be an effective treatment for adjuvant arthritis induced in rats. This treatment is most effective when applied shortly after the clinical manifestation of arthritis--i.e., 4-7 weeks after administration of Mycobacterium tuberculosis. Transplantation of bone marrow at a later stage results in a limited recovery, in that the inflammatory reaction regresses but the newly formed excessive bone is not eliminated. Local irradiation of the affected joints had no effect on the disease. It could also be excluded that the recovery of arthritis following marrow transplantation is due to lack of available antigen. Transplantation of syngeneic bone marrow is as effective as that of allogeneic bone marrow from a rat strain that is not susceptible to induction of adjuvant arthritis. The beneficial effect of this treatment cannot be ascribed to the immunosuppressive effect of total body irradiation, since treatment with the highly immunosuppressive drug Cyclosporin A resulted in a regression of the joint swelling but relapse occurred shortly after discontinuation of the treatment.

van Bekkum, Dirk W.; Bohre, Els P. M.; Houben, Paul F. J.; Knaan-Shanzer, Shoshan




PubMed Central

Breast cancer metastasis to bone is frequently accompanied by pain. What remains unclear is why this pain tends to become more severe and difficult to control with disease progression. Here we test the hypothesis that with disease progression sensory nerve fibers that innervate the breast cancer bearing bone undergo a pathological sprouting and reorganization, which in other non-malignant pathologies has been shown to generate and maintain chronic pain. Injection of human breast cancer cells (MDA-MB-231-BO) into the femoral intramedullary space of female athymic nude mice induces sprouting of calcitonin gene-related peptide (CGRP+) sensory nerve fibers. Nearly all CGRP+ nerve fibers that undergo sprouting also co-express tropomyosin receptor kinase A (TrkA+) and growth associated protein-43 (GAP43+). This ectopic sprouting occurs in periosteal sensory nerve fibers that are in close proximity to breast cancer cells, tumor-associated stromal cells and remodeled cortical bone. Therapeutic treatment with an antibody that sequesters nerve growth factor (NGF), administered when the pain and bone remodeling were first observed, blocks this ectopic sprouting and attenuates cancer pain. The present data suggest that the breast cancer cells and tumor-associated stromal cells express and release NGF, which drives bone pain and the pathological reorganization of nearby CGRP+ / TrkA+ / GAP43+ sensory nerve fibers.

Bloom, Aaron P.; Jimenez-Andrade, Juan M.; Taylor, Reid N.; Castaneda-Corral, Gabriela; Kaczmarska, Magdalena J.; Freeman, Katie T.; Coughlin, Kathleen A.; Ghilardi, Joseph R.; Kuskowski, Michael A.; Mantyh, Patrick W.



LPS Induces Greater Bone and PDL Loss in SPARC-null Mice  

PubMed Central

Individuals with periodontal disease have increased risk of tooth loss, particularly in cases with associated loss of alveolar bone and periodontal ligament (PDL). Current treatments do not predictably regenerate damaged PDL. Collagen I is the primary component of bone and PDL extracellular matrix. SPARC/Osteonectin (SP/ON) is implicated in the regulation of collagen content in healthy PDL. In this study, periodontal disease was induced by injections of lipopolysaccharide (LPS) from Aggregatibacter actinomycetemcomitans in wild-type (WT) and SP/ON-null C57/Bl6 mice. A 20-µg quantity of LPS was injected between the first and second molars 3 times a week for 4 weeks, whereas PBS control was injected into the contralateral maxilla. LPS injection resulted in a significant decrease in bone volume fraction in both genotypes; however, significantly greater bone loss was detected in SP/ON-null maxilla. SP/ON-null PDL exhibited more extensive degradation of connective tissue in the gingival tissues. Although total cell numbers in the PDL of SP/ON-null were not different from those in WT, the inflammatory infiltrate was reduced in SP/ON-null PDL. Histology of collagen fibers revealed marked reductions in collagen volume fraction and in thick collagen volume fraction in the PDL of SP/ON-null mice. SP/ON protects collagen content in PDL and in alveolar bone in experimental periodontal disease.

Trombetta-eSilva, J.; Yu, H.; Arias, D.N.; Rossa, C.; Kirkwood, K.L.; Bradshaw, A.D.



Bisphosphonate inhibits alveolar bone resorption in experimentally-induced peri-implantitis in dogs.  


The purpose of this study was to determine the effect of bisphosphonate on alveolar bone resorption in experimentally-induced peri-implantitis in beagle dogs. Experimental peri-implantitis was induced by ligation around the abutments, 6 months after placement of a fixture. Pamidronate (0.6 mg/kg) was injected intramuscularly every 3 days into each of 5 dogs. Another 5 dogs served as the control group and were injected with saline only. Peripheral blood and urine samples were collected every week up to 12 weeks after placement of the ligature. Standard X-rays were taken every week. Urinary deoxypyridinoline (DPD) and serum osteocalcin (OC) were evaluated by ELISA as markers of alveolar bone remodeling. X-ray films were analyzed with a computer image analyzer. After 12 weeks, the bone level was measured after removal of the gingival flap. The distance between the top surface of the fixture and the fundus of the defect was significantly lower in the Pamidronate group (1.59+/-0.55 mm, mean+/-SD) than in the control group (2.41+/-0.48 mm). Bone density analyzed from the X-ray films was significantly higher in the bisphosphonate group (69.2+/-8.7%, mean+/-SD) than in the control group (50.3+/-12.8%) after 2 to 8 weeks compared with the baseline value (100%). OC and DPD levels fluctuated during the experimental period. These findings suggest that bisphosphonate inhibits the progression of alveolar bone resorption during ligature-induced peri-implantitis in dogs. PMID:11251659

Shibutani, T; Inuduka, A; Horiki, I; Luan, Q; Iwayama, Y



Hwangryun-Haedok-Tang Fermented with Lactobacillus casei Suppresses Ovariectomy-Induced Bone Loss  

PubMed Central

Hwangryun-haedok-tang (HRT) is the common recipe in traditional Asian medicine, and microbial fermentation is used for the conventional methods for processing traditional medicine. We investigated the inhibitory effect of the n-butanol fraction of HRT (HRT-BU) and fHRT (fHRT-BU) on the RANKL-induced osteoclastogenesis in bone-marrow-derived macrophages. mRNA expression of osteoclastogenesis-related genes were evaluated by real-time QPCR. The activation of signaling pathways was determined by western blot analysis. The marker compounds of HRT-BU and fHRT-BU were analyzed by HPLC. The inhibitory effect of HRT or fHRT on ovariectomy-induced bone loss were evaluated using OVX rats with orally administered HRT, fHRT (300, 1000?mg/kg), or its vehicle for 12 weeks. fHRT-BU significantly inhibited RANKL-induced osteoclastogenesis, and phosphorylation of p38, IKK?/?, and NF-?Bp65 compared to HRT-BU. In addition, fHRT-BU also significantly inhibited the mRNA expression of Nf?b2, TNF-?, NFATc1, TRAP, ATPv0d2, and cathepsin K. Furthermore, administration of fHRT had a greater effect on the increase of BMD, and greater improved bone microstructure of the femora than that of HRT in ovariectomy rats. This study demonstrated that bacterial fermentation enhances the inhibitory effect of HRT on osteoclastogenesis and bone loss. These results suggest that fermented HRT might have the beneficial effects on bone disease by inhibiting osteoclastogenesis.

Shim, Ki-Shuk; Kim, Taesoo; Ha, Hyunil; Cho, Chang-Won; Kim, Han Sung; Seo, Dong-Hyun; Ma, Jin Yeul



Dietary emu oil supplementation suppresses 5-fluorouracil chemotherapy-induced inflammation, osteoclast formation, and bone loss.  


Cancer chemotherapy can cause osteopenia or osteoporosis, and yet the underlying mechanisms remain unclear, and currently, no preventative treatments are available. This study investigated damaging effects of 5-fluorouracil (5-FU) on histological, cellular, and molecular changes in the tibial metaphysis and potential protective benefits of emu oil (EO), which is known to possess a potent anti-inflammatory property. Female dark agouti rats were gavaged orally with EO or water (1 ml·day(-1)·rat(-1)) for 1 wk before a single ip injection of 5-FU (150 mg/kg) or saline (Sal) was given. The treatment groups were H(2)O + Sal, H(2)O + 5-FU, EO + 5-FU, and EO + Sal. Oral gavage was given throughout the whole period up to 1 day before euthanasia (days 3, 4, and 5 post-5-FU). Histological analysis showed that H(2)O + 5-FU significantly reduced heights of primary spongiosa on days 3 and 5 and trabecular bone volume of secondary spongiosa on days 3 and 4. It reduced density of osteoblasts slightly and caused an increase in the density of osteoclasts on trabecular bone surface on day 4. EO supplementation prevented reduction of osteoblasts and induction of osteoclasts and bone loss caused by 5-FU. Gene expression studies confirmed an inhibitory effect of EO on osteoclasts since it suppressed 5-FU-induced expression of proinflammatory and osteoclastogenic cytokine TNF?, osteoclast marker receptor activator of nuclear factor-?B, and osteoclast-associated receptor. Therefore, this study demonstrated that EO can counter 5-FU chemotherapy-induced inflammation in bone, preserve osteoblasts, suppress osteoclast formation, and potentially be useful in preventing 5-FU chemotherapy-induced bone loss. PMID:22436700

Raghu Nadhanan, Rethi; Abimosleh, Suzanne M; Su, Yu-Wen; Scherer, Michaela A; Howarth, Gordon S; Xian, Cory J



Effects of geometry of hydroxyapatite as a cell substratum in BMP-induced ectopic bone formation.  


Three different types of porous hydroxyapatite with pore sizes of 100-200 micrometer in diameter-porous particles of hydroxyapatite (PPHAP), porous blocks of hydroxyapatite (PBHAP), and honeycomb-shaped hydroxyapatite (HCHAP)-were compared in terms of their abilities to induce osteogenesis when implanted subcutaneously with recombinant human BMP-2 into rats and extracted at 1, 2, 3, and 4 weeks. Histologically, direct bone formation occurred in PPHAP and PBHAP while only endochondral ossification took place in HCHAP. Interestingly, cartilage in the central zones and bone in the orifice zones of the tunnels of the HCHAP were observed at 2 weeks. After 3 weeks, the cartilage disappeared and bone formation occurred throughout the inner surface of the tunnels of the HCHAP, always leaving space for capillaries within the tunnels. Alkaline phosphatase activity and osteocalcin content were the highest in HCHAP among the three hydroxyapatite implants. These results clearly indicate that BMP-induced bone formation is highly dependent on the geometry of the carrier, which provides feasible structural factors for vascularization. PMID:10880093

Jin, Q M; Takita, H; Kohgo, T; Atsumi, K; Itoh, H; Kuboki, Y



CXCR4 antagonism attenuates load-induced periosteal bone formation in mice.  


Mechanical loading is a key anabolic regulator of bone mass. Stromal cell-derived factor-1 (SDF-1) is a stem cell homing factor that is important in hematopoiesis, angiogenesis, and fracture healing, though its involvement in skeletal mechanoadaptation is virtually unknown. The objective of this study was to characterize skeletal expression patterns of SDF-1 and CXCR4, the receptor for SDF-1, and to determine the role of SDF-1 signaling in load-induced periosteal bone formation. Sixteen-week-old C57BL/6 mice were treated with PBS or AMD3100, an antagonist against CXCR4, and exposed to in vivo ulnar loading (2.8 N peak-to-peak, 2?Hz, 120 cycles). SDF-1 was expressed in cortical and trabecular osteocytes and marrow cells, and CXCR4 was primarily expressed in marrow cells. SDF-1 and CXCR4 expression was enhanced in response to mechanical stimulation. The CXCR4 receptor antagonist AMD3100 significantly attenuated load-induced bone formation and led to smaller adaptive changes in cortical geometric properties as determined by histomorphometric analysis. Our data suggest that SDF-1/CXCR4 signaling plays a critical role in skeletal mechanoadaptation, and may represent a unique therapeutic target for prevention and treatment of age-related and disuse bone loss. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1828-1838, 2013. PMID:23881789

Leucht, Philipp; Temiyasathit, Sara; Russell, Ashley; Arguello, Juan F; Jacobs, Christopher R; Helms, Jill A; Castillo, Alesha B



Medical treatment for a fish bone-induced ileal micro-perforation: a case report.  


Ingested fish bone induced intestinal perforations are seldom diagnosed preoperatively due to incomplete patient history taking and difficulties in image evidence identification. Most literature suggests early surgical intervention to prevent sepsis and complications resulting from fish bone migrations. We report the case of a 44-year-old man suffered from acute abdomen induced by a fish bone micro-perforation. The diagnosis was supported by computed tomography (CT) imaging of fish bone lodged in distal ileum and a history of fish ingestion recalled by the patient. Medical treatment was elected to manage the patient's condition instead of surgical intervention. The treatment resulted in a complete resolution of abdominal pain on hospital day number 4 without complication. Factors affecting clinical treatment decisions include the nature of micro-perforation, the patient's good overall health condition, and the early diagnosis before sepsis signs develop. Micro-perforation means the puncture of intestine wall without CT evidence of free air, purulent peritoneum or abscess. We subsequently reviewed the literature to support our decision to pursue medical instead of surgical intervention. PMID:23139620

Kuo, Chein-Chung; Jen, Tsu-Kang; Wen, Cheng-Hsin; Liu, Chih-Ping; Hsiao, Hai-Sung; Liu, Yao-Chi; Chen, Kuan-Ho



Medical treatment for a fish bone-induced ileal micro-perforation: A case report  

PubMed Central

Ingested fish bone induced intestinal perforations are seldom diagnosed preoperatively due to incomplete patient history taking and difficulties in image evidence identification. Most literature suggests early surgical intervention to prevent sepsis and complications resulting from fish bone migrations. We report the case of a 44-year-old man suffered from acute abdomen induced by a fish bone micro-perforation. The diagnosis was supported by computed tomography (CT) imaging of fish bone lodged in distal ileum and a history of fish ingestion recalled by the patient. Medical treatment was elected to manage the patient’s condition instead of surgical intervention. The treatment resulted in a complete resolution of abdominal pain on hospital day number 4 without complication. Factors affecting clinical treatment decisions include the nature of micro-perforation, the patient’s good overall health condition, and the early diagnosis before sepsis signs develop. Micro-perforation means the puncture of intestine wall without CT evidence of free air, purulent peritoneum or abscess. We subsequently reviewed the literature to support our decision to pursue medical instead of surgical intervention.

Kuo, Chein-Chung; Jen, Tsu-Kang; Wen, Cheng-Hsin; Liu, Chih-Ping; Hsiao, Hai-Sung; Liu, Yao-Chi; Chen, Kuan-Ho



Exercise-induced changes in the cortical bone of growing mice are bone- and gender-specific  

Microsoft Academic Search

Fracture risk and mechanical competence of bone are functions of bone mass and tissue quality, which in turn are dependent on the bone's mechanical environment. Male mice have a greater response to non-weight-bearing exercise than females, resulting in larger, stronger bones compared with control animals. The aim of this study was to test the hypothesis that short-term weight-bearing running during

Joseph M. Wallace; Rupak M. Rajachar; Matthew R. Allen; Susan A. Bloomfield; Pamela G. Robey; Marian F. Young; David H. Kohn



Breast Cancer Cells Induce Osteolytic Bone Lesions In vivo through a Reduction in Osteoblast Activity in Mice.  


Bone metastases are severely debilitating and have a significant impact on the quality of life of women with metastatic breast cancer. Treatment options are limited and in order to develop more targeted therapies, improved understanding of the complex mechanisms that lead to bone lesion development are warranted. Interestingly, whilst prostate-derived bone metastases are characterised by mixed or osteoblastic lesions, breast-derived bone metastases are characterised by osteolytic lesions, suggesting unique regulatory patterns. This study aimed to measure the changes in bone formation and bone resorption activity at two time-points (18 and 36 days) during development of the bone lesion following intratibial injection of MDA-MB-231 human breast cancer cells into the left tibiae of Severely Combined Immuno-Deficient (SCID) mice. The contralateral tibia was used as a control. Tibiae were extracted and processed for undecalcified histomorphometric analysis. We provide evidence that the early bone loss observed following exposure to MDA-MB-231 cells was due to a significant reduction in mineral apposition rate, rather than increased levels of bone resorption. This suggests that osteoblast activity was impaired in the presence of breast cancer cells, contrary to previous reports of osteoclast-dependent bone loss. Furthermore mRNA expression of Dickkopf Homolog 1 (DKK-1) and Noggin were confirmed in the MDA-MB-231 cell line, both of which antagonise osteoblast regulatory pathways. The observed bone loss following injection of cancer cells was due to an overall thinning of the trabecular bone struts rather than perforation of the bone tissue matrix (as measured by trabecular width and trabecular separation, respectively), suggesting an opportunity to reverse the cancer-induced bone changes. These novel insights into the mechanisms through which osteolytic bone lesions develop may be important in the development of new treatment strategies for metastatic breast cancer patients. PMID:24069136

Gregory, Laura S; Choi, Wilson; Burke, Leslie; Clements, Judith A



Breast Cancer Cells Induce Osteolytic Bone Lesions In vivo through a Reduction in Osteoblast Activity in Mice  

PubMed Central

Bone metastases are severely debilitating and have a significant impact on the quality of life of women with metastatic breast cancer. Treatment options are limited and in order to develop more targeted therapies, improved understanding of the complex mechanisms that lead to bone lesion development are warranted. Interestingly, whilst prostate-derived bone metastases are characterised by mixed or osteoblastic lesions, breast-derived bone metastases are characterised by osteolytic lesions, suggesting unique regulatory patterns. This study aimed to measure the changes in bone formation and bone resorption activity at two time-points (18 and 36 days) during development of the bone lesion following intratibial injection of MDA-MB-231 human breast cancer cells into the left tibiae of Severely Combined Immuno-Deficient (SCID) mice. The contralateral tibia was used as a control. Tibiae were extracted and processed for undecalcified histomorphometric analysis. We provide evidence that the early bone loss observed following exposure to MDA-MB-231 cells was due to a significant reduction in mineral apposition rate, rather than increased levels of bone resorption. This suggests that osteoblast activity was impaired in the presence of breast cancer cells, contrary to previous reports of osteoclast-dependent bone loss. Furthermore mRNA expression of Dickkopf Homolog 1 (DKK-1) and Noggin were confirmed in the MDA-MB-231 cell line, both of which antagonise osteoblast regulatory pathways. The observed bone loss following injection of cancer cells was due to an overall thinning of the trabecular bone struts rather than perforation of the bone tissue matrix (as measured by trabecular width and trabecular separation, respectively), suggesting an opportunity to reverse the cancer-induced bone changes. These novel insights into the mechanisms through which osteolytic bone lesions develop may be important in the development of new treatment strategies for metastatic breast cancer patients.

Gregory, Laura S.; Choi, Wilson; Burke, Leslie; Clements, Judith A.



Endogenously produced n-3 fatty acids protect against ovariectomy induced bone loss in fat-1 transgenic mice.  


Aging is associated with bone loss, leading to increased risk of fractures. Recently, there is growing interest in identifying nutritional supplements that can prevent bone loss with minimum side effects. There is increasing evidence for the beneficial effects of n-3 fatty acids in the prevention of bone loss. A transgenic mouse model (fat-1) that produces n-3 fatty acids endogenously and its wild type counterpart were used in this study to determine the effects of endogenously produced n-3 fatty acids on serum bone turnover markers, long bones, and lumbar vertebrae. Serum alkaline phosphatase and P1NP levels decreased significantly in wild type mice after ovariectomy. No significant changes were seen in osteocalcin. Cancellous and cortical bone mass were higher in the femur of fat-1 mice. In wild type mice, there was significant loss of bone after ovariectomy in the distal femur, femoral neck, proximal tibia, and fourth lumbar vertebra. However, in fat-1 mice, there was no, or significantly less, bone lost after ovariectomy in all the sites studied. We conclude that endogenously produced n-3 fatty acids can attenuate ovariectomy induced bone loss in the different bone sites studied, mainly as a consequence of decreased bone resorption at the endosteal surface. PMID:20393761

Banu, Jameela; Bhattacharya, Arunabh; Rahman, Mizanur; Kang, J X; Fernandes, Gabriel



The effect of temperature on radiation-induced radicals in irradiated chicken drumstick bones  

NASA Astrophysics Data System (ADS)

The effect of temperature on the ESR spectra of well characterized unirradiated and irradiated samples of chicken drumstick bones under standardized experimental conditions has been investigated in detail over the temperature range 100-450 K. No significant changes in the linewidth and g factor of the endogenous signal were observed, but the signal intensity was found to decrease markedly in an irreversible way when the temperature was increased. The radiation-induced signal turned out to be the sum of a narrow and a broad line which were assigned to an inorganic and an organic radical, respectively. The thermal stability of the radiation-induced inorganic radical used in poultry irradiation dose determination and in dating was found to be much better than that of organic and endogenous radicals. The results of the present work highlight the need to define properly calibration factors which can be used in conjunction with pre- or post-irradiation thermal treatment of chicken drumstick bones.

Polat, M.; Korkmaz, M.; Korkmaz, Ö.



Bone resorption and remodeling in murine collagenase-induced osteoarthritis after administration of glucosamine  

PubMed Central

Introduction Glucosamine is an amino-monosaccharide and precursor of glycosaminoglycans, major components of joint cartilage. Glucosamine has been clinically introduced for the treatment of osteoarthritis but the data about its protective role in disease are insufficient. The goal of this study was to investigate the effect of long term administration of glucosamine on bone resorption and remodeling. Methods The effect of glucosamine on bone resorption and remodeling was studied in a model of collagenase-induced osteoarthritis (CIOA). The levels of macrophage-inflammatory protein (MIP)-1?, protein regulated upon activation, normal T-cell expressed, and secreted (RANTES), soluble receptor activator of nuclear factor kappa-B ligand (RANKL), tumor necrosis factor (TNF)-?, and interleukin (IL)-6, 4 and 10 in synovial fluid were measured by enzyme-linked immunosorbent assay (ELISA). Cell populations in synovial extracts and the expression of RANKL, of receptors for TNF-? (TNF-?R) and interferon ? (IFN-?R) on clusters of differentiation (CD) three positive T cells were analyzed by flow cytometry. Transforming growth factor (TGF)-?3, bone morphogenetic protein (BMP)-2, phosphorylated protein mothers against decapentaplegic homolog 2 (pSMAD-2), RANKL and Dickkopf-1 protein (DKK-1) positive staining in CIOA joints were determined by immunohistochemistry. Results The administration of glucosamine hydrochloride in CIOA mice inhibited loss of glycosaminoglycans (GAGs) and proteoglycans (PGs) in cartilage, bone erosion and osteophyte formation. It decreased the levels of soluble RANKL and IL-6 and induced IL-10 increase in the CIOA joint fluids. Glucosamine limited the number of CD11b positive Ly6G neutrophils and RANKL positive CD3 T cells in the joint extracts. It suppressed bone resorption via down-regulation of RANKL expression and affected bone remodeling in CIOA by decreasing BMP-2, TGF-?3 and pSMAD-2 expression and up-regulating DKK-1 joint levels. Conclusions Our data suggest that glucosamine hydrochloride inhibits bone resorption through down-regulation of RANKL expression in the joints, via reduction of the number of RANKL positive CD3 T cells and the level of sRANKL in the joints extracts. These effects of glucosamine appear to be critical for the progression of CIOA and result in limited bone remodeling of the joints.



Protective effects of indole-3-carbinol on cyclophosphamide-induced clastogenecity in mouse bone marrow cells  

Microsoft Academic Search

Indole-3-carbinol (I3C) is present in many cruciferous vegetables and is known to possess protective properties against chemically induced toxicity and carcinogenesis. In the present study, the antimutagenic potential of I3C has been evaluated using in vivo chromosomal aberration (CA) assay as a cytogenetic end point. Chromosomal analysis was carried out in mouse bone marrow cells following administration of I3C (5

Yogeshwer Shukla; Bhawna Srivastava; Annu Arora; L KS Chauhan



PGC1beta mediates PPARgamma activation of osteoclastogenesis and rosiglitazone-induced bone loss.  


Long-term usage of rosiglitazone, a synthetic PPARgamma agonist, increases fracture rates among diabetic patients. PPARgamma suppresses osteoblastogenesis while activating osteoclastogenesis, suggesting that rosiglitazone decreases bone formation while sustaining or increasing bone resorption. Using mouse models with genetically altered PPARgamma, PGC1beta, or ERRalpha, here we show that PGC1beta is required for the resorption-enhancing effects of rosiglitazone. PPARgamma activation indirectly induces PGC1beta expression by downregulating beta-catenin and derepressing c-jun. PGC1beta, in turn, functions as a PPARgamma coactivator to stimulate osteoclast differentiation. Complementarily, PPARgamma also induces ERRalpha expression, which coordinates with PGC1beta to enhance mitochondrial biogenesis and osteoclast function. ERRalpha knockout mice exhibit osteoclast defects, revealing ERRalpha as an important regulator of osteoclastogenesis. Strikingly, PGC1beta deletion in osteoclasts confers complete resistance to rosiglitazone-induced bone loss. These findings identify PGC1beta as an essential mediator for the PPARgamma stimulation of osteoclastogenesis by targeting both PPARgamma itself and ERRalpha, thus activating two distinct transcriptional programs. PMID:20519122

Wei, Wei; Wang, Xueqian; Yang, Marie; Smith, Leslie C; Dechow, Paul C; Sonoda, Junichiro; Evans, Ronald M; Wan, Yihong



PGC1? Mediates PPAR? Activation of Osteoclastogenesis and Rosiglitazone-Induced Bone Loss  

PubMed Central

SUMMARY Long-term usage of rosiglitazone, a synthetic PPAR? agonist, increases fracture rates among diabetic patients. PPAR? suppresses osteoblastogenesis while activating osteoclastogenesis, suggesting that rosiglitazone decreases bone formation while sustaining or increasing bone resorption. Using mouse models with genetically altered PPAR?, PGC1? or ERR?, here we show that PGC1? is required for the resorption-enhancing effects of rosiglitazone. PPAR? activation indirectly induces PGC1? expression by down-regulating ?-catenin and derepressing c-jun. PGC1? in turn functions as a PPAR? coactivator to stimulate osteoclast differentiation. Complementarily, PPAR? also induces ERR? expression, which coordinates with PGC1? to enhance mitochondrial biogenesis and osteoclast function. ERR? knockout mice exhibit osteoclast defects, revealing ERR? as an important regulator of osteoclastogenesis. Strikingly, PGC1? deletion in osteoclasts confers complete resistance to rosiglitazone-induced bone loss. These findings identify PGC1? as an essential mediator for the PPAR? stimulation of osteoclastogenesis by targeting both PPAR? itself and ERR?, thus activating two distinct transcriptional programs.

Wei, Wei; Wang, Xueqian; Yang, Marie; Smith, Leslie C.; Dechow, Paul C.; Sonoda, Junichiro; Evans, Ronald M.; Wan, Yihong



Parathyroid hormone-related protein (pthrp) is a gravisensor for lung and bone.  

NASA Astrophysics Data System (ADS)

Parathyroid Hormone-related Protein (PTHrP) and its receptor represent a stretch- sensitive paracrine signaling mechanism (Torday, 1999) that may sense gravity. PTHrP has been shown to be essential for the development and homeostatic regulation of lung (Rubin et al, 2000) and bone (Kronenberg et al, 1994). Since both lung and bone structure and function are affected by microgravity, we hypothesized that microgravity down-regulates PTHrP signaling. To test this hypothesis, we suspended lung and bone cells in the microgravity environment of a rotating wall vessel apparatus, which simulates microgravity, for up to 72 hours. During the first 6-8 hours, PTHrP expression fell precipitously, decreasing by 80-90%; during the subsequent 64-66 hours, PTHrP expression remained at this newly established level. PTHrP production decreased from 5 pmol/ml/3hours to undetectable levels in culture medium from microgravity-exposed cells. The cells were then put back in culture at unit gravity for 24hours, and PTHrP expression and production returned to normal levels. Based on these findings, we have obtained bones from rats flown in space for 2 weeks (mission SLS-2, provided courtesy of the Biospecimen Facility, Ames Research Center, NASA, as a result of a peer-reviewed proposal). Analysis of PTHrP expression by femurs and tibias from these animals (n=5) revealed that PTHrP expression was 60% lower than in bones from ground-based rats. Interestingly, there were no differences in PTHrP exp ression by parietal bones, indicating that the effect of weightlessness on PTHrP expression is due to the unweighting of weight-bearing bones. This finding is consistent with other studies of microgravity-induced osteoporosis. The loss of the PTHrP signaling mechanism may be corrected using chemical agents that up-regulate this pathway.

Torday, J.


Parathyroid hormone-related protein is a gravisensor in lung and bone cell biology  

NASA Astrophysics Data System (ADS)

Parathyroid Hormone-related Protein (PTHrP) has been shown to be essential for the development and homeostatic regulation of lung and bone. Since both lung and bone structure and function are affected by microgravity, we hypothesized that 0 × g down-regulates PTHrP signaling. To test this hypothesis, we suspended lung and bone cells in the simulated microgravity environment of a Rotating Wall Vessel Bioreactor, which simulates microgravity, for up to 72 hours. During the first 8 hours of exposure to simulated 0 × g, PTHrP expression fell precipitously, decreasing by 80-90%; during the subsequent 64 hours, PTHrP expression remained at this newly established level of expression. PTHrP production decreased from 12 pg/ml/hour to 1 pg/ml/hour in culture medium from microgravity-exposed cells. The cells were then recultured at unit gravity for 24hours, and PTHrP expression and production returned to normal levels. Based on these findings, we have obtained bones from rats flown in space for 2 weeks (Mission STS-58, SL-2). Analysis of PTHrP expression by femurs and tibias from these animals (n=5) revealed that PTHrP expression was 60% lower than in bones from control ground-based rats. Interestingly, there were no differences in PTHrP expression by parietal bone from space-exposed versus ground-based animals, indicating that the effect of weightlessness on PTHrP expression is due to the unweighting of weight-bearing bones. This finding is consistent with other studies of microgravity-induced osteoporosis. The loss of the PTHrP signaling mechanism may be corrected using chemical agents that up-regulate this pathway. In conclusion, PTHrP represents a stretch-sensitive paracrine signaling mechanism that may sense gravity.

Torday, J. S.



Pyk2 regulates megakaryocyte-induced increases in osteoblast number and bone formation.  


Preclinical and clinical evidence from megakaryocyte (MK)-related diseases suggests that MKs play a significant role in maintaining bone homeostasis. Findings from our laboratories reveal that MKs significantly increase osteoblast (OB) number through direct MK-OB contact and the activation of integrins. We, therefore, examined the role of Pyk2, a tyrosine kinase known to be regulated downstream of integrins, in the MK-mediated enhancement of OBs. When OBs were co-cultured with MKs, total Pyk2 levels in OBs were significantly enhanced primarily because of increased Pyk2 gene transcription. Additionally, p53 and Mdm2 were both decreased in OBs upon MK stimulation, which would be permissive of cell cycle entry. We then demonstrated that OB number was markedly reduced when Pyk2-/- OBs, as opposed to wild-type (WT) OBs, were co-cultured with MKs. We also determined that MKs inhibit OB differentiation in the presence and absence of Pyk2 expression. Finally, given that MK-replete spleen cells from GATA-1-deficient mice can robustly stimulate OB proliferation and bone formation in WT mice, we adoptively transferred spleen cells from these mice into Pyk2-/- recipient mice. Importantly, GATA-1-deficient spleen cells failed to stimulate an increase in bone formation in Pyk2-/- mice, suggesting in vivo the important role of Pyk2 in the MK-induced increase in bone volume. Further understanding of the signaling pathways involved in the MK-mediated enhancement of OB number and bone formation will facilitate the development of novel anabolic therapies to treat bone loss diseases. PMID:23362087

Cheng, Ying-Hua; Hooker, R Adam; Nguyen, Khanh; Gerard-O'Riley, Rita; Waning, David L; Chitteti, Brahmananda R; Meijome, Tomas E; Chua, Hui Lin; Plett, Artur P; Orschell, Christie M; Srour, Edward F; Mayo, Lindsey D; Pavalko, Fredrick M; Bruzzaniti, Angela; Kacena, Melissa A



Effects of additional resistance training during diet-induced weight loss on bone mineral density in overweight premenopausal women  

Microsoft Academic Search

Bone loss accompanies a diet-induced weight loss and could be prevented with a combination of exercises. This study was conducted\\u000a to examine the effects of additional resistance training during diet-induced weight loss on whole-body and selected regional\\u000a bone mineral density (BMD). The participants of a 14-week weight-loss study were 42 overweight premenopausal Japanese women\\u000a who were randomly placed in either

Yoshio Nakata; Kazunori Ohkawara; Dong Jun Lee; Tomohiro Okura; Kiyoji Tanaka



Receptor activator of nuclear factor ?B ligand (RANKL) protein expression by B lymphocytes contributes to ovariectomy-induced bone loss.  


Production of the cytokine receptor activator of NF?B ligand (RANKL) by lymphocytes has been proposed as a mechanism by which sex steroid deficiency causes bone loss. However, there have been no studies that functionally link RANKL expression in lymphocytes with bone loss in this condition. Herein, we examined whether RANKL expression in either B or T lymphocytes contributes to ovariectomy-induced bone loss in mice. Mice harboring a conditional RANKL allele were crossed with CD19-Cre or Lck-Cre mice to delete RANKL in B or T lymphocytes, respectively. Deletion of RANKL from either cell type had no impact on bone mass in estrogen-replete mice up to 7 months of age. However, mice lacking RANKL in B lymphocytes were partially protected from the bone loss caused by ovariectomy. This protection occurred in cancellous, but not cortical, bone and was associated with a failure to increase osteoclast numbers in the conditional knock-out mice. Deletion of RANKL from T lymphocytes had no impact on ovariectomy-induced bone loss. These results demonstrate that lymphocyte RANKL is not involved in basal bone remodeling, but B cell RANKL does contribute to the increase in osteoclasts and cancellous bone loss that occurs after loss of estrogen. PMID:22782898

Onal, Melda; Xiong, Jinhu; Chen, Xinrong; Thostenson, Jeff D; Almeida, Maria; Manolagas, Stavros C; O'Brien, Charles A



A single intravenous administration of zoledronic acid prevents the bone loss and mechanical compromise induced by aromatase inhibition in rats.  


Recent evidence has demonstrated that long-term estrogen deprivation using aromatase inhibitor therapy in postmenopausal women with breast cancer results in bone loss and increased fracture risk. Bisphosphonates are potent inhibitors of bone resorption and have demonstrated efficacy in preventing bone loss in postmenopausal women with low bone mineral density (BMD) and in patients with breast cancer receiving estrogen deprivation therapy. Therefore, this study investigated the effects of the bisphosphonate zoledronic acid on BMD and bone strength in rats treated with the aromatase inhibitor, letrozole. Peripheral quantitative computed tomography demonstrated that treatment of rats with daily oral letrozole (1 mg/kg) induced significant bone loss and cortical thinning compared with control animals (P < 0.01). A single prior intravenous dose of zoledronic acid dose dependently protected against letrozole-induced bone loss and cortical thinning, with the highest evaluated dose (20 microg/kg) resulting in BMD values that were not significantly different from controls over the 24 weeks of letrozole treatment. Furthermore, biomechanical testing of the distal femoral metaphysis demonstrated that zoledronic acid (20 microg/kg) significantly prevented the decrease in stiffness and elastic modulus induced by letrozole treatment. Taken together, these data support the use of zoledronic acid for the prevention of bone loss in women with breast cancer receiving aromatase inhibitor therapy. PMID:16844441

Gasser, Jürg A; Green, Jonathan R; Shen, Victor; Ingold, Peter; Rebmann, Andrea; Bhatnagar, Ajay S; Evans, Dean B



Both spontaneous Ins2(+/-) and streptozotocin-induced type I diabetes cause bone loss in young mice.  


The adolescent skeleton undergoes accelerated growth determining overall bone density, length, and quality. Diseases such as type 1 diabetes (T1D), most often diagnosed in adolescents, can alter bone processes and promote bone loss. Studies examining type 1 diabetic (T1D) bone pathologies typically utilize adult mice and rely on pharmacologic models such as streptozotocin (STZ)-induced diabetic rodents. To test the effect of T1D on adolescent bone growth/density we used a novel juvenile genetic model (Ins2(+/-) mice) that spontaneously develop T1D at approximately 5 weeks of age and compared our findings with STZ-induced T1D mice. Compared to controls, both Ins2(+/-) and STZ-induced T1D mice displayed blood glucose levels greater than 300?mg/dl and reduced body, fat and muscle mass as well as femur trabecular bone density. STZ mice exhibited greater bone loss compared to Ins2(+/-) mice despite having lower blood glucose levels. Cortical bone was affected in STZ but not Ins2(+/-) mice. Osteocalcin serum protein and bone RNA levels decreased in both models. Consistent with studies in adult mice, STZ adolescent mice displayed increased marrow adiposity, however this was not observed in the Ins2(+/-) mice. Reduced femur length, decreased growth plate thickness and decreased collagen II expression in both model simplies impaired cartilage formation. In summary, both pharmacologic and spontaneous adolescent T1D mice demonstrated a bone synthesis and growth defect. STZ appears to cause a more severe phenotype. Thus, the Ins2(+/-) mouse could serve as a useful model to study adolescent T1D bone loss with fewer complications. PMID:22886636

Coe, Lindsay M; Zhang, Jing; McCabe, Laura R



Self-induced vomiting as a probable mechanism of an isolated hyoid bone fracture.  


Fractures of the laryngeal skeleton (hyoid bone and thyroid horns) are an important finding in a forensic autopsy because they are almost always caused by significant trauma and often are relevant in determining the cause and manner of death. In the forensic setting, these injuries are seen in some hangings and more frequently in manual strangulation. Less common mechanisms include direct blows, "choke holds," and hyperextension of the neck. We present a case of a 37-year-old woman who died of complications of acute ethanol intoxication. The case involves an incidental hyoid bone fracture unrelated to the cause of death as well as facial petechiae. After review of all of the medical records, autopsy findings and scene/police investigations-the key findings of facial petechial hemorrhages and hyoid bone fracture are best attributed to the mechanism of self-induced vomiting. This case emphasizes the importance of synthesizing autopsy findings with the patient's medical and social history to avoid unnecessary investigation or prosecution. This is the second known case of this novel mechanism of hyoid bone fracture in the medical literature and the first in the forensic literature. PMID:20585227

White, Joseph K; Carver, John



Optimal management of cancer treatment-induced bone loss: considerations for elderly patients.  


Hormone manipulation, commonly used in breast and prostate cancer, can result in significant bone loss. In multiple myeloma (MM), corticosteroids play an important role in therapy but increase the risk of fracture over that expected for any given bone mineral density. These adverse effects on the skeletal system are particularly relevant in the elderly population, in whom osteoporosis can significantly affect not only quality of life but also survival. The associated health and social care costs are becoming increasingly important. Screening with dual energy x-ray absorptiometry (DXA) scans and lifestyle advice on smoking, alcohol and dietary intake are essential parts of the management of patients with cancer treatment-induced bone loss. The value of exercise also cannot be underestimated. A careful drug review should be carried out to eliminate agents that may potentially exacerbate bone toxicity. Therapies to address bone toxicities include bisphosphonates, which have been shown to play an increasingly important role in preventing declines in bone health. The issues of compliance when oral agents are used should not be underestimated. Renal toxicity and osteonecrosis of the jaw are relevant toxicities, especially in the elderly. Cardiac toxicity has not been proven, but there is evidence to suggest that the suppression of bone turnover seen with some, although not all, bisphosphonates is not reversed following cessation of treatment. The implications of this finding need to be borne in mind when treating elderly patients. The possibility of atypical fractures in patients taking bisphosphonates also needs to be given consideration, although this remains a rare complication. Recently, the receptor activator of nuclear factor-?B ligand (RANKL) ligand antibody denosumab has been shown to be of value in fracture prevention, and its subcutaneous route of administration offers a potential advantage. Oncologists should also remember that tamoxifen, which has little effect on bone integrity, remains a useful drug for breast cancer patients. A multidisciplinary approach involving the hospital specialist, general practitioner, nurse and, most importantly, the patient, family and carers should ensure that the maximal benefit is received from the anti-cancer treatment, with minimal cost to the patient. As cancer cure rates increase, late toxicity is increasingly relevant and challenging. The skeletal system warrants more research to maximize the care of all our patients, especially the elderly, who may be most at risk. PMID:22054228

Tipples, Karen; Robinson, Anne



Application of a novel bone osteotomy plate leads to reduction in heat-induced bone tissue necrosis in sheep.  


Previous studies have shown substantial effect thermal damage can have on new bone formation following osteotomy. In this study we evaluated the extent of thermal damage which occurs in four different methods of osteotomy and the effects it can have on bone healing. We further wanted to test whether a special osteotomy plate we constructed can lead to diminished heat generation during osteotomy and enhanced bone healing. The four methods evaluated included osteotomy performed by chisel, a newly constructed osteotomy plate, Gigly and oscillating saw. Twelve adult sheep underwent osteotomy performed on both tibiae. Bone fragments were stabilized using a fixation plate. Callus size was assessed using standard radiographs. Densitometry and histological evaluation were performed at 8 weeks following osteotomy. Temperature measurements were performed both in vivo during the operation, and ex vivo on explanted tibiae. The defects healed without complications and showed typical course of secondary fracture healing with callus ingrowth into the osteotomy gap. Radiographic examination of bone healing showed a tendency towards more callus formation in bones osteotomized using Gigly and oscillating saw, but this difference lacked significance. Use of Gigly and oscillating saw elicited much higher temperatures at the bone cortex surface, which subsequently lead to slightly impaired bone healing according to histological analysis. BMD was equal among all bones. In conclusion, the time required for complete healing of the defect differed depended greatly on the instruments used. The newly constructed osteotomy plate showed best results based on histological findings of capillary and osteoblast density. PMID:19149233

Beki?, Marijo; Davila, Slavko; Hrskanovi?, Mato; Beki?, Marijana; Seiwerth, Sven; Erdelji?, Viktorija; Capak, Darko; Butkovi?, Vladimir



An Oligodeoxynucleotide That Induces Differentiation of Bone Marrow Mesenchymal Stem Cells to Osteoblasts in Vitro and Reduces Alveolar Bone Loss in Rats with Periodontitis  

PubMed Central

To investigate the effect of oligodeoxynucleotides (ODNs) on the differentiation of rat bone marrow mesenchymal stem cells (BMSCs) to osteoblasts, in order to find a candidate ODN with potential for the treatment of periodontitis, a series of ODNs were designed and selected to test their effect on the promotion of the differentiation of BMSCs to osteoblasts in vitro and on the repair of periodontal tissue in rats with periodontitis. It was found that MT01, one of the ODNs with the sequences of human mitochondrial DNA, stimulated the proliferation of BMSCs, the differentiation of BMSCs to osteoblasts and mRNA expression of bone-associated factors including Runx2, Osterix, OPG, RANKL and collagen I in vitro. In vivo study showed that MT01 prevented the loss of alveolar bone in the rats with periodontitis and induced the production of proteins of OPG and Osterix in the bone tissue. These results indicated that MT01 could induce differentiation of BMSCs to osteoblasts and inhibit the alveolar bone absorption in rats with periodontitis.

Shen, Yuqin; Feng, Zhiyuan; Lin, Chongtao; Hou, Xu; Wang, Xueju; Wang, Jing; Yu, Yongli; Wang, Liying; Sun, Xinhua



Cell proliferation, cell shape, and microtubule and cellulose microfibril organization of tobacco BY2 cells are not altered by exposure to near weightlessness in space  

Microsoft Academic Search

The microtubule cytoskeleton and the cell wall both play key roles in plant cell growth and division, determining the plant’s\\u000a final stature. At near weightlessness, tubulin polymerizes into microtubules in vitro, but these microtubules do not self-organize\\u000a in the ordered patterns observed at 1g. Likewise, at near weightlessness cortical microtubules in protoplasts have difficulty organizing into parallel arrays, which\\u000a are

Björn J. Sieberer; Henk Kieft; Tiny Franssen-Verheijen; Anne Mie C. Emons; Jan W. Vos



Green tea polyphenols improve bone microarchitecture in high-fat-diet-induced obese female rats through suppressing bone formation and erosion.  


This study evaluates the effects of green tea polyphenols (GTPs) on bone microarchitecture in high-fat-diet (HFD)-induced obese female rats. Thirty-six 3-month-old female rats were fed either a control diet or a HFD for 4 months. Animals in the control group continued on the control diet for another 4 months. Animals in the HFD group were divided into two groups, with 0.5?g/100?mL GTP (the HFD+GTP group) or without GTP (the HFD group) in drinking water, in addition to the HFD for another 4 months. Compared to the control group, the HFD group increased bone formation and erosion rates at the tibia, decreased trabecular volume and thickness, but had no impact on bone mineral density (BMD), trabecular number (Tb.N), and separation. Compared to the control group, the HFD+GTP group demonstrates a greater Tb.N at the proximal tibia, and a greater trabecular thickness at the femur and the lumbar vertebrae, but a smaller trabecular separation (Tb.Sp) and mineralizing surface at the proximal tibia, and a reduced endocortical mineral apposition rate (MAR) at the tibia shaft. Relative to the HFD group, the HFD+GTP group demonstrates (1) a higher BMD at the femur, a greater trabecular volume, thickness, and number at the proximal tibia, a larger cortical area and thickness at the tibial shaft, and a greater trabecular volume and thickness at the femur and the lumbar vertebrae, (2) a smaller Tb.Sp, MAR, bone formation rate, and eroded surface at the tibia. We concluded that GTP supplementation in drinking water improves bone microarchitecture in the HFD-induced obese female rats, possibly through suppressing bone turnover, resulting in a larger net bone volume. PMID:23631490

Shen, Chwan-Li; Chyu, Ming-Chien; Cao, Jay J; Yeh, James K



Osteoclast Differentiation Factor Mediates an Essential Signal for Bone Resorption Induced by 1?,25-Dihydroxyvitamin D 3, Prostaglandin E 2, or Parathyroid Hormone in the Microenvironment of Bone  

Microsoft Academic Search

Osteoclast differentiation factor (ODF), a ligand for osteoprotegerin (OPG)\\/osteoclastogenesis-inhibitory factor (OCIF), induces osteoclast-like cell formationin vitro.To elucidate the role of ODF in the microenvironment of bone, we examined effects of ODF, OPG\\/OCIF, and anti-ODF polyclonal antibody on bone resorption using a fetal mouse long bone culture system. A genetically engineered soluble-form ODF (sODF) elicited bone resorption in a concentration-dependent manner

Katsuyoshi Tsukii; Nobuyuki Shima; Shin-ichi Mochizuki; Kyoji Yamaguchi; Masahiko Kinosaki; Kazuki Yano; Osamu Shibata; Nobuyuki Udagawa; Hiroshi Yasuda; Tatsuo Suda; Kanji Higashio



Oxidized lipids enhance RANKL production by T lymphocytes: implications for lipid-induced bone loss  

PubMed Central

Osteoporosis is a systemic disease that is associated with increased morbidity, mortality and health care costs. Whereas osteoclasts and osteoblasts are the main regulators of bone homeostasis, recent studies underscore a key role for the immune system, particularly via activation-induced T lymphocyte production of Receptor Activator of NF?B Ligand (RANKL). Well-documented as a mediator of T lymphocyte/dendritic cell interactions, RANKL also stimulates the maturation and activation of bone-resorbing osteoclasts. Given that lipid oxidation products mediate inflammatory and metabolic disorders such as osteoporosis and atherosclerosis, and since oxidized lipids affect several T lymphocyte functions, we hypothesized that RANKL production might also be subject to modulation by oxidized lipids. Here, we show that short term exposure of both unstimulated and activated human T lymphocytes to minimally oxidized low density lipoprotein (LDL), but not native LDL, significantly enhances RANKL production and promotes expression of the lectin-like oxidized LDL receptor-1 (LOX-1). The effect, which is also observed with 8-iso-Prostaglandin E2, an inflammatory isoprostane produced by lipid peroxidation, is mediated via the NF?B pathway, and involves increased RANKL mRNA expression. The link between oxidized lipids and T lymphocytes is further reinforced by analysis of hyperlipidemic mice, in which bone loss is associated with increased RANKL mRNA in T lymphocytes and elevated RANKL serum levels. Our results suggest a novel pathway by which T lymphocytes contribute to bone changes, namely, via oxidized lipid enhancement of RANKL production. These findings may help elucidate clinical associations between cardiovascular disease and decreased bone mass, and may also lead to new immune-based approaches to osteoporosis.

Graham, Lucia S; Parhami, Farhad; Tintut, Yin; Kitchen, Christina M. R.; Demer, Linda L.; Effros, Rita B.



Pathobiology and management of prostate cancer-induced bone pain: recent insights and future treatments.  


Prostate cancer (PCa) has a high propensity for metastasis to bone. Despite the availability of multiple treatment options for relief of PCa-induced bone pain (PCIBP), satisfactory relief of intractable pain in patients with advanced bony metastases is challenging for the clinicians because currently available analgesic drugs are often limited by poor efficacy and/or dose-limiting side effects. Rodent models developed in the past decade show that the pathobiology of PCIBP comprises elements of inflammatory, neuropathic and ischemic pain arising from ectopic sprouting and sensitization of sensory nerve fibres within PCa-invaded bones. In addition, at the cellular level, PCIBP is underpinned by dynamic cross talk between metastatic PCa cells, cellular components of the bone matrix, factors associated with the bone microenvironment as well as peripheral components of the somatosensory system. These insights are aligned with the clinical management of PCIBP involving use of a multimodal treatment approach comprising analgesic agents (opioids, NSAIDs), radiotherapy, radioisotopes, cancer chemotherapy agents and bisphosphonates. However, a major drawback of most rodent models of PCIBP is their short-term applicability due to ethical concerns. Thus, it has been difficult to gain insight into the mal(adaptive) neuroplastic changes occurring at multiple levels of the somatosensory system that likely contribute to intractable pain at the advanced stages of metastatic disease. Specifically, the functional responsiveness of noxious circuitry as well as the neurochemical signature of a broad array of pro-hyperalgesic mediators in the dorsal root ganglia and spinal cord of rodent models of PCIBP is relatively poorly characterized. Hence, recent work from our laboratory to develop a protocol for an optimized rat model of PCIBP will enable these knowledge gaps to be addressed as well as identification of novel targets for drug discovery programs aimed at producing new analgesics for the improved relief of intractable PCIBP. PMID:23918298

Muralidharan, Arjun; Smith, Maree T



Ultrasonic tissue characterization for monitoring nanostructured TiO2-induced bone growth.  


The use of bioactive nanostructured TiO2 has recently been proposed for improving orthopaedic implant adhesion due to its improved biocompatibility with bone, since it induces: (i) osteoblast function, (ii) apatite nucleation and (iii) protein adsorption. The present work focuses on a non-ionizing radiation emitting technique for quantifying in real time the improvement in terms of mechanical properties of the surrounding bone due to the presence of the nanostructured TiO2 prepared by controlled precipitation and acid ageing. The mechanical strength is the ultimate goal of a bone implant and is directly related to the elastic moduli. Ultrasonics are high frequency mechanical waves and are therefore suited for characterizing elastic moduli. As opposed to echographic techniques, which are not correlated to elastic properties and are not able to penetrate bone, a low frequency ultrasonic transmission test is proposed, in which a P-wave is transmitted through the specimen and recorded. The problem is posed as an inverse problem, in which the unknown is a set of parameters that describe the mechanical constants of the sequence of layers. A finite element numerical model that depends on these parameters is used to predict the transformation of the waveform and compare to the measurement. The parameters that best describe the real tissue are obtained by minimizing the discrepancy between the real and numerically predicted waveforms. A sensitivity study to the uncertainties of the model is performed for establishing the feasibility of using this technique to investigate the macroscopic effect on bone growth of nanostructured TiO2 and its beneficial effect on implant adhesion. PMID:17664558

Rus, G; García-Martínez, J



Preliminary report on treatment of bone tumors with microwave-induced hyperthermia  

SciTech Connect

Between July, 1992, and February, 1995, 62 patients with various bone tumors were treated with microwave-induced hyperthermia. The series had 47 cases of malignant tumors and 15 cases with benign tumors; most of the tumors occurred at or near knee joints (53/62 = 85.4%). The surgical procedure consisted of separating the tumorous segment from surrounding normal tissues with a safe margin, cooling the normal tissues (including the vital neurovascular bundle and the intrajoint structures) with a water circulation system while heating the tumor simultaneously with the microwave antenna array, and providing an adequate soft-tissue cover for the dead bone. The tumor core temperature and the surface temperature reached 108 and 65 C, respectively. The duration of microwave irradiation was usually 40--50 minutes. Meanwhile, the temperature of the normal tissues was kept under 39 C. The minimal and maximal periods of clinical observation were 3 months and 36 months, respectively, and the mean follow-up period was 17 months. The 62 cases were evaluated from both oncological and orthopedic points of view. Five cases had local recurrence and required amputation. The 57 other cases had excellent local control. Six malignancy cases die of lung metastasis during a period of 1--2 years. Pathological fracture occurred at devitalized bone in five cases. In most of the cases, the knee joints functioned well, were stable and painless, and had almost full range of motion. Single-photon emission-computed tomography study in 16 cases revealed that revascularization of the devitalized tumorous bone segment could be accomplished in 1 year or more. These results show that the use of microwave hyperthermia for the treatment of bone tumors can be considered to be a definitive operation procedure that is safe and is well tolerated by patients. The oncological and orthopedic results are very encouraging.

Fan, Q.Y.; Ma, B.A.; Qiu, X.C.; Li, Y.L.; Ye, J.; Zhou, Y. [Fourth Military Medical Univ., Xi`an (China)



Bone Marrow Stromal Cell Transplantation Mitigates Radiation-Induced Gastrointestinal Syndrome in Mice  

PubMed Central

Background Nuclear accidents and terrorism presents a serious threat for mass casualty. While bone-marrow transplantation might mitigate hematopoietic syndrome, currently there are no approved medical countermeasures to alleviate radiation-induced gastrointestinal syndrome (RIGS), resulting from direct cytocidal effects on intestinal stem cells (ISC) and crypt stromal cells. We examined whether bone marrow-derived adherent stromal cell transplantation (BMSCT) could restitute irradiated intestinal stem cells niche and mitigate radiation-induced gastrointestinal syndrome. Methodology/Principal Findings Autologous bone marrow was cultured in mesenchymal basal medium and adherent cells were harvested for transplantation to C57Bl6 mice, 24 and 72 hours after lethal whole body irradiation (10.4 Gy) or abdominal irradiation (16–20 Gy) in a single fraction. Mesenchymal, endothelial and myeloid population were characterized by flow cytometry. Intestinal crypt regeneration and absorptive function was assessed by histopathology and xylose absorption assay, respectively. In contrast to 100% mortality in irradiated controls, BMSCT mitigated RIGS and rescued mice from radiation lethality after 18 Gy of abdominal irradiation or 10.4 Gy whole body irradiation with 100% survival (p<0.0007 and p<0.0009 respectively) beyond 25 days. Transplantation of enriched myeloid and non-myeloid fractions failed to improve survival. BMASCT induced ISC regeneration, restitution of the ISC niche and xylose absorption. Serum levels of intestinal radioprotective factors, such as, R-Spondin1, KGF, PDGF and FGF2, and anti-inflammatory cytokines were elevated, while inflammatory cytokines were down regulated. Conclusion/Significance Mitigation of lethal intestinal injury, following high doses of irradiation, can be achieved by intravenous transplantation of marrow-derived stromal cells, including mesenchymal, endothelial and macrophage cell population. BMASCT increases blood levels of intestinal growth factors and induces regeneration of the irradiated host ISC niche, thus providing a platform to discover potential radiation mitigators and protectors for acute radiation syndromes and chemo-radiation therapy of abdominal malignancies.

Saha, Subhrajit; Bhanja, Payel; Kabarriti, Rafi; Liu, Laibin; Alfieri, Alan A.; Guha, Chandan



Lipopolysaccharide-Induced Epithelial Monoamine Oxidase Mediates Alveolar Bone Loss in a Rat Chronic Wound Model  

PubMed Central

Reactive oxygen species (ROS) production is an antimicrobial response to pathogenic challenge that may, in the case of persistent infection, have deleterious effects on the tissue of origin. A rat periodontal disease model was used to study ROS-induced chronic epithelial inflammation and bone loss. Lipopolysaccharide (LPS) was applied for 8 weeks into the gingival sulcus, and histological analysis confirmed the onset of chronic disease. Junctional epithelium was collected from healthy and diseased animals using laser-capture microdissection, and expression microarray analysis was performed. Of 19,730 genes changed in disease, 42 were up-regulated ?4-fold. Three of the top 10 LPS-induced genes, monoamine oxidase B (MAO/B) and flavin-containing monooxygenase 1 and 2, are implicated in ROS signaling. LPS-associated induction of the ROS mediator H2O2, as well as MAO/B and tumor necrosis factor (TNF)-? levels were validated in the rat histological sections and a porcine junctional epithelial cell culture model. Topical MAO inhibitors significantly counteracted LPS-associated elevation of H2O2 production and TNF-? expression in vivo and in vitro, inhibited disease-associated apical migration and proliferation of junctional epithelium and inhibited induced systemic H2O2 levels and alveolar bone loss in vivo. These results suggest that LPS induces chronic wounds via elevated MAO/B-mediated increases in H2O2 and TNF-? activity by epithelial cells and is further associated with more distant effects on systemic oxidative stress and alveolar bone loss.

Ekuni, Daisuke; Firth, James D.; Nayer, Tarun; Tomofuji, Takaaki; Sanbe, Toshihiro; Irie, Koichiro; Yamamoto, Tatsuo; Oka, Takashi; Liu, Zhenzi; Vielkind, Juergen; Putnins, Edward E.



Monitoring radiation-induced changes in bone marrow histopathology with ultra-small superparamagnetic iron oxide (USPIO)-enhanced MRI.  


The purpose of this study was to monitor radiation-induced alterations of the blood-bone marrow barrier (BMB) and the reticuloendothelial system (RES) with AMI-227-enhanced magnetic resonance imaging (MRI). Twenty New Zealand white rabbits (n = 10 following total body irradiation and n = 10 controls) underwent AMI-227-enhanced MRI. Pulse sequences included dynamic fast low-angle shot (FLASH; TR/TE 50/4 msec, flip angle 60 degrees) MRI and static T1- and T2-weighted spin-echo (SE) and turbo-SE sequences of the lumbar spine and sacrum. Bone marrow enhancement was quantified as delta signal intensity (SI) (%) =|[(SIpost - SIpre)/SIpre] x 100%| and compared with histopathology, including iron stains and electron microscopy. Dynamic bone marrow deltaSI (%) data steadily increased up to 10-15 minutes after AMI-227 administration, while blood deltaSI (%) data stayed nearly constant, histologically corresponding to iron oxide leakage into the bone marrow interstitium. This bone marrow contrast enhancement increased significantly following irradiation, corresponding to alterations of the endothelial lining of the bone marrow sinusoids. Late postcontrast images exhibited a significant positive T1 enhancement and negative T2 enhancement of the normal bone marrow, which further increased with irradiation due to increased RES activity. Irradiation-induced changes in bone marrow physiology could be reliably assessed with AMI-227-enhanced MRI. PMID:10331759

Daldrup, H E; Link, T M; Blasius, S; Strozyk, A; Könemann, S; Jürgens, H; Rummeny, E J



Inhibition of GSK3 Abolishes Bacterial-Induced Periodontal Bone Loss in Mice  

PubMed Central

The tissue destruction that characterizes periodontitis is driven by the host response to bacterial pathogens. Inhibition of glycogen synthase kinase 3? (GSK3?) in innate cells leads to suppression of Toll-like receptor (TLR)-initiated proinflammatory cytokines under nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) p65 transcriptional control and promotion of cyclic adenosine monophosphate response element-binding (CREB)-dependent gene activation. Therefore, we hypothesized that the cell permeable GSK3-specific inhibitor, SB216763, would protect against alveolar bone loss induced by the key periodontal pathogen, Porphyromonas gingivalis (P. gingivalis), in a murine model. B6129SF2/J mice either were infected orally with P. gingivalis ATCC 33277; or treated with SB216763 and infected with P. gingivalis; sham infected; or exposed to vehicle only (dimethyl sulfoxide [DMSO]); or to GSK3 inhibitor only (SB216763). Alveolar bone loss and local (neutrophil infiltration and interleukin [IL]-17) and systemic (tumor necrosis factor [TNF], IL-6, Il-1? and IL-12/IL-23 p40) inflammatory indices also were monitored. SB216763 unequivocally abrogated mean P. gingivalis–induced bone resorption, measured at 14 predetermined points on the molars of defleshed maxillae as the distance from the cementoenamel junction to the alveolar bone crest (p < 0.05). The systemic cytokine response, the local neutrophil infiltration and the IL-17 expression were suppressed (p < 0.001). These data confirm the relevance of prior in vitro phenomena and establish GSK3 as a novel, efficacious therapeutic preventing periodontal disease progression in a susceptible host. These findings also may have relevance to other chronic inflammatory diseases and the systemic sequelae associated with periodontal infections.

Adamowicz, Karina; Wang, Huizhi; Jotwani, Ravi; Zeller, Iris; Potempa, Jan; Scott, David A



In-Vivo Effect of Andrographolide on Alveolar Bone Resorption Induced by Porphyromonas gingivalis and Its Relation with Antioxidant Enzymes  

PubMed Central

Alveolar bone resorption is one of the most important facts in denture construction. Porphyromonas gingivalis (Pg) causes alveolar bone resorption, and morphologic measurements are the most frequent methods to identify bone resorption in periodontal studies. This study has aimed at evaluating the effect of Andrographolide (AND) on alveolar bone resorption in rats induced by Pg. 24 healthy male Sprague Dawley rats were divided into four groups as follows: normal control group and three experimental groups challenged orally with Pg ATCC 33277 five times a week supplemented with 20?mg/kg and 10?mg/kg of AND for twelve weeks. Alveolar bones of the left and right sides of the mandible were assessed by a morphometric method. The bone level, that is, the distance from the alveolar bone crest to cementumenamel junction (CEJ), was measured using 6.1?:?1 zoom stereomicroscope and software. AND reduced the effect of Pg on alveolar bone resorption and decreased the serum levels of Hexanoyl-Lysine (HEL); furthermore the reduced glutathione/oxidised glutathione (GSH/GSSG) ratio in AND treated groups (10 and 20?mg/kg) significantly increased when compared with the Pg group (P < 0.05). We can conclude that AND suppresses alveolar bone resorption caused by Pg in rats.

Al Batran, Rami; Al-Bayaty, Fouad H.; Al-Obaidi, Mazen M. Jamil



Space Radiation and Bone Loss.  


Exposure to ionizing radiation may negatively impact skeletal integrity during extended spaceflight missions to the moon, Mars, or near-Earth asteroids. However, our understanding of the effects of radiation on bone is limited when compared to the effects of weightlessness. In addition to microgravity, astronauts will be exposed to space radiation from solar and cosmic sources. Historically, radiation exposure has been shown to damage both osteoblast precursors and local vasculature within the irradiated volume. The resulting suppression of bone formation and a general state of low bone-turnover is thought to be the primary contributor to bone loss and eventual fracture. Recent investigations using mouse models have identified a rapid, but transient, increase in osteoclast activity immediately after irradiation with both spaceflight and clinically-relevant radiation qualities and doses. Together with a chronic suppression of bone formation after radiation exposure, this acute skeletal damage may contribute to long-term deterioration of bone quality, potentially increasing fracture risk. Direct evidence for the damaging effects of radiation on human bone are primarily demonstrated by the increased incidence of fractures at sites that absorb high doses of radiation during cancer therapy: exposures are considerably higher than what could be expected during spaceflight. However, both the rapidity of bone damage and the chronic nature of the changes appear similar between exposure scenarios. This review will outline our current knowledge of space and clinical exploration exposure to ionizing radiation on skeletal health. PMID:22826632

Willey, Jeffrey S; Lloyd, Shane A J; Nelson, Gregory A; Bateman, Ted A



Latexin is involved in bone morphogenetic protein-2-induced chondrocyte differentiation  

SciTech Connect

Latexin is the only known carboxypeptidase A inhibitor in mammals. We previously demonstrated that BMP-2 significantly induced latexin expression in Runx2-deficient mesenchymal cells (RD-C6 cells), during chondrocyte and osteoblast differentiation. In this study, we investigated latexin expression in the skeleton and its role in chondrocyte differentiation. Immunohistochemical studies revealed that proliferating and prehypertrophic chondrocytes expressed latexin during skeletogenesis and bone fracture repair. In the early phase of bone fracture, latexin mRNA expression was dramatically upregulated. BMP-2 upregulated the expression of the mRNAs of latexin, Col2a1, and the gene encoding aggrecan (Agc1) in a micromass culture of C3H10T1/2 cells. Overexpression of latexin additively stimulated the BMP-2-induced expression of the mRNAs of Col2a, Agc1, and Col10a1. BMP-2 treatment upregulated Sox9 expression, and Sox9 stimulated the promoter activity of latexin. These results indicate that latexin is involved in BMP-2-induced chondrocyte differentiation and plays an important role in skeletogenesis and skeletal regeneration.

Kadouchi, Ichiro [Department of Orthopedic Surgery, Jichi Medical University, Shimotsuke, Tochigi (Japan); Section of Oral Pathology, Department of Oral Restitution, Graduate School of Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549 (Japan); Sakamoto, Kei [Section of Oral Pathology, Department of Oral Restitution, Graduate School of Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549 (Japan); Tangjiao, Liu [Section of Oral Pathology, Department of Oral Restitution, Graduate School of Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549 (Japan); Section of Oral Pathology, College of Stomatology, Dalian Medical University, Dalian (China); Murakami, Takashi; Kobayashi, Eiji [Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi (Japan); Hoshino, Yuichi [Department of Orthopedic Surgery, Jichi Medical University, Shimotsuke, Tochigi (Japan); Yamaguchi, Akira [Section of Oral Pathology, Department of Oral Restitution, Graduate School of Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549 (Japan); Global Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Graduate School of Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549 (Japan)], E-mail:



Daily transient decreases in plasma parathyroid hormone levels induced by the calcimimetic NPS R-568 slows the rate of bone loss but does not increase bone mass in ovariectomized rats  

Microsoft Academic Search

Daily parathyroid hormone (PTH) injections that transiently increase plasma PTH levels within the physiological range increase bone mass in osteopenic, ovariectomized (ovx) rats. This study tested the hypothesis that repeated transient decreases in plasma PTH levels from normal, induced by the daily oral administration of the calcimimetic NPS R-568, would induce an anabolic effect in bone of ovx rats with

M. A Miller; J Fox



Influence of variations in the angular rotational velocity of a spacecraft on thermal convection under conditions of weightlessness  

Microsoft Academic Search

Unlike the conventional approach where it is assumed that liquid motion under conditions of weightlessness is caused by vibrations\\u000a or residual quasisteady-state microaccelerations, the present paper examines convection caused by variations in the angular\\u000a rotational velocity of a spacecraft. It is shown that although the level of microaccelerations caused by variations in the\\u000a angular rotational velocity is extremely low for

Yu. A. Polovko; V. S. Yuferev



GEA 3162, a peroxynitrite donor, induces Bcl2-sensitive, p53-independent apoptosis in murine bone marrow cells  

Microsoft Academic Search

Apoptosis may be regulated by oxidants such as peroxynitrite (ONOO?). The tumour suppressor, p53, has been reported to play a crucial role in apoptosis induced by oxidants, therefore we assessed the ability of a ONOO? donor, GEA 3162, to activate caspases and induce mitochondrial permeability in a p53-deficient murine bone marrow cell line, Jaws II. Furthermore, these cells were stably

Emma L. Taylor; John T. Li; Joan C. Tupper; Adriano G. Rossi; Robert K. Winn; John M. Harlan



Fluorine determination in human and animal bones by particle-induced gamma-ray emission  

Microsoft Academic Search

Fluorine was determined in the iliac crest bones of patients and in ribs collected from post-mortem investigations by particle-induced\\u000a gamma-ray emission based on the 19F(p,p??)19F reaction, using 2.0\\/2.5 MeV protons. The results indicate that for 68% of the human samples the F concentration is in the\\u000a range 500–1999 ?g g–1. For comparison purposes fluorine was also determined in some animal

Chaturvedula S. Sastri; Venkatesh Iyengar; Gilbert Blondiaux; Yves Tessier; Hermann Petri; Peter Hoffmann; Namik K. Aras; Vladimir Zaichick; Hugo M. Ortner



Protection of mouse bone marrow from etoposide-induced genomic damage by dexrazoxane  

Microsoft Academic Search

Purpose  The objective of the current investigation is to determine whether non-toxic doses of the catalytic topoisomerase-II inhibitor,\\u000a dexrazoxane, have influence on the genomic damage induced by the anticancer topoisomerase-II poison, etoposide, on mice bone\\u000a marrow cells.\\u000a \\u000a \\u000a \\u000a Method  The scoring of micronuclei, chromosomal aberrations, and mitotic activity were undertaken as markers of cyto- and genotoxicity.\\u000a Oxidative damage markers such as reduced glutathione

Sabry M. Attia; Alaa A. Al-Anteet; Nouf M. Al-Rasheed; Abdulqader A. Alhaider; Mohammed M. Al-harbi



Long-term evaluation of recombinant human bone morphogenetic protein-2 induced bone formation with a biologic and synthetic delivery system.  


The efficacy of microspheres made of polylactic acid polyglycolic acid copolymer mixed with blood clot as a delivery system for recombinant human bone morphogenetic protein-2 (rhBMP-2) was evaluated and the long term behaviour of rhBMP-2 in rats was studied. Twenty micro grams of rhBMP-2 in 200 microliter carrier (blood coagulum and polylactic acid polyglycolic acid porous microspheres) were implanted subcutaneously over both sides of the chest muscles in 40 5-week-old male Long Evans rats. The control group were implanted with carrier alone. Specimens were retrieved after 3 days and weekly for 9 weeks. Outcome was measured by signs of bone formation on low power radiographs, and signs of bony growth on histological examination. There were no signs of foreign body or inflammatory reactions to the carrier in either group. In the experimental group signs of bone formation had started to appear by the end of the first week, and there was a gradual increase in both radio-opacity and size during the observation period. Histologically the bony growth was beginning to mature by 4 weeks and was fully mature by 7-9 weeks. In contrast there was no sign of cartilage or bone formation in the control group and the carrier had resorbed by 4-6 weeks. It is concluded that rhBMP-2 implanted in a carrier consisting of blood clot and porous microspheres made of polylactic acid polyglycolic acid induces rapid proliferation of mesenchymal cells that lead to formation of cartilage and bone by 7 days which had matured by 9 weeks. rhBMP-2 in this carrier may be useful clinically because of its capacity to induce early formation of bone. PMID:8909733

Alpaslan, C; Irie, K; Takahashi, K; Ohashi, N; Sakai, H; Nakajima, T; Ozawa, H



Transfusion of minor histocompatibility antigen-mismatched platelets induces rejection of bone marrow transplants in mice  

PubMed Central

Bone marrow transplantation (BMT) represents a cure for nonmalignant hematological disorders. However, compared with the stringent conditioning regimens used when performing BMT to treat hematological malignancies, the reduced intensity conditioning regimen used in the context of nonmalignant hematological disorders leads to substantially higher rates of BMT rejection, presumably due to an intact immune system. The relevant patient population typically receives transfusion support, often including platelets, and the frequency of BMT rejection correlates with the frequency of transfusion. Here, we demonstrate that immunity to transfused platelets contributes to subsequent BMT rejection in mice, even when the BMT donor and recipient are MHC matched. We used MHC-matched bone marrow because, although immunity to transfused platelets is best characterized in relation to HLA-specific antibodies, such antibodies are unlikely to play a role in clinical BMT rejection that is HLA matched. However, bone marrow is not matched in the clinic for minor histocompatibility antigens, such as those carried by platelets, and we report that transfusion of minor histocompatibility antigen–mismatched platelets induced subsequent BMT rejection. These findings indicate previously unappreciated sequelae of immunity to platelets in the context of transplantation and suggest that strategies to account for minor histocompatibility mismatching may help to reduce the chance of BMT rejection in human patients.

Patel, Seema R.; Cadwell, Chantel M.; Medford, Arielle; Zimring, James C.



Mediators of Inflammation-Induced Bone Damage in Arthritis and Their Control by Herbal Products  

PubMed Central

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial joints leading to bone and cartilage damage. Untreated inflammatory arthritis can result in severe deformities and disability. The use of anti-inflammatory agents and biologics has been the mainstay of treatment of RA. However, the prolonged use of such agents may lead to severe adverse reactions. In addition, many of these drugs are quite expensive. These limitations have necessitated the search for newer therapeutic agents for RA. Natural plant products offer a promising resource for potential antiarthritic agents. We describe here the cellular and soluble mediators of inflammation-induced bone damage (osteoimmunology) in arthritis. We also elaborate upon various herbal products that possess antiarthritic activity, particularly mentioning the specific target molecules. As the use of natural product supplements by RA patients is increasing, this paper presents timely and useful information about the mechanism of action of promising herbal products that can inhibit the progression of inflammation and bone damage in the course of arthritis.

Nanjundaiah, Siddaraju M.; Astry, Brian; Moudgil, Kamal D.



Plasminogen activator inhibitor-1 is involved in streptozotocin-induced bone loss in female mice.  


In diabetic patients, the risk of fracture is high because of impaired bone formation. However, the details of the mechanisms in the development of diabetic osteoporosis remain unclear. In the current study, we investigated the role of plasminogen activator inhibitor (PAI)-1 in the pathogenesis of type 1 diabetic osteoporosis by using PAI-1-deficient mice. Quantitative computed tomography analysis showed that PAI-1 deficiency protected against streptozotocin-induced bone loss in female mice but not in male mice. PAI-1 deficiency blunted the changes in the levels of Runx2, osterix, and alkaline phosphatase in tibia as well as serum osteocalcin levels suppressed by the diabetic state in female mice only. Furthermore, the osteoclast levels in tibia, suppressed in diabetes, were also blunted by PAI-1 deficiency in female mice. Streptozotocin markedly elevated the levels of PAI-1 mRNA in liver in female mice only. In vitro study demonstrated that treatment with active PAI-1 suppressed the levels of osteogenic genes and mineralization in primary osteoblasts from female mouse calvaria. In conclusion, the current study indicates that PAI-1 is involved in the pathogenesis of type 1 diabetic osteoporosis in females. The expression of PAI-1 in the liver and the sensitivity of bone cells to PAI-1 may be an underlying mechanism. PMID:23715621

Tamura, Yukinori; Kawao, Naoyuki; Okada, Kiyotaka; Yano, Masato; Okumoto, Katsumi; Matsuo, Osamu; Kaji, Hiroshi



Gingival lymphatic drainage protects against Porphyromonas gingivalis-induced bone loss in mice.  


Periodontitis is characterized by tissue destruction and bone loss mainly due to inflammatory responses after bacterial challenge of the gingiva. Gingiva is supplied with lymphatics that drain interstitial fluid and transport immune cells to the lymph nodes for antigen presentation; yet, the role of lymphatics in periodontal disease development is unknown. To investigate the lymphatic function after periodontal infection, we used K14-VEGF receptor 3-Ig (K14) mice that lack lymphatics in gingiva. Mice were orally infected with human Porphyromonas gingivalis and observed for 42 days. The infected K14 mice developed significantly more bone loss than the wild-type mice, and were associated with an increased number of macrophages and major histocompatibility complex class II antigen-presenting cells in the bone resorptional areas. The infected transgenic mice expressed a significant higher periodontal level of several proinflammatory cytokines, whereas the plasma level of P. gingivalis IgG was significantly lower than in the wild-type mice. No differences were found in immune cell distribution in draining lymph nodes between the strains. Our results show that a strong periodontal inflammatory response and a weakened systemic humoral B-cell response took place in K14 mice after infection. We conclude that gingival lymphatics protect against P. gingivalis-induced periodontitis, and we speculate that they are critical in the protection by clearance of infection and by promotion of humoral immune responses. PMID:22901755

Mkonyi, Lilian E; Bletsa, Athanasia; Bolstad, Anne I; Bakken, Vidar; Wiig, Helge; Berggreen, Ellen



Radiographic evaluation of the effect of obesity on alveolar bone in rats with ligature-induced periodontal disease  

PubMed Central

There is evidence that the lack of metabolic control of obese patients may accelerate periodontitis. The aim of this study was to evaluate radiographically the effect of cafeteria-diet-induced obesity on alveolar bone loss in rats subjected to periodontal disease. Twenty male Wistar rats were randomly divided into four groups: 1) control group, 2) control and ligature group; 3) cafeteria group; and 4) cafeteria and ligature group. The animals were evaluated for obesity and euthanized, and the mandible of each rat was removed to perform a radiographic evaluation of alveolar bone loss and its effect on diet-induced obesity. The results showed greater alveolar bone loss in the mice in Group 4 (P<0.01). Thus, we concluded that obese mice, on average, showed greater radiographic evidence of alveolar bone loss than mice undergoing induction of obesity.

do Nascimento, Cassiane Merigo; Cassol, Tiago; da Silva, Fernanda Soares; Bonfleur, Maria Lucia; Nassar, Carlos Augusto; Nassar, Patricia Oehlmeyer



Effects of diabetes mellitus on VEGF- induced proliferation response in bone marrow derived endothelial progenitor cells  

PubMed Central

Background This study examined effects of diabetes mellitus (DM) on cellular proliferation associated with vascular endothelial growth factor (VEGF)signaling in endothelial progenitor cells (EPC’s)and evaluated protein expression involved in cellular proliferation and pro-apoptotic signaling in chronically ischemic myocardium. Methods Insulin dependent DM was induced in yucatan miniswine with alloxan. Eight weeks after induction, chronic ischemia was induced by ameroid constrictor placement around the circumflex coronary artery. Seven weeks after ameroid constrictor, perfusion of ischemic territory was measured by isotope-labeled microspheres, and ischemic myocardium was harvested. Bone marrow (BM) samples were harvested from iliac bone and mononuclear cells (MNC’s) were cryopreserved. EPC’s were isolated from cryopreserved MNC’s in control (n=6) and DM swine (n=6). EPC proliferation was assessed. Results EPC proliferation was decreased in DM as compared to control (1.02±0.09, 0.40±0.04, p<0.01). VEGF induced EPC proliferation was impaired in DM as compared to control (p<0.01). Expression of ERK protein, an activator of VEGF induced cell proliferation, was decreased. AKT activation, an inhibitor of apoptosis, was decreased, while Bad, an activator of pro-apoptotic signaling, was elevated in the ischemic myocardium from DM. Collateral dependent perfusion was impaired in DM. Conclusion Impaired VEGF induced proliferation response in EPC as well as an increase in negative myocardial protein expression for cell proliferation and pro-apoptotic signaling via VEGF could be a therapeutic target to enhance the effects of pro-angiogenesis therapies in DM and other chronic illnesses.

Mieno, Shigetoshi; Boodhwani, Munir; Robich, Michael P.; Clements, Richard T.; Sodha, Neel R.; Sellke, Frank W.



Fracture-induced changes in bone turnover: a potential confounder in the use of biochemical markers in osteoporosis  

Microsoft Academic Search

To examine the short- and long-term bone metabolic effects of fracture assessed by biochemical markers, we utilized a clinical fracture model—proximal tibial osteotomy—and prospectively followed 14 patients. This model of an induced fracture of a major bone gives the advantage of assessing baseline levels prior to fracture. Follow-up occurred at 6–9 weeks, 4–7 months, 9–13 months, and 14–17 months after

Kristina Åkesson; Sanna-Maria Käkönen; Per Olof Josefsson; Magnus K. Karlsson; Karl J. Obrant; Kim Pettersson



Protection against Radiation-Induced Bone Marrow and Intestinal Injuries by Cordyceps sinensis, a Chinese Herbal Medicine  

Microsoft Academic Search

Liu, W-C., Wang, S-C., Tsai, M-L., Chen, M-C., Wang, Y-C., Hong, J-H., McBride, W. H. and Chiang, C-S. Protec- tion against Radiation-Induced Bone Marrow and Intestinal Injuries by Cordyceps sinensis, a Chinese Herbal Medicine. Radiat. Res. 166, 900-907 (2006). Bone marrow and intestinal damage limits the efficacy of radiotherapy for cancer and can result in death if the whole body

Wei-Chung Liu; Shu-Chi Wang; Min-Lung Tsai; Meng-Chi Chen; Ya-Chen Wang; Ji-Hong Hong; William H. McBride; Chi-Shiun Chiang



Fluorine concentrations in bone biopsy samples determined by proton-induced gamma-ray emission and cyclic neutron activation  

Microsoft Academic Search

Fluorine concentrations in bone biopsy samples taken from the iliac crest of subjects, divided into four groups depending\\u000a on the length of dialysis treatment, and aluminium levels in blood and bone pathology, in terms of osteoporosis, were determined\\u000a by two instrumental methods. Proton-induced gamma-ray emission (PIGE), making use of the resonance reaction of19F(p,??)16O at 872 keV, and cyclic neutron activation

N. M. Spyrou; W. J. Altaf; B. S. Gill; C. Jeynes; G. Nicolaou; R. Pietra; E. Sabbioni; M. Surian



Intermittent Therapy with 1,25 Vitamin D and Calcitonin Prevents Cyclosporin-Induced Alveolar Bone Loss in Rats  

Microsoft Academic Search

Bone loss associated with cyclosporin A (CsA) therapy can result in serious morbidity to patients. Intermittent administration\\u000a of 1,25 Vitamin D and calcitonin reduces osteopenia in a murine model of postmenopausal osteoporosis. The purpose of this\\u000a study was to evaluate the effects of this therapeutic approach on CsA-induced alveolar bone loss in rats. Forty male Wistar\\u000a rats were allocated to

Luís C. Spolidorio; Bruno S. Herrera; Leila S. Coimbra; Denise M. P. Spolidorio; Marcelo N. Muscará; C. Rossa



Bone morphogenetic proteins induce rabbit bone marrow-derived mesenchyme stem cells to differentiate into osteoblasts via BMP signals pathway.  


Bone marrow mesenchymal stem cells (BMMSCs) are multipotent stem cells that can differentiate into different blastoderm cells in vitro. In this study, BMMSCs in rabbit bone marrow were isolated by density gradient centrifuge separation, purified and expanded in vitro. BMP-2 and FGF 2 were used for differentiation into osteoblasts, and the results demonstrated that bone morphogenetic proteins (BMPs) could affect the differential direction of the BMMSCs. PCR assays indicated that BMP signals pathway played important roles in osteoblasts differentiation of BMMSCs, and the members included BMPRI, Smad 1, Smad 5, Smad 8, Runx 2, collage type I and osteopontin. This study provides a theoretical basis and experimental evidence for the therapeutic application of BMMSCs to the treatment of bone injury. PMID:23305318

Hu, Weihua; Ye, Yaping; Wang, Jiang; Zhang, Weikai; Chen, Anmin; Guo, Fengjing



Temporal Gene Expression Profiling during Rat Femoral Marrow Ablation-Induced Intramembranous Bone Regeneration  

PubMed Central

Enhanced understanding of differential gene expression and biological pathways associated with distinct phases of intramembranous bone regeneration following femoral marrow ablation surgery will improve future advancements regarding osseointegration of joint replacement implants, biomaterials design, and bone tissue engineering. A rat femoral marrow ablation model was performed and genome-wide microarray data were obtained from samples at 1, 3, 5, 7, 10, 14, 28, and 56 days post-ablation, with intact bones serving as controls at Day 0. Bayesian model-based clustering produced eight distinct groups amongst 9,062 significant gene probe sets based on similar temporal expression profiles, which were further categorized into three major temporal classes of increased, variable, and decreased expression. Osteoblastic- and osteoclastic-associated genes were found to be significantly expressed within the increased expression groups. Chondrogenesis was not detected histologically. Adipogenic marker genes were found within variable/decreased expression groups, emphasizing that adipogenesis was inhibited during osteogenesis. Differential biological processes and pathways associated with each major temporal group were identified, and significantly expressed genes involved were visually represented by heat maps. It was determined that the increased expression group exclusively contains genes involved in pathways for matrix metalloproteinases (MMPs), Wnt signaling, TGF-? signaling, and inflammatory pathways. Only the variable expression group contains genes associated with glycolysis and gluconeogenesis, the notch signaling pathway, natural killer cell mediated cytotoxicity, and the B cell receptor signaling pathway. The decreased group exclusively consists of genes involved in heme biosynthesis, the p53 signaling pathway, and the hematopoietic cell lineage. Significant biological pathways and transcription factors expressed at each time point post-ablation were also identified. These data present the first temporal gene expression profiling analysis of the rat genome during intramembranous bone regeneration induced by femoral marrow ablation.

Wise, Joel K.; Sena, Kotaro; Vranizan, Karen; Pollock, Jacob F.; Healy, Kevin E.; Hughes, W. Frank; Sumner, D. Rick; Virdi, Amarjit S.



The effects of vanadium (V) absorbed by Coprinus comatus on bone in streptozotocin-induced diabetic rats.  


The purpose of this study was to evaluate the effects of vanadium absorbed by Coprinus comatus (VACC) treatment on bone in streptozotocin (STZ)-induced diabetic rats. Forty-five Wistar female rats used were divided into three groups: (1) normal rats (control), (2) diabetic rats, and (3) diabetic rats treated with VACC. Normal and diabetic rats were given physiological saline, and VACC-treated rats were administered VACC intragastrically at doses of 0.18 mg vanadium/kg body weight once daily. Treatments were performed over a 12-week period. At sacrifice, one tibia and one femur were removed, subjected to micro computed tomography (micro-CT) for determination of trabecular bone structure, and then processed for histomorphometry to assess bone turnover. Another femoral was used for mechanical testing. In addition, bone samples were collected to evaluate the content of mineral substances in bones. Treatment with VACC increased trabecular bone volume fraction in diabetic rats. Vanadium-treated animals had significant increases in ultimate load, trabecular thickness, and osteoblast surface. However, vanadium treatment did not seem to affect bone stiffness, bone energy absorption, trabecular separation, and osteoclast number. P levels in the femurs of diabetic rats treated with VACC were significantly higher than those of diabetic animals. Ca levels in diabetic and diabetic rats treated with vanadium showed no obvious changes. In conclusion, our results provide an important proof of concept that VACC may represent a powerful approach to treating or reversing diabetic osteopathy in humans. PMID:20734239

Pei, Yi; Fu, Qin



Experimental estrogen-induced hyperprolactinemia results in bone-related hearing loss in the guinea pig.  


Our group (Horner KC, Guieu R, Magnan J, Chays A, Cazals Y. Neuropsychopharmacology 26: 135-138, 2002) has earlier described hyperprolactinemia in some patients presenting inner ear dysfunction. However, in that study, it was not possible to determine whether hyperprolactinemia was a cause or an effect of the symptoms. To investigate the effect of hyperprolactinemia on inner ear function, we first developed a model of hyperprolactinemia in estrogen-primed Fischer 344 rats and then performed functional studies on pigmented guinea pigs. Hyperprolactinemia induced, after 2 mo, a hearing loss of approximately 30-40 dB across all frequencies, as indicated by the compound action potential audiogram. During the 3rd mo, the hearing loss continued to deteriorate. The threshold shifts were more substantial in males than in females. Observations under a dissection microscope revealed bone dysmorphology of the bulla and the cochlea. Light microscopy observations of cryostat sections confirmed bone-related pathology of the bony cochlear bulla and the cochlear wall and revealed morphopathology of the stria vascularis and spiral ligament. Scanning electron microscopy revealed loss of hair cells and stereocilia damage, in particular in the upper three cochlear turns and the two outermost hair cell rows. The data provide the first evidence of otic capsule and hair cell pathology associated with estrogen-induced prolonged hyperprolactinemia and suggest that conditions such as pregnancy, anti-psychotic drug treatment, aging, and/or stress might lead to similar ear dysfunctions. PMID:17711987

Horner, Kathleen C; Cazals, Yves; Guieu, Régis; Lenoir, Marc; Sauze, Nicole



Identification of MicroRNAs Inhibiting TGF-?-Induced IL-11 Production in Bone Metastatic Breast Cancer Cells  

PubMed Central

Development of bone metastases is dependent on the cancer cell-bone cell interactions in the bone microenvironment. Transforming growth factor ? (TGF-?) is released from bone during osteoclastic bone resorption and induces production of osteolytic factors, such as interleukin 11 (IL-11), in breast cancer cells. IL-11 in turn increases osteolysis by stimulating osteoclast function, launching a vicious cycle of cancer growth and bone destruction. We aimed to identify and functionally characterize microRNAs (miRNAs) that mediate the bone metastatic process, focusing on miRNAs that regulate the TGF-? induction of IL-11. First, we profiled the expression of 455 miRNAs in a highly bone metastatic MDA-MB-231(SA) variant as compared to the parental MDA-MB-231 breast cancer cell line and found 16 miRNAs (3.5%) having a >3-fold expression difference between the two cell types. We then applied a cell-based overexpression screen with Pre-miRNA constructs to functionally identify miRNAs regulating TGF-?-induced IL-11 production. This analysis pinpointed miR-204, miR-211, and miR-379 as such key regulators. These miRNAs were shown to directly target IL11 by binding to its 3? UTR. MiR-379 also inhibited Smad2/3/4-mediated transcriptional activity. Gene expression analysis of miR-204 and miR-379-transfected cells indicated that these miRNAs downregulated the expression of several genes involved in TGF-? signaling, including prostaglandin-endoperoxide synthase 2 (PTGS2). In addition, there was a significant correlation between the genes downregulated by miR-379 and a set of genes upregulated in basal subtype of breast cancer. Taken together, the functional evidence and clinical correlations imply novel mechanistic links between miRNAs and the key steps in the bone metastatic process in breast cancer, with potential clinical relevance.

Pollari, Sirkku; Leivonen, Suvi-Katri; Perala, Merja; Fey, Vidal; Kakonen, Sanna-Maria; Kallioniemi, Olli



Hispidulin attenuates bone resorption and osteoclastogenesis via the RANKL-induced NF-?B and NFATc1 pathways.  


Hispidulin, a flavonoid that is known to have anti-inflammatory and anti-oxidant effects, attenuates osteoclastogenesis and bone resorption. To investigate the molecular mechanism of its inhibitory effect on osteoclastogenesis, we employed the receptor activator of the nuclear factor ?B (NF-?B) ligand (RANKL)-induced murine monocyte/macrophage RAW 264.7 cells and bone marrow-derived macrophages (BMMs) for osteoclastic differentiation in vitro. The inhibitory effect on in vitro osteoclastogenesis was evaluated by counting the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and by measuring the expression levels of osteoclast-specific genes such as matrix metalloproteinase 9 (MMP9), TRAP and cathepsin K. Similarly, hispidulin significantly inhibited osteoclast activity in RAW 264.7 cell as well as stimulated the ALP activity of MC3T3E1 cells. Furthermore, the in vivo suppressive effect on bone loss was assessed quantitatively in a lipopolysaccharide (LPS)-induced mouse model using microcomputational tomography (?CT) and histochemical analyses. Hispidulin was found to inhibit RANKL-induced activation of Jun N-terminal kinase (JNK) and p38, in addition to NF-?B in vitro experiment. Additionally, hispidulin decreased NFATc1 transcriptional activity in RANKL-induced osteoclastogenesis. This study identifies hispidulin as a potent inhibitor of osteoclastogenesis and bone resorption and provides evidence for its therapeutic potential to treat diseases involving abnormal bone lysis. PMID:23791609

Nepal, Manoj; Choi, Hwa Jung; Choi, Bo-Yun; Yang, Moon-Shik; Chae, Jung-Il; Li, Liang; Soh, Yunjo



iNOS-Derived Nitric Oxide Stimulates Osteoclast Activity and Alveolar Bone Loss in Ligature-Induced Periodontitis in Rats  

PubMed Central

Background Inflammatory stimuli activate inducible nitric oxide synthase (iNOS) in a variety of cell types, including osteoclasts (OC) and osteoblasts, resulting in sustained NO production. In this study, we evaluate the alveolar bone loss in rats with periodontitis under long-term iNOS inhibition, and the differentiation and activity of OC from iNOS-knockout (KO) mice in vitro. Methods Oral aminoguanidine (an iNOS inhibitor) or water treatment was started 2 weeks before induction of periodontitis. Rats were sacrificed 3, 7, or 14 days after ligature placement, and alveolar bone loss was evaluated. In vitro OC culture experiments were also performed to study the differentiation of freshly isolated bone marrow cells from both iNOS KO and wild-type C57BL/6 mice. OC were counted 6 days later after tartrate-resistant acid phosphatase staining (a marker of osteoclast identity), and bone resorption activity was assessed by counting the number of resorption pits on dentin disks. Results Rats with ligature showed progressive and significant alveolar bone loss compared to sham animals, and aminoguanidine treatment significantly inhibited ligature-induced bone loss at 7 and 14 days after the induction. In comparison to bone marrow cells from wild-type mice, cells from iNOS KO mice showed decreased OC growth and the resulting OC covered a smaller culture dish area and generated fewer resorption pit counts. Conclusion Our results demonstrate that iNOS inhibition prevents alveolar bone loss in a rat model of ligature-induced periodontitis, thus confirming that iNOS-derived NO plays a crucial role in the pathogenesis of periodontitis, probably by stimulating OC differentiation and activity.

Herrera, Bruno S.; Martins-Porto, Rodrigo; Maia-Dantas, Aline; Campi, Paula; Spolidorio, Luis C.; Costa, Soraia K.P.; Van Dyke, Thomas E.; Gyurko, Robert; Muscara, Marcelo N.



Confirmation of gravisensitivity in the slime mold physarum polycephalum under near weightlessness  

NASA Astrophysics Data System (ADS)

We have investigated Physarum polycephalum, a unicellular organism with no special gravity receptors, on its ability to react to gravity. The first experiments were 0 g-simulation experiments on the fast-rotating clinostat conducted with plasmodial strands of this acellular slime mold. In these earth-bound experiments the observed parameters were periodicity of the contractions and dilatations of the strand's ectoplasm as well as the periodicity and velocity of the striking cytoplasmic (endoplasmic) shuttle streaming. During 0 g-simulation these parameters showed significant changes indicating the existence of a gravisensitivity of the slime mold. The Space-Shuttle experiment (ESA-Biorack in D 1-Mission) should demonstrate the validity of the 0 g-simulation on the fast-rotating clinostat. The experiment was designed in a way enabling the registration of the same parameters as on the clinostat (using the light microscope in combination with a photo diode and a cinecamera). Only one of the two planned measurement sessions was fully successful and provided us with data confirming the results gained on the fast-rotating clinostat: The slime mold showed under real near weightlessness in the D 1-Space Shuttle Mission a transient frequency increase in its contraction rhythmicity and a (steady) increase in the streaming velocity of its endoplasm.

Block, I.; Briegleb, W.; Sobick, V.; Wohlfarth-Bottermann, K. E.


Countermeasure of the negative effects of weightlessness on physical systems in long-term space flights  

NASA Astrophysics Data System (ADS)

The system of countermcasure of microgravity effects has been developed in Russia that allowed to perform safely long-term space flights. This system that includes different means and methods such as special regimens of physical exercises, axial loading ("Pingiun") and antigravity suits, low body negative pressure device (LBNP, "Chibis") and "cuffs" and others has been used with certain variations at certain stages of flight in 27 successfully accomplished space flights that lasted from 60 to 439 days. The pre-, in- and postflight studies performed in 57 crew members of these flights have shown that the system of countermeasure is effective in preventing or diminishing to a great extent almost all the negative effects of weightlessness in flights of a year and more duration and that the intensity and duration of changes recorded in different body systems after flights do not correlate significantly to flight durations, correlating strongly to the volume and intensity of physical exercises used during flight and especially during concluding stage of it.

Kozlovskaya, I. B.; Grigoriev, A. I.; Stepantzov, V. I.


Granulocyte-macrophage colony-stimulating factor-induced antibody-dependent cellular cytotoxicity in bone marrow macrophages: application in bone marrow transplantation.  


Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been reported to induce antitumor activity in peripheral blood monocytes. We examined the role of GM-CSF on bone marrow (BM) macrophages in inducing antibody-dependent cellular cytotoxicity (ADCC) against murine and human tumor cells in vitro and in vivo with the aim of applying this approach in an autologous bone marrow transplantation (BMT) setting. GM-CSF induced a potent ADCC in BM macrophages against a murine melanoma in vitro. Treatment with GM-CSF alone or with antibody alone had no effect, whereas therapy with combination of both these agents resulted in a significant reduction in dissemination of melanoma both in a nontransplant as well as in BMT settings, with results being more optimal in the latter setting. Adoptive transfer of BM macrophages harvested from mice undergoing therapy with GM-CSF plus antibody significantly reduced the dissemination of melanoma in secondary recipients but only after irradiation, not in intact mice. GM-CSF also induced significant ADCC in human BM macrophages against a melanoma and a lymphoma in vitro and against a lymphoma implanted in nude mice in vivo. Again, these effects were more optimal after chemotherapy. These data suggest that treatment with GM-CSF plus tumor-specific monoclonal antibodies after BMT may induce an antitumor effect and help eradicate the minimal residual disease. PMID:8507882

Charak, B S; Agah, R; Mazumder, A



Mobilization of bone marrow stem cells with StemEnhance improves muscle regeneration in cardiotoxin-induced muscle injury.  


Bone marrow-derived stem cells have the ability to migrate to sites of tissue damage and participate in tissue regeneration. The number of circulating stem cells has been shown to be a key parameter in this process. Therefore, stimulating the mobilization of bone marrow stem cells may accelerate tissue regeneration in various animal models of injury. In this study we investigated the effect of the bone marrow stem cells mobilizer StemEnhance (SE), a water-soluble extract of the cyanophyta Aphanizomenon flos-aquae (AFA), on hematopoietic recovery after myeloablation as well as recovery from cardiotoxin-induced injury of the anterior tibialis muscle in mice. Control and SE-treated female mice were irradiated, and then transplanted with GFP(+) bone marrow stem cells and allowed to recover. Immediately after transplant, animals were gavaged daily with 300 mg/kg of SE in PBS or a PBS control. After hematopoietic recovery (23 days), mice were injected with cardiotoxin in the anterior tibialis muscle. Five weeks later, the anterior tibialis muscles were analyzed for incorporation of GFP(+) bone marrow-derived cells using fluorescence imaging. SE significantly enhanced recovery from cardiotoxin-injury. However, StemEnhance did not affect the growth of the animal and did not affect hematopoietic recovery after myeloablation, when compared to control. This study suggests that inducing mobilization of stem cells from the bone marrow is a strategy for muscle regeneration. PMID:20404540

Drapeau, Christian; Antarr, Donna; Ma, Huaiyu; Yang, Zhijian; Tang, Li; Hoffman, Robert M; Schaeffer, David J



A soluble activin Type IIA receptor induces bone formation and improves skeletal integrity  

Microsoft Academic Search

Diseases that affect the regulation of bone turnover can lead to skeletal fragility and increased fracture risk. Members of the TGF-beta superfamily have been shown to be involved in the regulation of bone mass. Activin A, a TGF-beta signaling ligand, is present at high levels in bone and may play a role in the regulation of bone metabolism. Here we

R. Scott Pearsall; Ernesto Canalis; Milton Cornwall-Brady; Kathryn W. Underwood; Brendan Haigis; Jeffrey Ucran; Ravindra Kumar; Eileen Pobre; Asya Grinberg; Eric D. Werner; Vaida Glatt; Lisa Stadmeyer; Deanna Smith; Jasbir Seehra; Mary L. Bouxsein



Hypoxia-inducible factor regulates osteoclast-mediated bone resorption: role of angiopoietin-like 4.  


Hypoxia and the hypoxia-inducible factor (HIF) transcription factor regulate angiogenic-osteogenic coupling and osteoclast-mediated bone resorption. To determine how HIF might coordinate osteoclast and osteoblast function, we studied angiopoietin-like 4 (ANGPTL4), the top HIF target gene in an Illumina HumanWG-6 v3.0 48k array of normoxic vs. hypoxic osteoclasts differentiated from human CD14(+) monocytes (14.3-fold induction, P<0.0004). ANGPTL4 mRNA and protein were induced by 24 h at 2% O(2) in human primary osteoclasts, monocytes, and osteoblasts. ANGPTL4 protein was observed by immunofluorescence in osteoclasts and osteoblasts in vivo. Normoxic inducers of HIF (CoCl(2), desferrioxamine, and l-mimosine) and 100 ng/ml ANGPTL4 stimulated osteoclastic resorption 2- to 3-fold in assays of lacunar dentine resorption, without affecting osteoclast viability. Isoform-specific HIF-1? small interfering RNA ablated hypoxic induction of ANGPTL4 and of resorption, which was rescued by addition of exogenous ANGPTL4 (P<0.001). In the osteoblastic Saos2 cell line, ANGPTL4 caused a dose-dependent increase in proliferation (P<0.01, 100 ng/ml) and, at lower doses (1-25 ng/ml), mineralization. These results demonstrate that HIF is sufficient to enhance osteoclast-mediated bone resorption and that ANGPTL4 can compensate for HIF-1? deficiency with respect to stimulation of osteoclast activity and also augments osteoblast proliferation and differentiation. PMID:20667978

Knowles, Helen J; Cleton-Jansen, Anne-Marie; Korsching, Eberhard; Athanasou, Nicholas A



Calcitriol improves streptozotocin-induced diabetes and recovers bone mineral density in diabetic rats.  


Vitamin D analogs exert a preventative effect on experimental diabetes, but whether or not they are able to halt progress of established diabetes is not yet known. Moreover, it is widely accepted that diabetes may induce osteoporosis, but the efficacy of vitamin D on diabetic osteoporosis is not clear. In order to help clarify these issues, we have tested the efficacy of calcitriol streptozotocin-induced diabetes. Streptozotocin (60 mg/Kg body weight) was injected in 3-month-old Wistar rats, randomly distributed into two groups: vehicle (olive oil) treated diabetic rats (D) and diabetic rats treated with 1.25-(OH)2D3 250 mg, three times a week (DT). Control animals (C) were treated with vehicle alone. The experiment lasted 8 weeks. The histology of the pancreata was evaluated. Blood glucose and calcium and phosphate in serum and urine were measured. Finally, bone mineral density (BMD) of tibia and lumbar vertebrae were evaluated. After 8 weeks, diabetes persisted in 85% of the diabetic rats (D group), but in only 45% of vitamin D-treated group (DT). At the end of the experiment, DT animals were separated into two groups, those still remaining diabetic (DT-NR) and reversed animals (DT-R). Moreover, bone loss was observed in diabetic animals (D), whereas BMD of DT-R rats showed similar values to those of controls (C). Our results suggest that 1.25(OH)2D3 improves diabetes and, as such, may recover BMD in streptozotocin-induced diabetic rats. PMID:15654497

Del Pino-Montes, J; Benito, G E; Fernández-Salazar, M P; Coveñas, R; Calvo, J J; Bouillon, R; Quesada, J M



Effects of angiotensin II type 1 receptor blocker on bones in mice with type 1 diabetes induced by streptozotocin.  


INTRODUCTION: This study was performed to address the pathological roles of the skeletal renin-angiotensin system (RAS) in type 1 diabetes-induced osteoporosis and the effects of the angiotensin II type 1 receptor blocker losartan on bones in diabetic mice. MATERIALS AND METHODS: Bone histomorphology was detected by H&E staining, Safranin O staining and X-ray radiography. Micro-CT was performed for the analysis of bone parameters. Gene and protein expression were determined by RT-PCR and immunoblotting. RESULTS: Type 1 diabetic mice displayed osteopenia phenotype, and losartan treatment had no osteoprotective effects on diabetic mice as shown by the reduction of bone mineral density and microarchitectural parameters at the proximal metaphysis of the tibia. The mRNA expression of AGT, renin receptor and ACE, and protein expression of renin and AT1R were markedly up-regulated in the bones of vehicle-treated diabetic mice compared to those of non-diabetic mice. The treatment with losartan further significantly increased the expression of AGT, renin, angiotensin II and AT1R, and reduced the expression of AT2R receptor as compared to those of diabetic mice. CONCLUSION: Local bone RAS functionally played a role in the development of type 1 diabetic osteoporosis, and losartan had no bone-sparing function in diabetes mice because of enhance skeletal RAS activity. PMID:23283823

Zhang, Yan; Diao, Teng-Yue; Gu, Sa-Sa; Wu, Shu-Yan; Gebru, Yoseph A; Chen, Xi; Wang, Jing-Yu; Ran, Shu; Wong, Man-Sau



Advanced glycation end products suppress lysyl oxidase and induce bone collagen degradation in a rat model of renal osteodystrophy.  


Renal osteodystrophy (ROD) is a major problem in patients with renal insufficiency. The present study was designed to elucidate the role of bone collagen changes and osteoblast differentiation in a rat model of ROD pathogenesis induced by adenine. Typical characteristics of renal failure, including increased serum urea nitrogen, creatinine, inorganic phosphorus, and intact parathyroid hormone levels, and decreased serum calcium and 1,25(OH)2D3 levels, were observed in adenine-induced rats. Micro-computed tomography analysis of the femur in adenine-induced rats showed decreased bone mineral density and osteoporotic changes, confirmed by the three-point bending test. The cancellous bone histomorphometric parameters of the tibia showed increased osteoblast number, decreased osteoclast surface with peritrabecular fibrosis, and increased osteoid tissue, indicating a severe mineralization disorder similar to clinical ROD. Scanning and transmission electron microscopy revealed irregular alignment and increased diameter of bone collagen fibrils in adenine-induced rats. Protein expression analysis showed greater accumulation of advanced glycation end products (AGEs) in peritrabecular osteoblasts of adenine-induced rats than in the controls. In contrast, suppressed expression of runt-related transcription factor 2, alkaline phosphatase, secreted phosphoprotein 1 (Spp1), and lysyl oxidase (Lox) mRNA levels, particularly the amount of active LOX protein, were observed. In in-vitro experiments, mineralizing MC3T3-E1 osteoblastic cells stimulated with AGE-modified bovine serum albumin had attenuated the expression of Spp1 mRNA levels and active LOX protein, with a decrease in extracellular nodules of mineralization. These observations provide clues to ROD pathogenesis, as they indicate that the suppression of osteoblast differentiation and decreased active LOX protein associated with accumulation of AGEs in osteoblasts caused structural abnormalities of bone collagen fibrils and a severe mineralization disorder, leading to bone fragility. PMID:23979426

Aoki, Chiharu; Uto, Kenta; Honda, Kazuho; Kato, Yoshiharu; Oda, Hideaki



Macrophage-Specific TLR2 Signaling Mediates Pathogen-Induced TNF-Dependent Inflammatory Oral Bone Loss  

PubMed Central

Porphyromonas gingivalis is a primary etiological agent of chronic periodontal disease, an infection-driven chronic inflammatory disease that leads to the resorption of tooth-supporting alveolar bone. We previously reported that TLR2 is required for P. gingivalis–induced alveolar bone loss in vivo, and our in vitro work implicated TNF as a key downstream mediator. In this study, we show that TNF-deficient (Tnf?/?) mice are resistant to alveolar bone loss following oral infection with P. gingivalis, and thus establish a central role for TNF in experimental periodontal disease. Using bone marrow–derived macrophages (BMDM) from wild-type and gene-specific knockout mice, we demonstrate that the initial inflammatory response to P. gingivalis in naive macrophages is MyD88 dependent and requires cooperative signaling of TLR2 and TLR4. The ability of P. gingivalis to activate cells via TLR2 or TLR4 was confirmed in TLR2- or TLR4-transformed human embryonic kidney cells. Additional studies using bacterial mutants demonstrated a role for fimbriae in the modulation of TLR-mediated activation of NF-?B. Whereas both TLR2 and TLR4 contributed to TNF production in naive macrophages, P. gingivalis preferentially exploited TLR2 in endotoxin-tolerant BMDM to trigger excessive TNF production. We found that TNF induced surface TLR2 expression and augmented TLR-induced cytokine production in P. gingivalis–stimulated BMDM, establishing a previously unidentified TNF-dependent feedback loop. Adoptive transfer of TLR2-expressing macrophages to TLR2-deficient mice restored the ability of P. gingivalis to induce alveolar bone loss in vivo. Collectively, our results identify a TLR2- and TNF-dependent macrophage-specific mechanism underlying pathogen-induced inflammatory bone loss in vivo.

Papadopoulos, George; Weinberg, Ellen O.; Massari, Paola; Gibson, Frank C.; Wetzler, Lee M.; Morgan, Elise F.



Repairing cartilage defects with bone marrow mesenchymal stem cells induced by CDMP and TGF-?1.  


The aim of this study was to explore the ability for chondrogenic differentiation of bone marrow mesenchymal stems cells (BMSCs) induced by either cartilage-derived morphogenetic protein 1 (CDMP-1) alone or in the presence of transforming growth factor-?1 (TGF-?1) in vivo and in vitro. BMSCs and poly-lactic acid/glycolic acid copolymer (PLGA) scaffold were analyzed for chondrogenic capacity induced by CDMP-1 and TGF-?1 in vivo and in vitro. Chondrogenic differentiation of BMSCs into chondrocytes using a high density pellet culture system was tested, whether they could be maintained in 3-D PLGA scaffold instead of pellet culture remains to be explored. Under the culture of high-density cell suspension and PLGA frame, BMSCs were observed the ability to repair cartilage defects by either CDMP-1 alone or in the presence of TGF-?1 in vitro. Then the cell-scaffold complex was implanted into animals for 4 and 8 weeks for in vivo test. The content of collagen type II and proteoglycan appeared to increase over time in the constructs of the induced groups (CDMP in the presence of TGF-?1), CDMP group and TGF group. However, the construct of the control group did not express them during the whole culture time. At 4 and 8 weeks, the collagen type II expression of the induced group was higher than the sum of TGF group and CDMP group by SSPS17.0 analysis. BMSCs and PLGA complex induced by CDMP-1 and TGF- ?1 can repair cartilage defects more effectively than that induced by CDMP-1 or TGF-?1 only. PMID:23460257

Wu, Gang; Cui, Ying; Ma, Linxiang; Pan, Xinyu; Wang, Xuefeng; Zhang, Ben



Patterns of bone diseases in transfusion-dependent homozygous thalassaemia major: predominance of osteoporosis and desferrioxamine-induced bone dysplasia  

Microsoft Academic Search

Objective: To study the radiographic skeletal changes in transfusion-dependent homozygous #-thalassaemia. Materials and methods: This was a retrospective review of radiographs of 41 homozygous #-thalassaemic patients over 3 years. These included 55 left hand radiographs for bone age, 37 chest radiographs, 7 scanograms of lower limbs, 8 knee radiographs and 3 skull radiographs. The radiographs were evaluated for the skeletal

Yu-Leung Chan; Lai-Man Pang; Ki-Wai Chik; Jack C. Cheng; Chi-Kong Li




Technology Transfer Automated Retrieval System (TEKTRAN)

We have previously reported preliminary data demonstrating significant bone loss at the end of gestation following alcohol consumption during pregnancy even when optimal diets are infused intragastrically (Ronis et al. Alc. Clin. Exp. Res. 26:142A, 2002). In the current study, we extended these stu...


Induction of bone-marrow eosinophilia in mice submitted to surgery is dependent on stress-induced secretion of glucocorticoids  

PubMed Central

We examined bone-marrow in mice receiving subcutaneous implants of heat-coagulated egg white, which are known to present chronic eosinophilic inflammation at the implant site. Egg white implants (EWIs) induced marked bone-marrow eosinophilia, and increased bone-marrow cell responses to granulocyte-macrophage colony-stimulating factor and interleukin-5 in culture. These effects were observed as early as 24 h and lasted for, at least, 30 days in implant recipients. We found, however, that increased eosinophil production was also observed in control mice which underwent surgery but received no EWI (sham-implanted mice), up to 15 days post-surgery. As this suggests an important contribution of nonspecific stress mechanisms to eosinopoiesis, we further evaluated the role of stress hormones produced by the adrenal glands in the bone-marrow eosinophilia of sham-implanted mice. Bone-marrow eosinophilia in mice undergoing surgery was dissociated from increases in other haemopoietic lineages. Surgery by itself increased circulating corticosterone levels by 24 h, and the increase was prevented by inhibition of adrenal glucocorticoid production by metyrapone. The effect of surgery on bone-marrow eosinophilia was prevented by pretreatment with both the glucocorticoid receptor antagonist, mifepristone, and metyrapone, and by surgical adrenalectomy. By contrast, cathecolamine receptor antagonists (propranolol, prazosin and yohimbine) were ineffective, indicating that cathecolamine release from the adrenal glands was not responsible for the effects on bone-marrow. These results highlight a critical role for stress-induced glucocorticoid hormones in selectively upregulating bone-marrow eosinopoiesis in mice submitted to surgery.

Elsas, Pedro Xavier; Neto, Heitor A Paula; Cheraim, Alessandra B; Magalhaes, Elisabeth S S; Accioly, Maria Theresa S; Carvalho, Vinicius F; e Silva, Patricia M R; Vargaftig, B B; Cunha, Fernando Q; Gaspar Elsas, Maria Ignez C



Lactobacillus fermentation enhances the inhibitory effect of Hwangryun-haedok-tang in an ovariectomy-induced bone loss  

PubMed Central

Background Hwangryun-haedok-tang (HRT) is traditional herbal medicine used to treat inflammatory-related diseases in Asia. However, its effect on osteoclastogenesis and bone loss is still unknown. In this study, we evaluated the effect of HRT and its fermented product (fHRT) on the receptor activator for the nuclear factor-?B ligand-induced osteoclastogenesis using murine bone marrow-derived macrophages and postmenopausal bone loss using an ovariectomy (OVX) rat model. Methods Tartrate resistant acid phosphatase (TRAP) staining was employed to evaluate osteoclast formation. mRNA level of transcription factor and protein levels of signaling molecules were determined by real-time quantitative polymerase chain reaction and Western blot analysis, respectively. Effect of HRT or fHRT on OVX-induced bone loss was evaluated using OVX rats orally administered HRT, or fHRT with 300 mg/kg for 12 weeks. Micro-CT analysis of femora was performed to analyze bone parameter. Results HRT or fHRT treatment significantly decreased TRAP activity and the number of TRAP positive multinuclear cells on osteoclastogenesis. Interestingly, these inhibitory effects of HRT were enhanced by fermentation. Furthermore, fHRT significantly inhibited mRNA and protein expression of nuclear factor of activated T cells cytoplasmic 1, which leads to down-regulation of NFATc1-regulated mRNA expressions such as TRAP, the d2 isoform of vacuolar ATPase V(0) domain, and cathepsin K. Administration of fHRT significantly inhibited the decrease of bone mineral density, and improved bone parameter of femora more than that of HRT and vehicle in OVX rats. Conclusions This study demonstrated that lactic bacterial fermentation fortifies the inhibitory effect of HRT on osteoclastogenesis and bone loss. These results suggest that fermented HRT might have the beneficial potential on osteoporosis by inhibiting osteoclastogenesis.



Osteoclast Response to Low Extracellular Sodium and the Mechanism of Hyponatremia-induced Bone Loss*  

PubMed Central

Our recent animal and human studies revealed that chronic hyponatremia is a previously unrecognized cause of osteoporosis that is associated with increased osteoclast numbers in a rat model of the human disease of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). We used cellular and molecular approaches to demonstrate that sustained low extracellular sodium ion concentrations ([Na+]) directly stimulate osteoclastogenesis and resorptive activity and to explore the mechanisms underlying this effect. Assays on murine preosteoclastic RAW 264.7 cells and on primary bone marrow monocytes both indicated that lowering the medium [Na+] dose-dependently increased osteoclast formation and resorptive activity. Low [Na+], rather than low osmolality, triggered these effects. Chronic reduction of [Na+] dose-dependently decreased intracellular calcium without depleting endoplasmic reticulum calcium stores. Moreover, we found that reduction of [Na+] dose-dependently decreased cellular uptake of radiolabeled ascorbic acid, and reduction of ascorbic acid in the culture medium mimicked the osteoclastogenic effect of low [Na+]. We also detected downstream effects of reduced ascorbic acid uptake, namely evidence of hyponatremia-induced oxidative stress. This was manifested by increased intracellular free oxygen radical accumulation and proportional changes in protein expression and phosphorylation, as indicated by Western blot analysis from cellular extracts and by increased serum 8-hydroxy-2?-deoxyguanosine levels in vivo in rats. Our results therefore reveal novel sodium signaling mechanisms in osteoclasts that may serve to mobilize sodium from bone stores during prolonged hyponatremia, thereby leading to a resorptive osteoporosis in patients with SIADH.

Barsony, Julia; Sugimura, Yoshihisa; Verbalis, Joseph G.



HOXA3 modulates injury-induced mobilization and recruitment of bone marrow-derived cells.  


The regulated recruitment and differentiation of multipotent bone marrow-derived cells (BMDCs) to sites of injury are critical for efficient wound healing. Previously we demonstrated that sustained expression of HOXA3 both accelerated wound healing and promoted angiogenesis in diabetic mice. In this study, we have used green fluorescent protein-positive bone marrow chimeras to investigate the effect of HOXA3 expression on recruitment of BMDCs to wounds. We hypothesized that the enhanced neovascularization induced by HOXA3 is due to enhanced mobilization, recruitment, and/or differentiation of BMDCs. Here we show that diabetic mice treated with HOXA3 displayed a significant increase in both mobilization and recruitment of endothelial progenitor cells compared with control mice. Importantly, we also found that HOXA3-treated mice had significantly fewer inflammatory cells recruited to the wound compared with control mice. Microarray analyses of HOXA3-treated wounds revealed that indeed HOXA3 locally increased expression of genes that selectively promote stem/progenitor cell mobilization and recruitment while also suppressing expression of numerous members of the proinflammatory nuclear factor kappaB pathway, including myeloid differentiation primary response gene 88 and toll-interacting protein. Thus HOXA3 accelerates wound repair by mobilizing endothelial progenitor cells and attenuating the excessive inflammatory response of chronic wounds. PMID:19544454

Mace, Kimberly A; Restivo, Terry E; Rinn, John L; Paquet, Agnes C; Chang, Howard Y; Young, David M; Boudreau, Nancy J



HOXA3 Modulates Injury-Induced Mobilization and Recruitment of Bone Marrow-Derived Cells  

PubMed Central

The regulated recruitment and differentiation of multipotent bone marrow-derived cells (BMDCs) to sites of injury are critical for efficient wound healing. Previously we demonstrated that sustained expression of HOXA3 both accelerated wound healing and promoted angiogenesis in diabetic mice. In this study, we have used green fluorescent protein-positive bone marrow chimeras to investigate the effect of HOXA3 expression on recruitment of BMDCs to wounds. We hypothesized that the enhanced neovascularization induced by HOXA3 is due to enhanced mobilization, recruitment, and/or differentiation of BMDCs. Here we show that diabetic mice treated with HOXA3 displayed a significant increase in both mobilization and recruitment of endothelial progenitor cells compared with control mice. Importantly, we also found that HOXA3-treated mice had significantly fewer inflammatory cells recruited to the wound compared with control mice. Microarray analyses of HOXA3-treated wounds revealed that indeed HOXA3 locally increased expression of genes that selectively promote stem/progenitor cell mobilization and recruitment while also suppressing expression of numerous members of the proinflammatory nuclear factor ?B pathway, including myeloid differentiation primary response gene 88 and toll-interacting protein. Thus HOXA3 accelerates wound repair by mobilizing endothelial progenitor cells and attenuating the excessive inflammatory response of chronic wounds.

Mace, Kimberly A; Restivo, Terry E; Rinn, John L; Paquet, Agnes C; Chang, Howard Y; Young, David M; Boudreau, Nancy J



Bone morphogenetic protein-4 strongly potentiates growth factor-induced proliferation of mammary epithelial cells  

SciTech Connect

Bone morphogenetic proteins (BMPs) are multifunctional cytokines that elicit pleiotropic effects on biological processes such as cell proliferation, cell differentiation and tissue morphogenesis. With respect to cell proliferation, BMPs can exert either mitogenic or anti-mitogenic activities, depending on the target cells and their context. Here, we report that in low-density cultures of immortalized mammary epithelial cells, BMP-4 did not stimulate cell proliferation by itself. However, when added in combination with suboptimal concentrations of fibroblast growth factor (FGF)-2, FGF-7, FGF-10, epidermal growth factor (EGF) or hepatocyte growth factor (HGF), BMP-4 potently enhanced growth factor-induced cell proliferation. These results reveal a hitherto unsuspected interplay between BMP-4 and growth factors in the regulation of mammary epithelial cell proliferation. We suggest that the ability of BMP-4 to potentiate the mitogenic activity of multiple growth factors may contribute to mammary gland ductal morphogenesis as well as to breast cancer progression.

Montesano, Roberto [Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Rue-Michel-Servet, 1, CH-1211 Geneva 4 (Switzerland)], E-mail:; Sarkoezi, Rita; Schramek, Herbert [Department of Internal Medicine IV, Nephrology and Hypertensiology, Innsbruck Medical University, Innsbruck (Austria)



Variation of flow-induced stresses within scaffolds used in bone tissue engineering  

NASA Astrophysics Data System (ADS)

Bone tissue engineering is often based on seeding adult stem cells on porous scaffolds and subsequently placing these scaffolds in flow perfusion bioreactors to stimulate cell differentiation and cell growth. In the present study, the distribution of stresses in structured porous scaffolds under flow is investigated by calculating the probability density function of flow-induced stresses in different scaffold geometries with simulations. The physical reason for the development of particular stress distributions is further explored, and it is found that the direction of flow relative to the internal architecture of the porous scaffold is important for stress distributions. When the flow direction is random relative to the configuration of the geometric elements making up the scaffold, it is found that a common distribution, such as the one suggested by Voronov et al. (Appl. Phys. Let., 2010, 97:024101), can be used to describe the stress distribution.

Papavassiliou, Dimitrios; Pham, Ngoc; Voronov, Roman; Sikavitsas, Vassilios



CpG oligodeoxynucleotide induces bone marrow precursor cells into myeloid-derived suppressor cells.  


Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) perform a number of functions in different immunological settings. In standard in vitro experiments, DCs are produced from mouse bone marrow (BM) cells in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4. Our previous study demonstrated that BM precursor cells could differentiate into MDSCs when co-cultured with poly (I:C). In the present study, BM precursor cells cultured in GM-CSF and IL-4 were treated with CpG oligodeoxynucleotide (CpG ODN). We observed that Gr1+CD11b+ cells exhibiting MDSC functions accumulated in the co-culture system. A similar phenomenon was also observed in Listeria monocytogenes-infected mice. In conclusion, we demonstrated that prolonged CpG ODN stimulation could inhibit the development of DCs and induce the differentiation of BM precursor cells into MDSCs. PMID:23982226

Chen, Jie; Deng, Chengyu; Shi, Qingmin; Jiang, Jun; Zhang, Yongbo; Shan, Wei; Sun, Weimin



Enhancement of ectopic osteoid formation following the dual release of bone morphogenetic protein 2 and Wnt1 inducible signaling pathway protein 1 from gelatin sponges.  


Bone morphogenetic protein (BMP) 2-incorporated gelatin sponge is effective for in vivo osteoinduction. However, the modeling capacity of bone decreases with age. As atrial to stimulate effective bone formation for animals with decreased osteogenic potential, Wnt1 inducible signaling pathway protein (WISP) 1, an osteoblastic regulator, was combined with gelatin sponge incorporating BMP2. Osteopontin (Opn) geneexpression was increased in vitro for mouse bone marrow stromal cells (BMSC) cultured in gelatin sponges incorporating BMP2 and WISP1 compared with those incorporating BMP2 or WISP1 alone. In vivo synergistic effect of BMP2 and WISP1 on the ectopic osteoid formation was observed when gelatin sponges incorporating BMP2 and WISP1 were implanted subcutaneously into middle-aged mice with decreased bone formation potential. It is concluded that the scaffold incorporating multiple osteoinductive agents could be effective in inducing bone formation in those with age-related decreased potential of bone formation. PMID:21570720

Kohara, Hiroshi; Tabata, Yasuhiko



Wnt signaling pathways participate in Astragalus injection-induced differentiation of bone marrow mesenchymal stem cells.  


Bone marrow mesenchymal stem cells (MSCs) have the capacity for self-renewal and multi-directional differentiation, and MSCs can differentiate into neuron-like cells under certain conditions. In this study, we used the traditional Chinese medicine Astragalus as an inducer. After 7 days of induction, the expression of specific markers was detected in each induced group by immunocytochemical staining. The results of real-time quantitative PCR and Western blot confirmed the immunocytochemistry analysis. We also tested some key genes and proteins of the Wnt signaling pathway, and found that they were increased in Astragalus-treated groups. After treatment with lithium chloride (LiCl), the protein expression of phospho GSK-3? and ?-catenin was increased in each group compared to the corresponding group without LiCl. These findings demonstrate that Astragalus injection can induce differentiation of MSCs into neuron-like cells and suggest that the process of differentiation might be mediated by activation of Wnt signaling pathways. PMID:23954827

Zhong, Jingfei; Cao, Hui; Chen, Zhonghua; Zhou, Fei; Tan, Xiangling



Osteopontin is associated with nuclear factor {kappa}B gene expression during tail-suspension-induced bone loss  

SciTech Connect

Osteoporosis due to unloading-induced bone loss is a critical issue in the modern aging society. Although the mechanisms underlying this phenomenon are largely unknown, osteopontin (OPN) is one of the critical mediators required for unloading-induced bone loss [M. Ishijima, S.R. Rittling, T. Yamashita, K. Tsuji, H. Kurosawa, A. Nifuji, D.T. Denhardt, and M. Noda, Enhancement of osteoclastic bone resorption and suppression of osteoblastic bone formation in response to reduced mechanical stress do not occur in the absence of osteopontin, J Exp Med, 193 (2001) 399-404]. To clarify the molecular bases for OPN actions, we carried out microarray analyses on the genes expressed in the femoral bone marrow cells in wild type and OPN-/- mice. The removal of the mechanical load induced bone loss in wild type, but not in OPN-/- mice, as previously reported. Expression analysis of 9586 cDNAs on a microarray system revealed that OPN deficiency blocked tail-suspension-induced expression of ten genes (group A). This observation was confirmed based on semi-quantitative RT-PCR analyses. On the other hand, expression of four genes (group B) was not altered by tail suspension in wild type but was enhanced in OPN-deficient mice. NF-{kappa}B p105 subunit gene (Nfkb1) was found in group A and Bax in group B. p53 gene expression was upregulated by tail suspension in wild type mice, but it was no longer observed in OPN-/- mice. These data indicate that OPN acts to mediate mechanical stress signaling upstream to the genes encoding apoptosis-related molecules, and its action is associated with alteration of the genes.

Ishijima, Muneaki [Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 3-10, Kanda-Surugadai 2-Chome, Chiyoda-Ku, Tokyo 101-0062 (Japan); Ezura, Yoichi [Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 3-10, Kanda-Surugadai 2-Chome, Chiyoda-Ku, Tokyo 101-0062 (Japan) and Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, Kawasaki (Japan)]. E-mail:; Tsuji, Kunikazu [Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 3-10, Kanda-Surugadai 2-Chome, Chiyoda-Ku, Tokyo 101-0062 (Japan)] (and others)



Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction.  


To confirm whether human cancer-induced stromal cells are derived from bone marrow, bone marrow (BM) cells obtained from beta-galactosidase transgenic and recombination activating gene 1 (RAG-1) deficient double-mutant mice (H-2b) were transplanted into sublethally irradiated severe combined immunodeficient (SCID) mice (H-2d). The human pancreatic cancer cell line Capan-1 was subcutaneously xenotransplanted into SCID recipients and stromal formation was analyzed on day 14 and on day 28. Immunohistochemical and immunofluorescence studies revealed that BM-derived endothelial cells (X-gal/CD31 or H-2b/CD31 double-positive cells) and myofibroblasts (X-gal/alpha-smooth muscle actin or H-2b/alpha-smooth muscle actin double-positive cells) were present within and around the cancer nests. On day 14, the frequencies of BM-derived endothelial cells and BM-derived myofibroblasts were 25.3+/-4.4% and 12.7+/-9.6%, respectively. On day 28, the frequency of BM-derived endothelial cells was 26.7+/-9.7%, which was similar to the value on day 14. However, the frequency of BM-derived myofibroblasts was significantly higher (39.8+/-17.1%) on day 28 than on day 14 (P<0.05). The topoisomerase IIalpha-positive ratio was 2.2+/-1.2% for the H-2b-positive myofibroblasts, as opposed to only 0.3+/-0.4% for the H-2b-negative myofibroblasts, significant proliferative activity was observed in the BM-derived myofibroblasts (P<0.05). Our results indicate that BM-derived myofibroblasts become a major component of cancer-induced stromal cells in the later stage of tumor development. PMID:12943687

Ishii, Genichiro; Sangai, Takafumi; Oda, Tatsuya; Aoyagi, Yasuyuki; Hasebe, Takahiro; Kanomata, Naoki; Endoh, Yasushi; Okumura, Chie; Okuhara, Yoko; Magae, Junji; Emura, Makito; Ochiya, Takahiro; Ochiai, Atsushi



The role of weightlessness in the genetic damage from preflight gamma-irradiation of organisms in experiments aboard the Salyut 6 orbital station  

NASA Astrophysics Data System (ADS)

The effect of weightlessness on chromosomal aberration frequency in preflight irradiated Crepis capillaris seeds, on the viability, fertility and mutation frequency in Arabidopsis thaliana, and on the frequency of nondisjunction and loss of X chromosomes in preflight irradiated Drosophila melanogaster gametes was studied aboard the Salyut 6 orbital station. The following effects were observed: a flight-time dependent amplification of the effects of preflight ?-irradiation in A. thaliana with respect to all the parameters studied; unequal effects in seeds and seedlings of Crepis capillaris; and a significant increase in the frequency of nondisjunction and loss of chromosomes during meiosis in Drosophila females. These observations are discussed in terms of the data of ground-based model experiments and flight experiments with a different time of exposure of objects to weightlessness. An attempt is made to elucidate the role of weightlessness in the modification of ionizing radiation effects.

Vaulina, E. N.; Anikeeva, I. D.; Kostina, L. N.; Kogan, I. G.; Palmbakh, L. R.; Mashinsky, A. L.


Effects of ovariectomy and estrogen replacement therapy on arthritis and bone mineral density in rats with collagen-induced arthritis  

Microsoft Academic Search

We investigated the effects of ovariectomy (ovx) and estrogen replacement therapy (ERT) on bone mineral density (BMD) and arthritis severity in rats with collagen-induced arthritis (CIA). Seven-month-old female Sprague-Dawley rats were separated into a sham group (n = 8), CIA group (n = 14), ovx group (n = 10), CIA + ovx group (n = 11), and CIA + ovx

D Yamasaki; M Enokida; T Okano; H Hagino; R Teshima



The influence of p53 functions on radiation-induced inflammatory bystander-type signaling in murine bone marrow.  


Radiation-induced bystander and abscopal effects, in which DNA damage is produced by inter-cellular communication, indicate mechanisms of generating damage in addition to those observed in directly irradiated cells. In this article, we show that the bone marrow of irradiated p53(+/+) mice, but not p53(-/-) mice, produces the inflammatory pro-apoptotic cytokines FasL and TNF-? able to induce p53-independent apoptosis in vitro in nonirradiated p53(-/-) bone marrow cells. Using a congenic sex-mismatch bone marrow transplantation protocol to generate chimeric mice, p53(-/-) hemopoietic cells functioning in a p53(+/+) bone marrow stromal microenvironment exhibited greater cell killing after irradiation than p53(-/-) hemopoietic cells in a p53(-/-) microenvironment. Cytogenetic analysis demonstrated fewer damaged p53(-/-) cells in a p53(+/+) microenvironment than p53(-/-) cells in a p53(-/-) microenvironment. Using the two different model systems, the findings implicate inflammatory tissue processes induced as a consequence of p53-dependent cellular responses to the initial radiation damage, producing cytokines that subsequently induce ongoing p53-independent apoptosis. As inactivation of the p53 tumor suppressor pathway is a common event in malignant cells developing in a stromal microenvironment that has normal p53 function, the signaling processes identified in the current investigations have potential implications for disease pathogenesis and therapy. PMID:23578188

Lorimore, Sally A; Rastogi, Shubhra; Mukherjee, Debayan; Coates, Philip J; Wright, Eric G



Minor histocompatibility antigens on transfused leukoreduced units of red blood cells induce bone marrow transplant rejection in a mouse model  

PubMed Central

When successful, human leukocyte antigen (HLA)–matched bone marrow transplantation with reduced-intensity conditioning is a cure for several nonmalignant hematologic disorders that require chronic transfusion, such as sickle cell disease and aplastic anemia. However, there are unusually high bone marrow transplant (BMT) rejection rates in these patients. Rejection correlates with the number of transfusions before bone marrow transplantation, and it has been hypothesized that preimmunization to antigens on transfused blood may prime BMT rejection. Using a novel mouse model of red blood cell (RBC) transfusion and major histocompatibility complex–matched bone marrow transplantation, we report that transfusion of RBC products induced BMT rejection across minor histocompatibility antigen (mHA) barriers. It has been proposed that contaminating leukocytes are responsible for transfusion-induced BMT rejection; however, filter leukoreduction did not prevent rejection in the current studies. Moreover, we generated a novel transgenic mouse with RBC-specific expression of a model mHA and demonstrated that transfusion of RBCs induced a CD8+ T-cell response. Together, these data suggest that mHAs on RBCs themselves are capable of inducing BMT rejection. Cellular immunization to mHAs is neither monitored nor managed by current transfusion medicine practice; however, the current data suggest that mHAs on RBCs may represent an unappreciated and significant consequence of RBC transfusion.

Desmarets, Maxime; Cadwell, Chantel M.; Peterson, Kenneth R.; Neades, Renee



A rat model of bone inflammation-induced pain by intra-tibial complete Freund's adjuvant injection  

Microsoft Academic Search

In prior studies, models of inflammatory pain were produced through injecting complete Freund's adjuvant (CFA) or capsaicin directly into either the deep somatic tissue or the animal's hind paw. In contrast, bone cancer-induced pain (BCIP) was simulated through injecting tumor cells into the cavity of the femur or the tibia. It has been reported that, due to differences in afferent

Chang-Jiang Yang; Xiao-Wei Wang; Xiu Li; Gen-Cheng Wu; Yan-Qing Wang; Qi-Liang Mao-Ying



Pretreatment with capsaicin in a rat osteoarthritis model reduces the symptoms of pain and bone damage induced by monosodium iodoacetate  

Microsoft Academic Search

A rat model of osteoarthritis was used to investigate the effect of pre-treatment with capsaicin on the symptoms of osteoarthritis induced by the injection of monosodium iodoacetate. This model mimics both histopathology and symptoms associated of human osteoarthritis. Injection of monosodium iodoacetate, an inhibitor of glycolysis, into the femorotibial joints of rodents promotes loss of articular trabecular bone and invokes

Karel-Martijn Kalff; Mohammed El Mouedden; Jan van Egmond; Jan Veening; L. A. B. Joosten; Gert Jan Scheffer; Theo Meert; Kris Vissers



[Motion sickness in lower vertebrates: studies under conditions of weightlessness and under land conditions].  


The review presents literature data and results of the author's studies with the goal to find out whether lower animals are susceptible to motion sickness. In our studies, fish and amphibians were tested for 2 h and more by using a rotating device (f = 0.24Nz, a(centrifugal) = 0.144 g) and a parallel swing (f = 0.2 Nz, a(horizontal) = 0.059 g). The performed studies did not reveal in 4 fish species and in toads any characteristic reactions of motion sickness (sopite syndrome, prodromal preparatory behavior, vomiting). At the same time, in toads characteristic stress reactions appeared (escape response, an increase in the number of urinations, inhibition of appetite), as well as some other reactions not associated with motion sickness (regular head movements, eye retraction). In trout fry this stimulation promoted dividing individuals into groups different by locomotor reaction to stress, as well as revealing individuals with a well-expressed compensatory reaction that we called the otolithotropic reaction. Analysis of results obtained by other authors confirms our conclusion. Thus, lower vertebrates, unlike mammals, are immune to motion sickness either under land conditions or under conditions of weightlessness. On the basis of available experimental data and theoretical concepts of mechanisms of motion sickness development formulated in several hypotheses (mismatch hypothesis, Traisman's hypothesis, resonance hypothesis) a synthetic hypothesis of motion sickness is presented that has the conceptual significance. According to the hypothesis, unusual stimulation producing sensomotor or senso-sensory conflict or action of vestibular and visual stimuli of about 0.2 Hz frequency is perceived by CNS as poisoning and causes corresponding reactions. The motion sickness actually is a byproduct of technical evolution. It is suggested that lower vertebrates, unlike mammals, lack a hypothetical center of subjective "nauseating" sensations; therefore they are immune to motion sickness. PMID:23401973

Lychakov, D V


Estimating the chance of success of archaeometric analyses of bone: UV-induced bone fluorescence compared to histological screening  

Microsoft Academic Search

For most archaeometric analyses on archaeological bone material, such as the determination of the isotopic composition or genetic approaches, an advanced degree of diagenetic alteration can make designated analysis impossible. Since the lack of a positive signal is mostly seen only after time consuming and cost intensive sample processing, the need for an easy-to-apply screening method that allows a pre-selection

Nadja Hoke; Joachim Burger; Christine Weber; Norbert Benecke; Gisela Grupe; Michaela Harbeck



Bone morphogenetic protein 4: Potential regulator of shear stress-induced graft neointimal atrophy  

PubMed Central

Objective Placement in baboons of a distal femoral arteriovenous fistula increases shear stress through aortoiliac polytetrafluoroethylene (PTFE) grafts and induces regression of a preformed neointima. Atrophy of the neointima might be controlled by shear stress-induced genes, including the bone morphogenetic proteins (BMPs). We have investigated the expression and function of BMPs 2, 4, and 5 in the graft neointima and in cultured baboon smooth muscle cells (SMCs). Methods Baboons received bilateral aortoiliac PTFE grafts and 8 weeks later, a unilateral femoral arteriovenous fistula. Results Quantitative polymerase chain reaction showed that high shear stress increased BMP2, 4, and 5 messenger RNA (mRNA) in graft intima between 1 and 7 days, while noggin (a BMP inhibitor) mRNA was decreased. BMP4 most potently (60% inhibition) inhibited platelet-derived growth factor-stimulated SMC proliferation compared with BMP2 and BMP5 (31% and 26%, respectively). BMP4 also increased SMC death by 190% ±10%. Noggin reversed the antiproliferative and proapoptotic effects of BMP4. Finally, Western blotting confirmed BMP4 protein upregulation by high shear stress at 4 days. BMP4 expression demonstrated by in situ hybridization was confined to endothelial cells. Conclusions Increased BMPs (particularly BMP4) coupled with decreased noggin may promote high shear stress-mediated graft neointimal atrophy by inhibiting SMC proliferation and increasing SMC death. Clinical Relevance Pharmacologic therapy to prevent luminal stenosis or restenosis after vascular reconstruction is directed at inhibiting intimal hyperplasia and smooth muscle cell growth. An alternative approach might be to induce intimal atrophy after luminal narrowing has developed. This approach would be particularly useful for treating stenosis in stented vessels or synthetic bypass grafts because intimal hyperplasia is the only mechanism for luminal narrowing. Furthermore, it would permit the physician to treat the population of patients (about 30%) who actually develop a problem with stenosis or restenosis. We have previously provided proof of principle that an established neointima can be induced to atrophy in baboon polytetrafluoroethylene grafts, but not in normal artery, by simply switching from normal to high blood flow and shear stress. In this study, we provide evidence that members of the bone morphogenetic protein family may play a role in this neointimal atrophy.

Hsieh, Patrick C. H.; Kenagy, Richard D.; Mulvihill, Eileen R.; Jeanette, Joseph P.; Wang, Xi; Chang, Cindy M. C.; Yao, Zizhen; Ruzzo, Walter L.; Justice, Suzanne; Hudkins, Kelly L.; Alpers, Charles E.; Berceli, Scott; Clowes, Alexander W.



Comparison of bone scan and radiograph sensitivity in the detection of steroid-induced ischemic necrosis of bone  

SciTech Connect

A prospective study of bone scanning for detection of ischemic necrosis of bone (INB) was performed in 36 patients (97% female, age range 16-36 yrs.) with systemic lupus erythematosis (SLE). Since the hips, knees, and shoulders are usually affected by INB in patients with SLE, 300 K converging collimator images of these joints were obtained on film and in digital format 2 to 3 hours after the injection of 20 mCi (740 MBq) of Tc-99m methylene diphosphonate. All patients underwent radiography of the joints, and 10 had intraosseous pressure determinations in the marrow space of affected joints (n=31) for independent assessment of INB. Scans showed abnormally increased joint activity in 28 of the 36 patients. A total of 97 joints showed abnormalities, 19% in the hips, 34% in the knees, and 47% in the shoulders. Twenty-four of 27 joints with elevated bone marrow pressure (BMP) had abnormal scans (sensitivity = 89%), and scans were abnormal in 2 of 4 joints with normal pressures (specificity = 50%). The positive predicitive value of the scans compared with BMP measurements was 92% (24/26). Eleven of 27 joints with abnormal BMP had abnormal radiographs, a sensitivity of 41%.

Conklin, J.J.; Alderson, P.O.; Zizic, T.M.; Hungerford, D.S.; Densereaux, J.Y.; Gober, A.; Wagner, H.N.



Comparison of bone scan and radiograph sensitivity in the detection of steroid-induced ischemic necrosis of bone  

SciTech Connect

A prospective study of bone scanning for detection of ischemic necrosis of bone (INB) was performed in 36 patients (97% female, age range 16-36 yrs.) with systemic lupus erythematosis (SLE). Since the hips, knees, and shoulders are usually affected by INB in patients with SLE, 300 K converging collimator images of these joints were obtained on film and in digital format 2 to 3 hours after the injection of 20 mCi (740 MBq) of Tc-99m methylene diphosphonate. All patients underwent radiography of the joints, and 10 had intraosseous pressure determinations in the marrow space of affected joints (n . 31) for independent assessment of INB. Scans showed abnormally increased joint activity in 28 of the 36 patients. A total of 97 joints showed abnormalities, 19% in the hips, 34% in the knees, and 47% in the shoulders. Twenty-four of 27 joints with elevated bone marrow pressure (BMP) had abnormal scans (sensitivity . 89%), and scans were abnormal in 2 of 4 joints with normal pressures (specificity . 50%). The positive predictive value of the scans compared with BMP measurements was 92% (24/26). Eleven of 27 joints with abnormal BMP had abnormal radiographs, a sensitivity of 41%.

Conklin, J.J.; Alderson, P.O.; Zizic, T.M.; Hungerford, D.S.; Densereaux, J.Y.; Gober, A.; Wagner, H.N.



Visual enhancement of micro CT bone density images  

NASA Astrophysics Data System (ADS)

The primary goal of this research was to provide image processing support to aid in the identification of those subjects most affected by bone loss when exposed to weightlessness and provide insight into the causes for large variability. Past research has demonstrated that genetically distinct strains of mice exhibit different degrees of bone loss when subjected to simulated weightlessness. Bone loss is quantified by in vivo computed tomography (CT) imaging. The first step in evaluating bone density is to segment gray scale images into separate regions of bone and background. Two of the most common methods for implementing image segmentation are thresholding and edge detection. Thresholding is generally considered the simplest segmentation process which can be obtained by having a user visually select a threshold using a sliding scale. This is a highly subjective process with great potential for variation from one observer to another. One way to reduce inter-observer variability is to have several users independently set the threshold and average their results but this is a very time consuming process. A better approach is to apply an objective adaptive technique such as the Riddler / Calvard method. In our study we have concluded that thresholding was better than edge detection and pre-processing these images with an iterative deconvolution algorithm prior to adaptive thresholding yields superior visualization when compared with images that have not been pre-processed or images that have been pre-processed with a filter.

DaPonte, John S.; Clark, Michael; Damon, Megan; Kamins, Rebecca; Sadowski, Thomas; Tirrell, Charles



Marrow-tumor interactions: the role of the bone marrow in controlling chemically induced tumors. 1983 annual progress report  

SciTech Connect

Our work has defined two experimental tumor systems in which we have shown that there is interaction between the bone marrow and certain neoplasms. We have documented that these interactions are important in host responses against tumors. Our experiments have assigned a major role to bone marrow in the growth inhibition of methylcholanthrene-induced (MCA) sarcomas. We have discovered that the bone marrow contains Natural Tumor Growth Regulatory Cells (NTRC) that in collaboration with immunocytes specifially sensitized to a tumor are capable of neutralizing that tumor. In addition, we have shown that a mammary carcinoma of mice significantly alters the pattern of hemopoiesis and disturbs lymphocyte and stem populations in the bone marrow. Our approach has been to pursue multiple convergent lines of attack, since the host response against various cancers is complex, relying on the interaction of several cell types which exercise their tumor neutralization effect probably through various mechanisms. A unique component of our work is the investigation of the influence neoplasms exert on the production of various types of bone marrow cells which can function or can differentiate into cells that participate in the host's antitumor responses. The focus of the work has remained the same and we have continued to define the identity of the bone marrow derived cells involved in tumor neutralization and the mechanisms through which they exert their function.

Not Available



The CXCR4-SDF1alpha axis is a critical mediator of rhabdomyosarcoma metastatic signaling induced by bone marrow stroma.  


Rhabdomyosarcoma (RMS) is the most common malignant soft-tissue tumor of childhood. Nearly 15% of children present with metastatic disease, frequently involving the lungs and bone marrow. The prognosis for patients with metastatic RMS is dismal, with an estimated 3-year overall survival of 30%. Stromal-cell derived factor 1-alpha (SDF1alpha, CXCL12) is a chemokine that plays a crucial role in the metastatic attraction of tumor cells expressing its receptor, CXCR4. We investigated the role of the bone marrow microenvironment on RMS signaling through the CXCR4/SDF1alpha pathway in cell lines and primary tumors. Conditioned media (CM) isolated from cultured patient-derived bone marrow stromal cells (BMS) induced migration and proliferation in multiple RMS cell lines. CXCR4 was expressed in RMS cell lines and primary tumors, with higher expression in alveolar subtype RMS. Further, SDF1alpha was secreted by all BMS cultures and potently induced the migration and proliferation of RMS cells. Small molecule or blocking antibody-mediated inhibition of CXCR4 or SDF1alpha suppressed RMS cell migration towards BMS-CM, confirming the activity of this axis. Our study provides strong evidence for the involvement of the bone marrow microenvironment and CXCR4/SDF1alpha signaling in metastasis of RMS. These results form the basis for future studies to delineate the mechanisms of bone marrow metastasis in RMS. PMID:17768666

Strahm, Brigitte; Durbin, Adam D; Sexsmith, Elizabeth; Malkin, David



[Secondary Osteoporosis or Secondary Contributors to Bone Loss in Fracture. Therapeutic strategy for glucocorticoid-induced osteoporosis].  


Glucocorticoid is widely used to treat a variety of diseases and causes a number of significant side effects. Glucocorticoid-induced osteoporosis (GIOP) is known as a serious adverse effect during long-term glucocorticoid therapy. Guideline in Japan recommends bisphosphonates as first-line drugs. Bisphosphonates increase bone mineral density (BMD) and reduce vertebral fracture risk in patient beginning or continuing glucocorticoid treatment. As well as increased bone resorption, GIOP could induce severe suppression of bone formation. Although bisphosphonates are effective for GIOP, anabolic therapeutic strategies should be considered as alternative therapy in GIOP. Teripatratide (PTH (1-34) ) , a bone anabolic drug, is widely used in primary osteoporosis with severe osteoporotic fracture or extremely low bone mass, and has been reported to increase BMD and to reduce the risk of fractures also in GIOP. Denosumab, an anti receptor activator of nuclear factor-?B ligand, recently approved as a drug for postmenopausal osteoporosis was also effective for GIOP in clinical trials, and would be new candidate to treat GIOP. PMID:23999371

Hayakawa, Nobuki; Suzuki, Atsushi



Bone morphogenetic protein-7 inhibits silica-induced pulmonary fibrosis in rats.  


Bone morphogenetic protein-7 (BMP-7) has been shown to inhibit liver and renal fibrosis in in vivo and vitro studies. There is no study to investigate BMP-7's role in the development of pulmonary fibrosis induced by silica. In the current study, we used the rat model to explore the potential antifibrotic role of BMP-7 and its underlying mechanism in silica-induced pulmonary fibrosis. Sixty Wistar rats were randomly assigned into three groups. Control group received saline, silica group received silica and BMP-7 treated group received silica and BMP-7. BMP-7 was administered to silica-treated rats intraperitoneally at a dose of 300?g/kg/injection from day 8 to day 30 every other day. After the animals were sacrificed on day 15 and 30, hydroxyproline levels, the protein expressions of BMP/Smad and TGF-?/Smad signaling, and histopathology in lung tissues were analyzed. The hydroxyproline contents in BMP-7 treated groups were significantly lower than the silica groups (P<0.05). Histopathological results showed BMP-7 could reduce the progression of silica induced fibrosis. Furthermore, the expression of p-Smad1/5/8, a marker of BMP/Smad signaling, was significantly up-regulated in BMP-7 treated groups (P<0.05) compared with the silica groups. On the contrary, the expression of p-Smad2/3, a marker for TGF-?/Smad signaling, reduced significantly in BMP-7-treated groups compared with silica groups (P<0.05). In conclusion, the pulmonary fibrosis induced by silica in rats was significantly reduced with the therapeutic treatment of BMP-7. The antifibrotic effect of BMP-7 could be related to the activation of BMP/Smad signaling and inhibition of TGF-?/Smad pathways. PMID:23639248

Yang, Gengxia; Zhu, Zhonghui; Wang, Yan; Gao, Ai; Niu, Piye; Tian, Lin



Sinomenine Suppresses Osteoclast Formation and Mycobacterium tuberculosis H37Ra-Induced Bone Loss by Modulating RANKL Signaling Pathways.  


Receptor activator of NF-?B ligand (RANKL) is essential for osteoclastogenesis. Targeting RANKL signaling pathways has been an encouraging strategy for treating lytic bone diseases such as osteoporosis and rheumatoid arthritis (RA). Sinomenine (SIN), derived from Chinese medicinal plant Sinomenioumacutum, is an active compound to treat RA, but its effect on osteoclasts has been hitherto unknown. In the present study, SIN was found to ameliorate M. tuberculosis H37Ra (Mt)-induced bone loss in rats with a decreased serum level of TRACP5b and RANKL, and an increased level of osteoprotegerin (OPG). In vitro study also showed that SIN could inhibit RANKL-induced osteoclast formation and bone resorption. The osteoclastic specific marker genes induced by RANKL including c-Src, MMP-9, TRACP were inhibited by SIN in a dose dependent manner. Signal transduction studies showed that SIN could obviously reduce the expression of RANK adaptor molecule TRAF6 and down-regulate RANKL-induced NF-?B activation. It decreased the RANKL-induced p38, JNK posphorylation but not ERK1/2 posphorylation. SIN could also reduce RANKL-mediated calcium influx which is associated with TRAF6/c-Src complex. Finally, SIN suppressed RANKL induced AP-1 and NFAT transcription, as well as the gene expression of NFATc1 and AP-1 components (Fra-1, Fra-2, c-Fos). The protein expression of c-Fos and TRAF6 were also inhibited by SIN after RANKL stimulation. Taken together, SIN could attenuate osteoclast formation and Mt-induced bone loss by mediating RANKL signaling pathways. PMID:24066131

Li, Xiaojuan; He, Longgang; Hu, Yiping; Duan, Heng; Li, Xianglian; Tan, Suiyi; Zou, Min; Gu, Chunping; Zeng, Xiangzhou; Yu, Le; Xu, Jiake; Liu, Shuwen



Sinomenine Suppresses Osteoclast Formation and Mycobacterium tuberculosis H37Ra-Induced Bone Loss by Modulating RANKL Signaling Pathways  

PubMed Central

Receptor activator of NF-?B ligand (RANKL) is essential for osteoclastogenesis. Targeting RANKL signaling pathways has been an encouraging strategy for treating lytic bone diseases such as osteoporosis and rheumatoid arthritis (RA). Sinomenine (SIN), derived from Chinese medicinal plant Sinomenioumacutum, is an active compound to treat RA, but its effect on osteoclasts has been hitherto unknown. In the present study, SIN was found to ameliorate M. tuberculosis H37Ra (Mt)-induced bone loss in rats with a decreased serum level of TRACP5b and RANKL, and an increased level of osteoprotegerin (OPG). In vitro study also showed that SIN could inhibit RANKL-induced osteoclast formation and bone resorption. The osteoclastic specific marker genes induced by RANKL including c-Src, MMP-9, TRACP were inhibited by SIN in a dose dependent manner. Signal transduction studies showed that SIN could obviously reduce the expression of RANK adaptor molecule TRAF6 and down-regulate RANKL-induced NF-?B activation. It decreased the RANKL-induced p38, JNK posphorylation but not ERK1/2 posphorylation. SIN could also reduce RANKL-mediated calcium influx which is associated with TRAF6/c-Src complex. Finally, SIN suppressed RANKL induced AP-1 and NFAT transcription, as well as the gene expression of NFATc1 and AP-1 components (Fra-1, Fra-2, c-Fos). The protein expression of c-Fos and TRAF6 were also inhibited by SIN after RANKL stimulation. Taken together, SIN could attenuate osteoclast formation and Mt-induced bone loss by mediating RANKL signaling pathways.

Li, Xiaojuan; He, Longgang; Hu, Yiping; Duan, Heng; Li, Xianglian; Tan, Suiyi; Zou, Min; Gu, Chunping; Zeng, Xiangzhou; Yu, Le; Xu, Jiake; Liu, Shuwen



Ovariectomy-Induced Changes in Aged Beagles: Histomorphometry of Rib Cortical Bone  

Microsoft Academic Search

.   Bone loss associated with estrogen depletion is well documented in cancellous bone but less well characterized in cortical\\u000a bone. The effects of ovariectomy on the aged beagle skeleton were studied by histomorphometric analysis of the cortical bone\\u000a in sequential rib biopsies. Biopsies were taken from each ovariectomized or sham-operated dog at the time of surgery and at\\u000a 1, 4,

A. K. Wilson; M. H. Bhattacharyya; S. Miller; A. Mani; N. Sacco-Gibson



High dietary calcium intake does not counteract disuse-induced bone loss  

Microsoft Academic Search

Reduction of mechanical stress on bone inhibits osteoblast-mediated bone formation, increases osteoclast-mediated bone resorption, and leads to what has been called disuse osteoporosis. Prolonged therapeutic bed rest, immobilization and space flight are common causes of disuse osteoporosis. There are sufficient data supporting the use of calcium in combination with vitamin D in the prevention and treatment of postmenopausal osteoporosis. In

N. Baecker; A. Boese; S. M. Smith; M. Heer



Different bone sesitivity to malformations induced by procarbazine in fetal rats.  


The study aimed at to induce cleft-lip-alveolus-palate (CLAP) applying procarbazine in rat fetuses at the 14(th) day of pregnancy, to supply thiocyanate and/or folic acid sufficient for preventive treatment and subsequently to investigate cleft extent in the palatal area as well as bone maturity. In this animal model, female primiparous inbred rats (LEW.1A) were used. The gravid animals were separated into treatment groups: group K (control), group P (procarbazine), group TP (thiocyanate and procarbazine) and group FTP (folic acid, thiocyanate, procarbazine). The results reveal that procarbazine may induce clefts in the palate area. Clefts occurred most frequently in group TP and mainly comprised subtotal clefts of the posterior secondary palate. As for palatal length, group FTP displayed the longest palate which was significantly different only from group K. A different picture was shown for the secondary palate with group TP displaying the shortest values which were significantly different from those in groups K, P, and FTP. Thus, group TP showed the most marked negative changes both for cleft frequency and palatal length as compared to group K and the other groups. The preventive application of either thiocyanate (TP) or thiocaynate and folic acid combined (group FTP) failed to completely prevent cleft formation in the palate area. In conclusion, a preventive effect on palatal clefts and growth inhibition could not be proved for the vitaminoid thiocyanate. PMID:19075321

Weingartner, J; Proff, P; Fanghanel, J; Kundt, G; Gedrange, T; Kubein-Meesenburg, D; Gredes, T



The Orphan Nuclear Receptor Estrogen Receptor-related Receptor ? Negatively Regulates BMP2-induced Osteoblast Differentiation and Bone Formation*  

PubMed Central

Estrogen receptor-related receptor ? (ERR?/ERR3/NR3B3) is a member of the orphan nuclear receptor with important functions in development and homeostasis. Recently it has been reported that ERR? is involved in osteoblast differentiation and bone formation. In the present study we examined the role of ERR? in osteoblast differentiation. Here, we showed that ERR? is expressed in osteoblast progenitors and primary osteoblasts, and its expression is increased temporarily by BMP2. Overexpression of ERR? reduced BMP2-induced alkaline phosphatase activity and osteocalcin production as well as calcified nodule formation, whereas inhibition of ERR? expression significantly enhanced BMP2-induced osteogenic differentiation and mineralization, suggesting that endogenous ERR? plays an important role in osteoblast differentiation. In addition, ERR? significantly repressed Runx2 transactivity on osteocalcin and bone sialoprotein promoters. We also observed that ERR? physically interacts with Runx2 in vitro and in vivo and competes with p300 to repress Runx2 transactivity. Notably, intramuscular injection of ERR? strongly inhibited BMP2-induced ectopic bone formation in a dose-dependent manner. Taken together, these results suggest that ERR? is a novel negative regulator of osteoblast differentiation and bone formation via its regulation of Runx2 transactivity.

Jeong, Byung-Chul; Lee, Yong-Soo; Park, Yun-Yong; Bae, In-Ho; Kim, Don-Kyu; Koo, Seung-Hoi; Choi, Hong-Ran; Kim, Sun-Hun; Franceschi, Renny T.; Koh, Jeong-Tae; Choi, Hueng-Sik



Comparison between amputation-induced demineralization and age-related bone loss using digital X-ray radiogrammetry.  


Digital X-ray radiogrammetry (DXR) is a computer-assisted automatic osteodensitometric tool. This study was performed to compare DXR measurements between bone changes following amputation trauma and age-related bone loss. Thirty-five men, who had undergone finger amputations, received a baseline examination and 2--3 serial measurements. As a second group, 215 males older than 70yr were enrolled. All patients obtained standardized hand radiographs. The following DXR parameters evaluating metacarpals were considered: cortical bone mineral density (DXR-BMD), cortical thickness (DXR-CT), metacarpal index (DXR-MCI), outer bone diameter (width; DXR-W), and inner medullary diameter (DXR-MD). In the amputation group, the DXR parameters showed an accentuated initial decrease between first and second measurements (DRX-BMD--12.7%, DXR-CT--14.2%, DXR-W--8.6%, DXR-MCI--6.1%; p<0.001) followed by a less pronounced reduction between second and third radiographs (DRX-BMD--0.5%, DXR-CT--1.5%, DXR-W--0.1%, DXR-MCI--1.3%). DXR-MD revealed a reduction of--3.6% (p<0.05) between first and second estimates and a non-significant increase (+1.1%) between second and third measurements. When compared with the second and third estimates in the amputation group, men older than 70yr presented lower DXR-BMD, DXR-CT, and DXR-MCI values (p<0.001), but larger metacarpal outer and inner bone diameters (DXR-W and DXR-MD; p<0.001). DXR-MD of the elderly men group was also more extended when compared with the baseline measurements of the amputation cohort (p<0.001). The early accentuated cortical bone loss and particularly the pronounced decrease of the outer bone width seem to be characteristic for amputation-induced osteoporosis, suggesting that this might be a distinct secondary osteoporosis entity. When compared with amputation-associated osteoporosis, where the bone loss occurs to a higher extent in the outer bone diameter than in the medullary cavity, the age-related bone changes lead more to an increase of the medullary diameter than of the outer bone width. PMID:22560013

Schäfer, Max-Ludwig; Böttcher, Joachim; Pfeil, Alexander; Hansch, Andreas; Malich, Ansgar; Maurer, Martin H; Streitparth, Florian; Röttgen, Rainer; Renz, Diane M


Chitosan-poly(butylene succinate) scaffolds and human bone marrow stromal cells induce bone repair in a mouse calvaria model  

Microsoft Academic Search

Tissue engineering sustains the need of a three-dimensional (3D)\\u000d\\u000a scaffold to promote the regeneration of tissues in volume. Usually,\\u000d\\u000a scaffolds are seeded with an adequate cell population, allowing their\\u000d\\u000a growth and maturation upon implantation in vivo. Previous studies\\u000d\\u000a obtained by our group evidenced significant growth patterns and\\u000d\\u000a osteogenic differentiation of human bone marrow mesenchymal stem cells\\u000d\\u000a (hBMSCs) when seeded and

A. R. Costa-Pinto; V. M. Correlo; P. C. Sol; M. Bhattacharya; S. Srouji; E. Livne; R. L. Reis; N. M. Neves



Bone Marrow-Derived c-kitPositive Cells Attenuate Neonatal Hyperoxia-Induced Lung Injury.  


Rationale: Recent studies suggest that bone marrow (BM)-derived stem cells have therapeutic efficacy in neonatal hyperoxia-induced lung injury (HILI). c-kit, a tyrosine kinase receptor which regulates angiogenesis, is expressed on several populations of BM-derived cells. Preterm infants exposed to hyperoxia have decreased lung angiogenesis. Here, we tested the hypothesis that administration of bone marrow derived c-kitpos cells would improve angiogenesis in neonatal rats with HILI. Objectives: To determine whether intra-tracheal (IT) administration of BM-derived c-kitpos cells attenuates neonatal HILI. Methods: Rat pups exposed to either normobaric normoxia (21%O2) or hyperoxia (90%O2) from postnatal day (P) 2 to P15 were randomly assigned to receive either IT BM-derived Green Fluorescent Protein (GFP) pos c-kitneg cells (PL) or BM-derived GFPpos c-kitpos cells on P8. The effect of cell therapy on lung angiogenesis, alveolarization, pulmonary hypertension, vascular remodeling, cell proliferation and apoptosis was determined at P15. Cell engraftment was determined by GFP immunostaining. Data are expressed as mean ± SD and analyzed by ANOVA. Measurements and Main Results: As compared to PL, the IT administration of BM-derived c-kitpos cells to neonatal rodents with HILI improved alveolarization as evidenced by increased lung septation and decreased mean linear intercept. This was accompanied by an increase in lung vascular density, a decrease in lung apoptosis, and an increase in the secretion of pro-angiogenic factors. There was no difference in pulmonary vascular remodeling or the degree of pulmonary hypertension. Confocal Microscopy demonstrated that 1% of total lung cells were GFPpos cells. Conclusion: IT administration of BM-derived c-kitpos cells improves lung alveolarization and angiogenesis in neonatal HILI and this may be secondary to an improvement in the lung angiogenic milieu. PMID:23759597

Ramachandran, Shalini; Suguihara, Cleide; Drummond, Shelley; Chatzistergos, Konstantinos; Klim, Jammie; Torres, Eneida; Huang, Jian; Hehre, Dorothy; Rodrigues, Claudia O; McNiece, Ian K; Hare, Joshua M; Young, Karen C



Inflammatory cytokines induce a unique mineralizing phenotype in mesenchymal stem cells derived from human bone marrow.  


Bone marrow contains mesenchymal stem cells (MSCs) that can differentiate along multiple mesenchymal lineages. In this capacity they are thought to be important in the intrinsic turnover and repair of connective tissues while also serving as a basis for tissue engineering and regenerative medicine. However, little is known of the biological responses of human MSCs to inflammatory conditions. When cultured with IL-1?, marrow-derived MSCs from 8 of 10 human subjects deposited copious hydroxyapatite, in which authenticity was confirmed by Fourier transform infrared spectroscopy. Transmission electron microscopy revealed the production of fine needles of hydroxyapatite in conjunction with matrix vesicles. Alkaline phosphatase activity did not increase in response to inflammatory mediators, but PPi production fell, reflecting lower ectonucleotide pyrophosphatase activity in cells and matrix vesicles. Because PPi is the major physiological inhibitor of mineralization, its decline generated permissive conditions for hydroxyapatite formation. This is in contrast to MSCs treated with dexamethasone, where PPi levels did not fall and mineralization was fuelled by a large and rapid increase in alkaline phosphatase activity. Bone sialoprotein was the only osteoblast marker strongly induced by IL-1?; thus these cells do not become osteoblasts despite depositing abundant mineral. RT-PCR did not detect transcripts indicative of alternative mesenchymal lineages, including chondrocytes, myoblasts, adipocytes, ligament, tendon, or vascular smooth muscle cells. IL-1? phosphorylated multiple MAPKs and activated nuclear factor-?B (NF-?B). Certain inhibitors of MAPK and PI3K, but not NF-?B, prevented mineralization. The findings are of importance to soft tissue mineralization, tissue engineering, and regenerative medicine. PMID:23970554

Ferreira, Elisabeth; Porter, Ryan M; Wehling, Nathalie; O'Sullivan, Regina P; Liu, Fangjun; Boskey, Adele; Estok, Daniel M; Harris, Mitchell B; Vrahas, Mark S; Evans, Christopher H; Wells, James W



Collagen/silk fibroin bi-template induced biomimetic bone-like substitutes.  


A novel bi-template induced co-assembly method was employed to fabricate biomimetic bone substitute materials, collagen (COL)-fibroin/hydroxyapatite (COL-SF/HA) composite by using a combination of Type I COL and silk fibroin (SF) molecular templates. As a control, COL/HA and SF/HA composites were also synthesized via single-template assembly technology. The structure and morphology of the resulting assembly composites were investigated by X-ray diffractometer, Fourier transform infrared spectra, transmission electron microscope, and thermogravimetric analysis. Their sizes and size distributions were measured by DLS. The results indicated that the mineral phases in COL-SF/HA, COL-HA, and SF-HA composites were needle-like nano-HA crystals. In comparison to those in COL-HA and SF-HA, the mineral phase in COL-SF/HA displayed smaller size and more narrow distribution. Of all above biomimetic composites, the HA was well assembled with molecular template(s), and the organic content of the composite was about 12%-20%, which was quite similar to the natural bone in composition. CD and SDS-PAGE were used to examine the secondary structure and subunit composition of template proteins. The results revealed that the spatial structure of co-assembly template proteins played a pivotal role in controlling and regulating HA crystal nucleation and growth. Based on the experimental results above, a possible co-assembly mechanism for the HA growing on fibrous bi-template proteins was suggested. PMID:19705470

Wang, Jianglin; Zhou, Wei; Hu, Wei; Zhou, Lei; Wang, Shenqi; Zhang, Shengmin



The effects of intranasal budesonide on allergen-induced production of interleukin-5 and eotaxin, airways, blood, and bone marrow eosinophilia, and eosinophil progenitor expansion in sensitized mice.  


We have previously demonstrated that allergen inhalation induces expansion of bone marrow eosinophil progenitors in sensitized mice and subjects with asthma and that the inhaled corticosteroid, budesonide, reduced baseline but not allergen-induced increase in bone marrow eosinophil/basophil progenitors (EoB-CFU) in subjects with asthma. Here, we evaluated the effects of intranasal budesonide on allergen-induced increases in interleukin (IL)-5 and eotaxin in the airway and peripheral blood, expansion of bone marrow Eo-CFU and eosinophilia in bone marrow, peripheral blood and airway, as well as airway hyperresponsiveness, in ovalbumin (OVA)-sensitized mice. Budesonide treatment attenuated allergen-induced eosinophilia in bone marrow, peripheral blood, and airways as well as allergen-induced increases in bone marrow eosinophil progenitors but not allergen-induced increases in IL-5 or eotaxin 12 h following the second of two daily exposures to allergen; at later time points treatment was associated with attenuation of IL-5, eosinophilia, Eo-CFU, and airway hyperresponsiveness. These results suggest that a component of the mechanism by which corticosteroid treatment attenuates allergen-induced airway inflammation is through suppression of bone marrow eosinophilopoiesis, and that this is likely not mediated simply through the blocking of IL-5 production at the airway. PMID:12119225

Shen, Huahao; O'Byrne, Paul M; Ellis, Russ; Wattie, Jennifer; Tang, Chibing; Inman, Mark D



Effect of dietary-induced metabolic acidosis and ovariectomy on bone mineral density and markers of bone turnover  

Microsoft Academic Search

Dietary-induced metabolic acidosis (DIMA) has been implicated as a significant confounder in the development of osteoporosis. Twenty-four mature ewes were randomly assigned to four groups of six sheep. Group 1 consumed a control diet (ND); group 2 consumed a normal diet (ND) and had ovariectomy (OVX), group 3 consumed a diet that induced metabolic acidosis (MA), without OVX, and group

Jennifer M. MacLeay; Jerry D. Olson; A. Simon Turner



Fluorine concentrations in bone biopsy samples determined by proton-induced gamma-ray emission and cyclic neutron activation.  


Fluorine concentrations in bone biopsy samples taken from the iliac crest of subjects, divided into four groups depending on the length of dialysis treatment, and aluminium levels in blood and bone pathology, in terms of osteoporosis, were determined by two instrumental methods. Proton-induced gamma-ray emission (PIGE), making use of the resonance reaction of 19F(p, alpha gamma)16O at 872 keV, and cyclic neutron activation analysis (CNAA), using the 19F(n, gamma)20F reaction in a reactor irradiation facility, were employed. Rutherford backscattering (RBS) was used to calculate the volume, and, hence, mass of the sample excited in PIGE by determining the major element composition of the samples in order to express results in terms of concentration. From this preliminary investigation, a relationship is suggested between fluorine concentrations in bone and aluminium levels in the system. PMID:1704715

Spyrou, N M; Altaf, W J; Gill, B S; Jeynes, C; Nicolaou, G; Pietra, R; Sabbioni, E; Surian, M


Metalloproteinases (MMPs -2, -3) are involved in TGF-beta and IGF-1-induced bone defect healing in 20-month-old female rats.  


Matrix metalloproteinases are important in the physiological and pathological degradation of extracellular matrix including that of bone and cartilage. The process of bone defect healing is associated with formation of cartilage callus and cancelous bone. With maturation and aging, the response of skeletal tissues to injury is limited. The ability of growth factors to enhance bone defect healing in aged rats was studied. Partial bone defects were induced in femurs of aged rats. A single dose of IGF-1, TGF-beta+IGF-1 or saline was inserted in the defect and bones were examined after 2 and 4 weeks. Morphology revealed that after 2 weeks of treatment with TGF-beta the defects were filled with mesenchyme-like tissue and delicate bone trabeculae. Positive staining for metalloproteinase-2 (MMP-2) was shown at the sites of new bone formation. In defects treated with IGF-1 or TGF-beta+IGF-1 nodules of cartilage and fine bone trabeculae along with positive staining for both MMP-2 and MMP-3 were demonstrated in the healing defects. After 4 weeks radiology revealed mineralization in defects treated with TGF-beta and less pronounced mineralization after treatment with IGF-1, or with TGF-beta+IGF-1, whereas only partial healing of the defects was observed in control specimens. MMP-2 and MMP-3 were detected at sites of new bone formation after treatment with TGF-beta, IGF-1, and TGF-beta+IGF-1. It is concluded that TGF-beta and IGF-1 induced bone defect healing in aged rats. TGF-beta induced bone formation while IGF-1 induced cartilage and than bone formation via endochondral ossification. The localization of MMP-2 and MMP-3 in the healing defects reflected the synthesis of bone or cartilage matrices in the defect, reflecting the involvement of MMPs in the process of bone formation and endochondral ossification. The ability to induce bone defect healing in aging is of great clinical importance and understanding the involvement of MMPs in this process can contribute to future treatment with growth factors to enhance bone defect healing in 20-month-old female rats. PMID:14764345

Blumenfeld, I; Srouji, S; Peled, M; Livne, E


Spinal interleukin-33 and its receptor ST2 contribute to bone cancer-induced pain in mice.  


Cancer pain, particularly bone cancer pain, affects the quality of life of cancer patients, and current treatments are limited. Interleukin (IL)-33, a new member of the IL-1 super family, has been reported to be involved in the modulation of inflammatory pain. However, studies focused on its role in the modulation of cancer pain have been rare. The present study was designed to investigate whether spinal IL-33/ST2 signaling was involved in bone cancer-induced pain in mice. Bone cancer was induced via intra-femoral inoculation of 4T1 mammary carcinoma cells. The mice inoculated with carcinoma cells showed mechanical allodynia, heat hyperalgesia and a reduction in limb use, whereas phosphate-buffered saline or heat-killed cells-injected mice showed no significant difference compared to non-treated mice. The pain hypersensitive behaviors worsened over time and with bone destruction. Both the mRNA and the protein levels of IL-33 and relative cytokines (IL-1?, IL-6, TNF-a) were significantly increased in the spinal cord after the inoculation of carcinoma cells. Intrathecal administration of ST2 antibody to block IL-33/ST2 signaling alleviated pain behaviors in a dose-dependent manner in bone cancer pain mice compared with vehicle-injected mice. Moreover, the ST2(-/-) mice showed a significant amelioration of limb use and heat hyperalgesia compared to wild-type mice. Meanwhile, concentrations of spinal IL-1?, IL-6 and TNF-a in the cancer-bearing ST2(-/-) mice had no significant changes. These data further suggested that IL-33/ST2 signaling played a vital role in cancer pain. Our results provided evidence that IL-33 and its receptor ST2 may be a potential therapeutic target for the treatment of pain in bone cancer patients. PMID:23988433

Zhao, J; Zhang, H; Liu, S-B; Han, P; Hu, S; Li, Q; Wang, Z-F; Mao-Ying, Q-L; Chen, H-M; Jiang, J-W; Wu, G-C; Mi, W-L; Wang, Y-Q



Selenium combined with vitamin E and vitamin C restores structural alterations of bones in heparin-induced osteoporosis.  


The aim of this study was to investigate the effect of heparin on osteoporosis initiation, and the effect of selenium plus vitamins E and C, and the sole combination of vitamins E and C on the progress of osteoporosis induced by heparin through histologic means. Adult female New Zealand white rabbits were divided into three experimental and three control groups. The experimental rabbits were injected with 1000 IU/kg/day heparin (Liquemine) for 4 weeks. These six groups were administered deionized water (CI and EI), 100 mg/kg/day L-ascorbic acid plus 100 mg/kg/day alpha-tocopherol acetate (CII and EII), and 0.05 mg/kg/day sodium selenite, plus these vitamins orally, with a gastric catheter (CIII and EIII), respectively. At the end of the experimental period, the femurs of the animals were collected and investigated under a light photomicroscope. Heparin caused important alterations in bone, such as an improper lamellar structure and a large uncalcified bone matrix. These findings implied the early phase of osteoporosis induced by heparin use. The combination of vitamins E and C given to the experimental rabbits partially prevented this bone tissue destruction. When sodium selenite was given together with vitamins E and C to the osteoporosis model rabbits, the long bone tissue had almost the same structure as in normal rabbits, for example the development of numerous bone trabeculae. Our results suggest that a combination of sodium selenite with vitamins E and C was more effective than combinations of single vitamins to prevent structural alterations in these model bones. PMID:14677021

Turan, Belma; Can, Belgin; Delilbasi, Ertan



Bone Turnover Markers Correlate with Implant fixation in a Rat Model Using LPS Doped Particles to Induced Implant Loosening1  

PubMed Central

Revision surgery for particle-induced implant loosening in total joint replacement is expected to increase dramatically over the next few decades. This study was designed to investigate if local tissue and serum markers of bone remodeling reflect implant fixation following administration of lipopolysaccharide (LPS)-doped polyethylene (PE) particles in a rat model. 24 rats received bilateral implantation of intramedullary titanium rods in the distal femur, followed by weekly bilateral intra-articular injection of either LPS-doped PE particles (n = 12) or vehicle which contained no particles (n= 12) for 12 weeks. The group in which the particles were injected had increased serum C-terminal telopeptide of type I collagen, decreased serum osteocalcin, increased peri-implant eroded surface, decreased peri-implant bone volume, and decreased mechanical pull-out strength compared to the controls. Implant fixation strength was positively correlated with peri-implant bone volume and serum osteocalcin and inversely correlated with serum C-terminal telopeptide of type I collagen, while energy to yield was positively correlated with serum osteocalcin and inversely correlated with the number of tartrate resistant acid phosphatase positive cells at the interface and the amount of peri-implant eroded surface. There was no effect on trabecular bone volume at a remote site. Thus, the particle-induced impaired fixation in this rat model was directly associated with local and serum markers of elevated bone resorption and depressed bone formation, supporting the rationale of exploring both anti-catabolic and anabolic strategies to treat and prevent particle-related implant osteolysis and loosening and indicating that serum markers may prove useful in tracking implant fixation.

Liu, Shuo; Virdi, Amarjit S.; Sena, Kotaro; Hughes, W. Frank; Sumner, Dale R.



[Secondary Osteoporosis or Secondary Contributors to Bone Loss in Fracture. Metabolic bone disease and fracture induced by drugs].  


Many medications can increase fracture risk. Osteoporosis is classified as either primary or secondary. Drug-induced osteoporosis is a type of secondary osteoporosis. Glucocorticoids are the most common cause of drug-induced osteoporosis. But other drugs can increase fracture risk, such as thyroxine overdose, gonadotropin-releasing hormone (GnRH) agonists, aromatase inhibitors, thiazolidines, proton pump inhibitors, loop diuretics, anticoagulant drugs, selective serotonin reuptake inhibitors (SSRI) , tricyclic antidepressants, anticonvulsant, and so on. This review will discuss clinical trials and the mechanisms underlying drug-induced fracture. PMID:23999367

Suzuki, Hisanori



A Promising Approach for Treatment of Tumor-Induced Bone Diseases: Utilizing Bisphosphonate Derivatives of Nucleoside Antimetabolites*  

PubMed Central

Despite palliative treatments, tumor-induced bone disease (TIBD) remains highly debilitating for many cancer patients and progression typically results in death within two years. Therefore, more effective therapies with enhanced antiresorptive and cytotoxic characteristics are needed. We developed bisphosphonate-chemotherapeutic conjugates designed to bind bone and hydrolyze, releasing both compounds, thereby targeting both osteoclasts and tumor cells. This study examined the effects of our lead compound, MBC-11 (the anhydride formed between arabinocytidine (AraC)-5’-phosphate and etidronate), on bone tumor burden, bone volume, femur bone mineral density (BMD), and overall survival using two distinct mouse models of TIBD, the 4T1/luc breast cancer and the KAS-6/1-MIP1? multiple myeloma models. In mice orthotopically inoculated with 4T1/luc mouse mammary cells, MBC-11 (0.04 µg/day; s.c.) reduced the incidence of bone metastases to 40% (4/10), compared to 90% (9/10; p=0.057) and 100% (5/5; p=0.04) of PBS- or similarly-dosed, zoledronate-treated mice, respectively. MBC-11 also significantly decreased bone tumor burden compared to PBS- or zoledronate-treated mice (p=0.021, p=0.017, respectively). MBC-11 and zoledronate (0.04 µg/day) significantly increased bone volume by two- and four-fold, respectively, compared to PBS-treated mice (p=0.005, p<0.001, respectively). In mice systemically injected with human multiple myeloma KAS-6/1-MIP1? cells, 0.04 and 4.0 µg/day MBC-11 improved femur BMD by 13% and 16%, respectively, compared to PBS (p=0.025, p=0.017, respectively) at 10 weeks post-tumor cell injection and increased mean survival to 95 days compared to 77 days in mice treated with PBS (p=0.047). Similar doses of zoledronate also improved femur BMD (p?0.01 vs PBS) and increased mean survival to 86 days, but this was not significantly different than in PBS-treated mice (p=0.53). These results demonstrate that MBC-11 decreases bone tumor burden, maintains bone structure, and may increase overall survival, warranting further investigation as a treatment for TIBD.

Reinholz, Monica M.; Zinnen, Shawn P.; Dueck, Amylou C.; Dingli, David; Reinholz, Gregory G.; Jonart, Leslie A.; Kitzmann, Kathleen A.; Bruzek, Amy K.; Negron, Vivian; Abdalla, Abdalla K.; Arendt, Bonnie K.; Croatt, Anthony J.; Sanchez-Perez, Luis; Sebesta, David P.; Lonnberg, Harri; Yoneda, Toshiyuki; Nath, Karl A.; Jelinek, Diane F.; Russell, Stephen J.; Ingle, James N.; Spelsberg, Thomas C.; (Hal) Dixon, Henry B.F.; Karpeisky, Alexander; Lingle, Wilma L.



Bone mineral measurement: Skylab experiment M-078.  


The observation that bone mineral is lost in patients who are either immobilized or remain in bed for extended periods of time formed the basis for the concern that large amounts of bone mineral may be lost during long periods of weightlessness. This concern was magnified when early X-ray densitometry studies suggested that rather large amounts of mineral could be lost during rather short periods of weightlessness (4-14 days). Even though these Gemini results have recently been modified, they still reflect substantial losses in the upper extremity. This led to a series of prolonged bed-rest studies (30-36 weeks) which, in addition to careful calcium balance, also employed a newer, more precise method of estimating bone mineral in the radius, ulna, and os calcis. It employed an essentially monoenergetic photon source (125I) and a scintillation detector operating in a rectilinear scanning mode to measure bone mineral by the absorptiometric technique. Bed-rest studies revealed variable mineral losses but suggested that little if any is lost during 4-6 weeks, with variable amounts being lost in 8 weeks. Losses up to 40% were noted in the os calcis after 9 months, with essentially none in the radius and ulna. When this technique was employed during the Apollo 14, 15, and 16 missions, only one crewman (CMP Apollo 15) showed significant losses in the os calcis and none in the radius or ulna. These results were, therefore, in concert with the bed-rest data but at variance with the earlier Gemini data. The variability observed during bed rest was reconciled when it was observed that the rate of loss could be correlated with the initial 24-hour urinary hydroxyproline excretion and the initial os calcis mineral content. Prediction terms were established. Measurements of the SL-II crew after 28 days of weightlessness revealed no significant bone mineral losses. The Skylab data lie within the predicted limits obtained from the bed-rest data. The relevance of the prediction terms to the Skylab and longer missions discussed. PMID:11841089

Vogel, J M


Bone grafts in dentistry  

PubMed Central

Bone grafts are used as a filler and scaffold to facilitate bone formation and promote wound healing. These grafts are bioresorbable and have no antigen-antibody reaction. These bone grafts act as a mineral reservoir which induces new bone formation.

Kumar, Prasanna; Vinitha, Belliappa; Fathima, Ghousia



RANKL inhibition combined with tamoxifen treatment increases anti-tumor efficacy and prevents tumor-induced bone destruction in an estrogen receptor-positive breast cancer bone metastasis model.  


Tumor cells in bone can induce the activation of osteoclasts, which mediate bone resorption and release of growth factors and calcium from the bone matrix, resulting in a cycle of tumor growth and bone breakdown. Targeting the bone microenvironment by the inhibition of RANKL, an essential mediator of osteoclast function, not only prevents tumor-induced osteolysis but also decreases skeletal tumor burden in preclinical models. The inhibition of skeletal tumor progression after the inhibition of osteoclasts is via interruption of the "vicious cycle" of tumor/bone interactions. The majority of breast cancer patients at risk for bone metastases harbor estrogen receptor-positive (ER+) tumors. We developed a mouse model for ER+ breast cancer bone metastasis and evaluated the effect of RANKL inhibition on tumor-induced osteolysis and skeletal tumor growth both alone and in combination with tamoxifen. Luciferase-labeled MCF-7 cells (MCF-7Luc) formed metastatic foci in the hind limbs following intracardiac injection and caused mixed osteolytic/osteoblastic lesions. RANKL inhibition by OPG-Fc treatment blocked osteoclast activity and prevented tumor-induced osteolysis, as well as caused a marked decrease in skeletal tumor burden. Tamoxifen as a single agent reduced MCF-7Luc tumor growth in the hind limbs. In a combination experiment, OPG-Fc plus tamoxifen resulted in significantly greater tumor growth inhibition than either single agent alone. Histologic analysis revealed a decrease in the proliferation of tumor cells by both single agents, which was enhanced in the combination treatment. Upon treatment with OPG-Fc alone or in combination with tamoxifen, there was a complete absence of osteolytic lesions, demonstrating the ability of RANKL inhibition to prevent skeletal related morbidity in an ER+ model. The combination approach of targeting osteoclasts and the bone microenvironment by RANKL inhibition and the tumor directly via hormonal therapy may provide additional benefit to reducing skeletal tumor progression in ER+ breast cancer patients. PMID:22926264

Canon, Jude; Bryant, Rebecca; Roudier, Martine; Branstetter, Daniel G; Dougall, William C



MyD88 is essential for alveolar bone loss induced by Aggregatibacter actinomycetemcomitans lipopolysaccharide in mice.  


Aggregatibacter actinomycetemcomitans is a Gram-negative bacteria highly associated with localized aggressive periodontitis. The recognition of microbial factors, such as lipopolysaccharide from A. actinomycetemcomitans (Aa LPS), in the oral environment is made mainly by surface receptors known as Toll-like receptors (TLR). TLR4 is the major LPS receptor. This interaction leads to the production of inflammatory cytokines by myeloid differentiation primary-response protein 88 (MyD88) -dependent and -independent pathways, which may involve the adaptor Toll/interleukin-1 receptor-domain-containing adaptor inducing interferon-? (TRIF). The aim of this study was to assess the involvement of MyD88 in alveolar bone loss induced by Aa LPS in mice. C57BL6/J wild-type (WT) mice, MyD88, TRIF or TRIF/MyD88 knockout mice received 10 injections of Aa LPS strain FDC Y4 (5 ?g in 3 ?l), in the palatal gingival tissue of the right first molar, every 48 h. Phosphate-buffered saline was injected in the opposite side and used as control. Animals were sacrificed 24 h after the 10th injection and the maxillae were removed for macroscopic and biochemical analyses. The injections of Aa LPS induced significant alveolar bone loss in WT mice. In the absence of MyD88 or TRIF/MyD88 no bone loss induced by Aa LPS was observed. In contrast, responses in TRIF(-/-) mice were similar to those in WT mice. Diminished bone loss in the absence of MyD88 was associated with fewer TRAP-positive cells and increased expression of osteoblast markers, RUNX2 and osteopontin. There was also reduced tumor necrosis factor-? production in MyD88(-/-) mice. There was less osteoclast differentiation of hematopoietic bone marrow cells from MyD88(-/-) mice after Aa LPS stimulation. Hence, the signaling through MyD88 is pivotal for Aa LPS-induced osteoclast formation and alveolar bone loss. PMID:23906379

Madeira, M F M; Queiroz-Junior, C M; Cisalpino, D; Werneck, S M C; Kikuchi, H; Fujise, O; Ryffel, B; Silva, T A; Teixeira, M M; Souza, D G



Effects of Doxycycline on Mechanical Properties of Bones in Rats with Ovariectomy-Induced Osteopenia  

Microsoft Academic Search

Tetracyclines have been reported to inhibit bone resorption and intensify bone formation. The aim of the present study was to investigate the effects of doxycycline (20 mg\\/kg PO daily for 28 days) on bone mechanical properties in bilaterally ovariectomized and sham-operated rats. The experiment was carried out on 3-month-old Wistar rats. Mechanical properties of the whole femur (extrinsic stiffness, ultimate and

M. Pytlik; J. Folwarczna; W. Janiec




Technology Transfer Automated Retrieval System (TEKTRAN)

Lactation-induced bone loss is promptly restored in the post-weaning period by a process of anabolic rebuilding, the endocrine and molecular basis of which still remains enigmatic. Ethanol (EtOH) consumption during this post-weaning period prevents the recovery of bone density and may be a significa...


Effects of Murine and Human Bone Marrow-Derived Mesenchymal Stem Cells on Cuprizone Induced Demyelination  

PubMed Central

For the treatment of patients with multiple sclerosis there are no regenerative approaches to enhance remyelination. Mesenchymal stem cells (MSC) have been proposed to exert such regenerative functions. Intravenous administration of human MSC reduced the clinical severity of experimental autoimmune encephalomyelitis (EAE), an animal model mimicking some aspects of multiple sclerosis. However, it is not clear if this effect was achieved by systemic immunomodulation or if there is an active neuroregeneration in the central nervous system (CNS). In order to investigate remyelination and regeneration in the CNS we analysed the effects of intravenously and intranasally applied murine and human bone marrow-derived MSC on cuprizone induced demyelination, a toxic animal model which allows analysis of remyelination without the influence of the peripheral immune system. In contrast to EAE no effects of MSC on de- and remyelination and glial cell reactions were found. In addition, neither murine nor human MSC entered the lesions in the CNS in this toxic model. In conclusion, MSC are not directed into CNS lesions in the cuprizone model where the blood-brain-barrier is intact and thus cannot provide support for regenerative processes.

Gudi, Viktoria; Hoffmann, Andrea; Salinas Tejedor, Laura; Janssen, Stefanie; Prajeeth, Chittappen Kandiyil; Baumgartner, Wolfgang; Kavelaars, Annemieke; Heijnen, Cobi J.; van Velthoven, Cindy; Hansmann, Florian; Skripuletz, Thomas; Stangel, Martin



Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone  

PubMed Central

Prostate cancer (CaP) forms osteoblastic skeletal metastases with an underlying osteoclastic component. However, the importance of osteoclastogenesis in the development of CaP skeletal lesions is unknown. In the present study, we demonstrate that CaP cells directly induce osteoclastogenesis from osteoclast precursors in the absence of underlying stroma in vitro. CaP cells produced a soluble form of receptor activator of NF-?B ligand (RANKL), which accounted for the CaP-mediated osteoclastogenesis. To evaluate for the importance of osteoclastogenesis on CaP tumor development in vivo, CaP cells were injected both intratibially and subcutaneously in the same mice, followed by administration of the decoy receptor for RANKL, osteoprotegerin (OPG). OPG completely prevented the establishment of mixed osteolytic/osteoblastic tibial tumors, as were observed in vehicle-treated animals, but it had no effect on subcutaneous tumor growth. Consistent with the role of osteoclasts in tumor development, osteoclast numbers were elevated at the bone/tumor interface in the vehicle-treated mice compared with the normal values in the OPG-treated mice. Furthermore, OPG had no effect on CaP cell viability, proliferation, or basal apoptotic rate in vitro. These results emphasize the important role that osteoclast activity plays in the establishment of CaP skeletal metastases, including those with an osteoblastic component.

Zhang, Jian; Dai, Jinlu; Qi, Yinghua; Lin, Din-Lii; Smith, Peter; Strayhorn, Chris; Mizokami, Atsushi; Fu, Zheng; Westman, John; Keller, Evan T.



High-impact loading training induces bone hyperresorption activity in young elite female gymnasts.  


The aim of this study was to investigate the effect of intensive exercise on bone turnover (as reflected by bone resorption) in young elite female gymnasts. Forty-five healthy girls including 24 gymnasts (11.9+/-2 yr) and 21 controls (12.3+/-1.4 yr) were studied. Body weight, height, bone age and body composition were measured. Bone mineral density (BMD) was assessed at the whole body, lumbar vertebrae, hip and radius by means of DXA. Volumetric density (BMAD) was calculated. Bone velocity (SOS) and attenuation (BUA) were measured by QUS at the calcaneus. Urinary androstenedione (delta4), dehydroepiandrosterone sulfate (DHEA-S), and CrossLaps (CTx) were measured. BMD and BMAD were significantly greater in the gymnasts at all sites except whole body. SOS was found significantly higher. Delta4 values were significantly lower in the gymnasts. The distribution of the subjects according to Tanner stages was not different between groups. CTx levels were significantly higher in the gymnasts (989.08+/-154.63 microg/mmol Cr.) vs controls (580.25+/-123.99 microg/mmol Cr., p=0.02). CTx values decreased from Tanner stage 1 to stage 4 in each group, the gymnasts' levels always being higher than those of the controls. In conclusion, gymnastics seems to stimulate bone resorption activity in highly-trained young females. The coexistence of bone hyperresorption and higher BMD in gymnasts suggests increased bone turnover resulting in increased bone density in these subjects. PMID:11220709

Jaffré, C; Courteix, D; Dine, G; Lac, G; Delamarche, P; Benhamou, L



Anti-leukemic therapies induce cytogenetic changes of human bone marrow-derived mesenchymal stem cells.  


Both bone marrow hematopoietic cells (BM-HCs) and mesenchymal stem cells (BM-MSCs) may have cytogenetic aberrations in leukemic patients, and anti-leukemic therapy may induce cytogenetic remission of BM-HCs. The impact of anti-leukemic therapy on BM-MSCs remains unknown. Cytogenetic studies of BM-MSCs from 15 leukemic patients with documented cytogenetic abnormalities of BM-HCs were investigated. To see the influence of anti-leukemic therapy on BM-MSCs, cytogenetic studies were carried out in seven of them after the completion of anti-leukemic therapy, including anthracycline/Ara-C-based chemotherapy in two patients, high-dose busulfan/cyclophosphamide-based allogeneic transplantation in two patients, and total body irradiation (TBI)-based allogeneic transplantation in three patients. To simulate the effect of TBI in vitro, three BM-MSCs from one leukemic patient and two normal adults were irradiated using the same dosage and dosing schedule of TBI and cytogenetics were re-examined after irradiation. At the diagnosis of leukemia, two BM-MSCs had cytogenetic aberration, which were completely different to their BM-HCs counterpart. After the completion of anti-leukemic therapy, cytogenetic aberration was no longer detectable in one patient. Unexpectedly, BM-MSCs from three patients receiving TBI-based allogeneic transplantation acquired new, clonal cytogenetic abnormalities after transplantation. Similarly, complex cytogenetic abnormalities were found in all the three BM-MSCs exposed to in vitro irradiation. In conclusion, anti-leukemic treatments induce not only "cytogenetic remission" but also new cytogenetic abnormalities of BM-MSCs. TBI especially exerts detrimental effect on the chromosomal integrity of BM-MSCs and highlights the equal importance of investigating long-term adverse effect of anti-leukemic therapy on BM-MSCs as opposed to beneficial effect on BM-HCs. PMID:21573981

Yeh, Su-Peng; Lo, Wen-Jyi; Lin, Chiao-Lin; Liao, Yu-Min; Lin, Chen-Yuan; Bai, Li-Yuan; Liang, Ji-An; Chiu, Chang-Fang



Inhibition of megakaryocyte development in the bone marrow underlies dengue virus-induced thrombocytopenia in humanized mice.  


A characteristic clinical feature of dengue virus infection is thrombocytopenia, though its underlying mechanism is not definitively determined. By adoptive transfer of human CD34(+) fetal liver cells into immunodeficient mice, we have constructed humanized mice with significant levels of human platelets, monocytes/macrophages, and hepatocytes. Infection of these mice with both lab-adapted and clinical strains of dengue virus induces characteristic human hematological changes, including transient leukopenia and thrombocytopenia. We show that the specific depletion of human platelets is not mediated by antibodies in the periphery or reduced production of human thrombopoietin in the liver but reduction of human megakaryocytes and megakaryocyte progenitors in the bone marrow of the infected mice. These findings identify inhibition of platelet production in the bone marrow as a key mechanism underlying dengue-induced thrombocytopenia and suggest the utility of the improved humanized mouse model in studying dengue virus infection and pathogenesis in a human cell context. PMID:23966397

Sridharan, Aishwarya; Chen, Qingfeng; Tang, Kin Fai; Ooi, Eng Eong; Hibberd, Martin L; Chen, Jianzhu



197. Do Bone Marrow-Derived Progenitor Cells Contribute to VEGF-Induced PostNatal Neovascularization?  

Microsoft Academic Search

Bone marrow-derived cells have been recently proposed to participate in the development of new blood vessels during physiological and pathological angiogenesis in adult organisms.AAV-mediated expression of human vascular endothelial growth factor (VEGF165) in normoperfused skeletal muscle of mice is able to induce a significant increase in capillary density and in the formation of a-SMA-positive arteriolae (Arsic, N, et al. 2003.

Lorena Zentilin; Sabrina Tafuro; Nikola Arsic; Serena Zacchigna; Milena Sinigaglia; Sara Tomasi; Lucia Pattarini; Marina Dapas; Mauro Giacca



Increased cathepsin K and tartrate-resistant acid phosphatase expression in bone of streptozotocin-induced diabetic rats  

Microsoft Academic Search

The effect of insulin-dependent diabetes mellitus (IDDM) on bone metabolism was evaluated using the streptozotocin (STZ)-induced diabetic rat 1 week after the induction of diabetes. The urinary excretion of cross-linked N-telopeptides of type I collagen (NTx) and deoxypyridinoline (Dpd) in diabetic rats increased to 3.6-fold and 1.2-fold the control level, respectively. The amount of hydroxyproline and calcium in the distal femur

Mamiko Hie; Masumi Shimono; Kayoko Fujii; Ikuyo Tsukamoto



Characterization of brain and bone-metastasizing clones selected from an ethylnitrosourea-induced rat mammary carcinoma  

Microsoft Academic Search

An animal model for breast cancer, brain and bone metastasis was developed using ENU1564, a cell line established from a metastatic mammary adenocarcinoma induced by N-ethyl-N-nitrosourea in a female Berlin-Druckrey IV rat. The original tumor isolate (designated FP1) spontaneously metastasizes to regional lymph nodes and lung following orthotopic inoculation into mammary fat pad (mfp) and metastasizes widely following left cardiac

D. Greg Hall; G. Stoica



BCR Ligation Induces Receptor Editing in IgM +IgD ? Bone Marrow B Cells In Vitro  

Microsoft Academic Search

The ability of BCR cross-linking to stimulate receptor editing was analyzed in vitro using bone marrow B cells from immunoglobulin (Ig) transgenic (Tg) and non-Tg mice. In cultured Ig-Tg cells, BCR ligation induced receptor editing as measured by up-regulation of RAG gene expression, light chain gene DNA rearrangements, and expression of ?-light chain protein in cells that previously expressed ?.

Marc Hertz; David Nemazee



Hepatocyte Growth Factor Induces Differentiation of Adult Rat Bone Marrow Cells into a Hepatocyte Lineage in Vitro  

Microsoft Academic Search

Bone marrow (BM) cells originally include alpha-fetoprotein (AFP)- and c-Met [a receptor for hepatocyte growth factor (HGF)]-expressing cells. In vitro treatment of BM cells with HGF induced albumin-expressing hepatocyte-like cells. Furthermore, those hepatocyte-like cells expressed cytokeratins 8 and 18, which are typically expressed in normal adult hepatocytes. These findings demonstrate that BM cells include AFP-expressing hepatic progenitor cells that can

Seh-Hoon Oh; Masahiro Miyazaki; Hirosuke Kouchi; Yusuke Inoue; Masakiyo Sakaguchi; Toshiya Tsuji; Nobuyuki Shima; Kanji Higashio; Masayoshi Namba



Bone tissue formation in sheep muscles induced by a biphasic calcium phosphate ceramic and fibrin glue composite  

Microsoft Academic Search

Some biomaterials are able to induce ectopic bone formation in muscles of large animals. The osteoinductive potential of macro-\\u000a micro-porous biphasic calcium phosphate (MBCP) ceramic granules with fibrin glue was evaluated by intramuscular implantation\\u000a for 6 months in six adult female sheep. The MBCP granules were 1–2 mm in size and were composed of hydroxyapatite (HA) and\\u000a beta-tricalcium phosphate (?-TCP) in a

Damien Le Nihouannen; Afchine Saffarzadeh; Olivier Gauthier; Françoise Moreau; Paul Pilet; Reiner Spaethe; Pierre Layrolle; Guy Daculsi



Transcriptional program of bone morphogenetic protein-2-induced epithelial and smooth muscle differentiation of pluripotent human embryonal carcinoma cells  

Microsoft Academic Search

Pluripotent human embryonal carcinoma NTera2\\/cloneD1 (NT2\\/D1) cells respond to multiple vertebrate patterning factors and offer a unique model system to investigate the signaling events associated with lineage determination and cell differentiation. Here, we define the temporal changes in global gene expression patterns in NT2\\/D1 cells upon treatment with bone morphogenetic protein-2 (BMP-2). Exposure to BMP-2 rapidly induced the expression of

Rajendrakumar S. V. Chadalavada; Jane Houldsworth; Adam B. Olshen; George J. Bosl; Lorenz Studer; R. S. K. Chaganti



353. Retrovirally-Marked Human Bone Marrow Derived Mesenchymal Stem Cells Attenuate Radiation Induced Pneumonitis in a Xenotransplant Model  

Microsoft Academic Search

Thoracic radiation is used to treat patients with malignancies to improve survival and decrease symptoms. Radiation induced lung toxicity limits thoracic radiation doses and volumes and can restrict therapeutic use of radiation. Clinical radiation pneumonitis can be life-threatening, despite aggressive steroid treatment, especially in those patients with pre-existing pulmonary disease.We hypothesize that bone marrow derived mesenchymal stem cells (BMSC) assist

Andrew Hope; Todd E. Meyerrose; Jan A. Nolta



Canine bone marrow cells differentiate into hepatocyte-like cells and placental hydrolysate is a potential inducer  

Microsoft Academic Search

Hepatocyte growth factor (HGF) can stimulate human and rat bone marrow (BM) cells to differentiate into hepatocytes. A human placental hydrolysate (hPH) stimulates proliferation of hepatocytes, but its role as a potential inducer of BM cells to form hepatocytes is unclear. To determine if canine BM cells stimulated with HGF or hPH differentiate into hepatocyte-like cells, BM cells were cultured

Sakurako Neo; Takefumi Ishikawa; Kikumi Ogiwara; Norio Kansaku; Miyuki Nakamura; Masashi Watanabe; Masaharu Hisasue; Ryo Tsuchiya; Takatsugu Yamada



The Effects of Vanadium (V) Absorbed by Coprinus comatus on Bone in Streptozotocin-induced Diabetic Rats  

Microsoft Academic Search

The purpose of this study was to evaluate the effects of vanadium absorbed by Coprinus comatus (VACC) treatment on bone in streptozotocin (STZ)-induced diabetic rats. Forty-five Wistar female rats used were divided into\\u000a three groups: (1) normal rats (control), (2) diabetic rats, and (3) diabetic rats treated with VACC. Normal and diabetic rats\\u000a were given physiological saline, and VACC-treated rats

Yi Pei; Qin Fu


Protective effect of zinc supplementation against cadmium-induced oxidative stress and the RANK/RANKL/OPG system imbalance in the bone tissue of rats.  


It was investigated whether protective influence of zinc (Zn) against cadmium (Cd)-induced disorders in bone metabolism may be related to its antioxidative properties and impact on the receptor activator of nuclear factor (NF)-?? (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system. Numerous indices of oxidative/antioxidative status, and Cd and Zn were determined in the distal femur of the rats administered Zn (30 and 60mg/l) or/and Cd (5 and 50mg/l) for 6months. Soluble RANKL (sRANKL) and OPG were measured in the bone and serum. Zn supplementation importantly protected from Cd-induced oxidative stress preventing protein, DNA, and lipid oxidation in the bone. Moreover, Zn protected from the Cd-induced increase in sRANKL concentration and the sRANKL/OPG ratio, and decrease in OPG concentration in the bone and serum. Numerous correlations were noted between indices of the oxidative/antioxidative bone status, concentrations of sRANKL and OPG in the bone and serum, as well as the bone concentrations of Zn and Cd, and previously reported by us in these animals (Brzóska et al., 2007) indices of bone turnover and bone mineral density. The results allow us to conclude that the ability of Zn to prevent from oxidative stress and the RANK/RANKL/OPG system imbalance may be implicated in the mechanisms of its protective impact against Cd-induced bone damage. This paper is the first report from an in vivo study providing evidence that beneficial Zn impact on the skeleton under exposure to Cd is related to the improvement of the bone tissue oxidative/antioxidative status and mediating the RANK/RANKL/OPG system. PMID:23726800

Brzóska, Malgorzata M; Rogalska, Joanna



Mechanisms Inducing Low Bone Density in Duchenne Muscular Dystrophy in Mice and Humans  

PubMed Central

Patients affected by Duchenne muscular dystrophy (DMD) and dystrophic MDX mice were investigated in this study for their bone phenotype and systemic regulators of bone turnover. Micro–computed tomographic (µCT) and histomorphometric analyses showed reduced bone mass and higher osteoclast and bone resorption parameters in MDX mice compared with wild-type mice, whereas osteoblast parameters and mineral apposition rate were lower. In a panel of circulating pro-osteoclastogenic cytokines evaluated in the MDX sera, interleukin 6 (IL-6) was increased compared with wild-type mice. Likewise, DMD patients showed low bone mineral density (BMD) Z-scores and high bone-resorption marker and serum IL-6. Human primary osteoblasts from healthy donors incubated with 10% sera from DMD patients showed decreased nodule mineralization. Many osteogenic genes were downregulated in these cultures, including osterix and osteocalcin, by a mechanism blunted by an IL-6-neutralizing antibody. In contrast, the mRNAs of osteoclastogenic cytokines IL6, IL11, inhibin-?A, and TGF?2 were increased, although only IL-6 was found to be high in the circulation. Consistently, enhancement of osteoclastogenesis was noted in cultures of circulating mononuclear precursors from DMD patients or from healthy donors cultured in the presence of DMD sera or IL-6. Circulating IL-6 also played a dominant role in osteoclast formation because ex vivo wild-type calvarial bones cultured with 10% sera of MDX mice showed increase osteoclast and bone-resorption parameters that were dampen by treatment with an IL-6 antibody. These results point to IL-6 as an important mediator of bone loss in DMD and suggest that targeted anti-IL-6 therapy may have a positive impact on the bone phenotype in these patients. © 2011 American Society for Bone and Mineral Research

Rufo, Anna; Del Fattore, Andrea; Capulli, Mattia; Carvello, Francesco; De Pasquale, Loredana; Ferrari, Serge; Pierroz, Dominique; Morandi, Lucia; De Simone, Michele; Rucci, Nadia; Bertini, Enrico; Bianchi, Maria Luisa; De Benedetti, Fabrizio; Teti, Anna



A bisphosphonate that does not affect osteoclasts prevents osteoblast and osteocyte apoptosis and the loss of bone strength induced by glucocorticoids in mice  

PubMed Central

Although a major effect of bisphosphonates on bone is inhibition of resorption resulting from their ability to interfere with osteoclast function, these agents also prevent osteoblast and osteocyte apoptosis in vitro and in vivo. However, the contribution of the latter property to the overall beneficial effects of the drugs on bone remains unknown. We compared herein the action on glucocorticoid-induced bone disease of the classical bisphosphonate alendronate with that of IG9402, a bisphosphonate analog that preserves osteoblast and osteocyte viability but does not induce osteoclast apoptosis in vitro. The bisphosphonates were injected daily (2.3 ?mol/kg) to 5-month-old Swiss Webster mice (6–11 per group), starting three days prior to implantation of pellets releasing the glucocorticoid prednisolone (2.1 mg/kg/d). IG9402 did not affect levels of circulating C-telopeptide or osteocalcin, markers of resorption and formation, respectively, nor did it decrease mRNA levels of osteocalcin or collagen1A1 in bone. On the other hand, alendronate decreased all these parameters. Moreover, IG9402 did not reduce cancellous mineralizing surface, mineral apposition rate or bone formation rate, whereas alendronate induced a decrease in each of these bone formation measures. These findings demonstrate that in contrast to alendronate, IG9402 does not inhibit bone turnover. Both alendronate and IG9402, on the other hand, activated survival kinase signaling in vivo, as evidenced by induction of ERK phosphorylation in bone. Furthermore, both bisphosphonates prevented the increase in osteoblast and osteocyte apoptosis as well as the decrease in vertebral bone mass and strength induced by glucocorticoids. We conclude that a bisphosphonate that does not affect osteoclasts prevents osteoblast and osteocyte apoptosis and the loss of bone strength induced by glucocorticoids in mice.

Plotkin, L.I.; Bivi, Nicoletta; Bellido, T.



BMP7 Induces Dormancy of Prostatic Tumor Stem Cell in Bone.  

National Technical Information Service (NTIS)

Bone is the most common metastatic site for prostate cancer. The growth of the tumor cells in the bone is generally slow and they often become dormant until an appropriate microenviroment is established for their re- growth. The recent stem cell theory pr...

A. Kobayashi



Monitoring natural frequency for osseointegration and bone remodeling induced by dental implants  

Microsoft Academic Search

Dental implantation to a certain extent changes the biomechanical environment, thereby leading to the surrounding supporting bone to remodel. Computational remodeling has been well established in lone bone community and a range of mathematical formulae have been available with acceptable accuracy and effectiveness. However, there has been limited information and remodeling data available for dental scenarios, despite its predominate importance

Wei Li; Daniel Lin; Qing Li; Michael Swain



Tumor-induced injury of primary afferent sensory nerve fibers in bone cancer pain  

Microsoft Academic Search

Bone is the most common site of chronic pain in patients with metastatic cancer. What remains unclear are the mechanisms that generate this pain and why bone cancer pain can be so severe and refractory to treatment with opioids. Here we show that following injection and confinement of NCTC 2472 osteolytic tumor cells within the mouse femur, tumor cells sensitize

Christopher M. Peters; Joseph R. Ghilardi; Cathy P. Keyser; Kazufumi Kubota; Theodore H. Lindsay; Nancy M. Luger; David B. Mach; Matthew J. Schwei; Molly A. Sevcik; Patrick W. Mantyh



Leptin administration does not prevent the bone mineral metabolism changes induced by weight loss.  


The objective was to examine the effects of weight loss and leptin administration following weight loss on calciotropic hormones and bone turnover. This was a prospective, single-blinded study of 12 subjects (8 women, 4 men; 2 nonobese, 10 obese; age range, 19-46 years) who were studied on an inpatient basis while maintaining their usual weight [Wt(initial)] and during maintenance of 10% weight loss while receiving twice-daily injections of either a placebo [Wt(-10%P)] or replacement doses of leptin [Wt(-10%L)]. The main outcome measures were markers of bone formation (bone alkaline phosphatase and procollagen type 1 amino terminal propeptide) and resorption (N-telopeptide) as well as parathyroid hormone, calcium, and 25-hydroxy vitamin D measured from fasting morning serum. As expected, serum leptin declined with weight loss. Bone alkaline phosphatase decreased by 12.3% ± 3.9% between Wt(initial) and Wt(-10%P) and remained suppressed after leptin administration (both P < .01 compared with baseline). N-telopeptides increased by 37.2% ± 11.3% from Wt(initial) to Wt(-10%L) (P < .01). Procollagen type 1 amino terminal propeptide, parathyroid hormone, calcium, and 25-hydroxy vitamin D did not change. These results suggest that both decreased bone formation and increased bone resorption underlie bone loss associated with weight loss. Leptin administration did not prevent the uncoupling of bone remodeling that accompanies weight loss. PMID:21489573

Conroy, Rushika; Girotra, Monica; Shane, Elizabeth; McMahon, Donald J; Pavlovich, Katherine H; Leibel, Rudolph L; Rosenbaum, Michael; Korner, Judith



A superior semicircular canal dehiscence-induced air-bone gap in chinchilla.  


An SCD is a pathologic hole (or dehiscence) in the bone separating the superior semicircular canal from the cranial cavity that has been associated with a conductive hearing loss in patients with SCD syndrome. The conductive loss is defined by an audiometrically determined air-bone gap that results from the combination of a decrease in sensitivity to air-conducted sound and an increase in sensitivity to bone-conducted sound. Our goal is to demonstrate, through physiological measurements in an animal model, that mechanically altering the superior semicircular canal (SC) by introducing a hole (dehiscence) is sufficient to cause such an air-bone gap. We surgically introduced holes into the SC of chinchilla ears and evaluated auditory sensitivity (cochlear potential) in response to both air- and bone-conducted stimuli. The introduction of the SC hole led to a low-frequency (<2000 Hz) decrease in sensitivity to air-conducted stimuli and a low-frequency (<1000 Hz) increase in sensitivity to bone-conducted stimuli resulting in an air-bone gap. This result was consistent and reversible. The air-bone gaps in the animal results are qualitatively consistent with findings in patients with SCD syndrome. PMID:20638462

Songer, Jocelyn E; Rosowski, John J



Targeted Disruption of the Wnt Regulator Kremen Induces Limb Defects and High Bone Density? †  

PubMed Central

Kremen1 and Kremen2 (Krm1 and Krm2) are transmembrane coreceptors for Dickkopf1 (Dkk1), an antagonist of Wnt/?-catenin signaling. The physiological relevance of Kremen proteins in mammals as Wnt modulators is unresolved. We generated and characterized Krm mutant mice and found that double mutants show enhanced Wnt signaling accompanied by ectopic postaxial forelimb digits and expanded apical ectodermal ridges. Triple mutant Krm1?/? Krm2?/? Dkk1+/? mice show enhanced growth of ectopic digits, indicating that Dkk1 and Krm genes genetically interact during limb development. Wnt/?-catenin signaling also plays a critical role in bone formation. Single Krm mutants show normal bone formation and bone mass, while double mutants show increased bone volume and bone formation parameters. Our study provides the first genetic evidence for a functional interaction of Kremen proteins with Dkk1 as negative regulators of Wnt/?-catenin signaling and reveals that Kremen proteins are not universally required for Dkk1 function.

Ellwanger, Kristina; Saito, Hiroaki; Clement-Lacroix, Philippe; Maltry, Nicole; Niedermeyer, Joachim; Lee, Woon Kyu; Baron, Roland; Rawadi, Georges; Westphal, Heiner; Niehrs, Christof



A New Piezoelectric Actuator Induces Bone Formation In Vivo: A Preliminary Study  

PubMed Central

This in vivo study presents the preliminary results of the use of a novel piezoelectric actuator for orthopedic application. The innovative use of the converse piezoelectric effect to mechanically stimulate bone was achieved with polyvinylidene fluoride actuators implanted in osteotomy cuts in sheep femur and tibia. The biological response around the osteotomies was assessed through histology and histomorphometry in nondecalcified sections and histochemistry and immunohistochemistry in decalcified sections, namely, through Masson's trichrome, and labeling of osteopontin, proliferating cell nuclear antigen, and tartrate-resistant acid phosphatase. After one-month implantation, total bone area and new bone area were significantly higher around actuators when compared to static controls. Bone deposition rate was also significantly higher in the mechanically stimulated areas. In these areas, osteopontin increased expression was observed. The present in vivo study suggests that piezoelectric materials and the converse piezoelectric effect may be used to effectively stimulate bone growth.

Reis, Joana; Frias, Clara; Canto e Castro, Carlos; Botelho, Maria Luisa; Marques, Antonio Torres; Simoes, Jose Antonio Oliveira; Capela e Silva, Fernando; Potes, Jose



Vitamin D deficiency induces early signs of aging in human bone, increasing the risk of fracture.  


Vitamin D deficiency is a widespread medical condition that plays a major role in human bone health. Fracture susceptibility in the context of low vitamin D has been primarily associated with defective mineralization of collagenous matrix (osteoid). However, bone's fracture resistance is due to toughening mechanisms at various hierarchical levels ranging from the nano- to the microstructure. Thus, we hypothesize that the increase in fracture risk with vitamin D deficiency may be triggered by numerous pathological changes and may not solely derive from the absence of mineralized bone. We found that the characteristic increase in osteoid-covered surfaces in vitamin D-deficient bone hampers remodeling of the remaining mineralized bone tissue. Using spatially resolved synchrotron bone mineral density distribution analyses and spectroscopic techniques, we observed that the bone tissue within the osteoid frame has a higher mineral content with mature collagen and mineral constituents, which are characteristic of aged tissue. In situ fracture mechanics measurements and synchrotron radiation micro-computed tomography of the crack path indicated that vitamin D deficiency increases both the initiation and propagation of cracks by 22 to 31%. Thus, vitamin D deficiency is not simply associated with diminished bone mass. Our analyses reveal the aged nature of the remaining mineralized bone and its greatly decreased fracture resistance. Through a combination of characterization techniques spanning multiple size scales, our study expands the current clinical understanding of the pathophysiology of vitamin D deficiency and helps explain why well-balanced vitamin D levels are essential to maintain bone's structural integrity. PMID:23843449

Busse, Björn; Bale, Hrishikesh A; Zimmermann, Elizabeth A; Panganiban, Brian; Barth, Holly D; Carriero, Alessandra; Vettorazzi, Eik; Zustin, Josef; Hahn, Michael; Ager, Joel W; Püschel, Klaus; Amling, Michael; Ritchie, Robert O



Influence of standing surface waves on thermocapillary convection stability and crystal growth in weightlessness  

NASA Astrophysics Data System (ADS)

Numerical investigation of thermocapillary flows and crystal growth by the floating zone method had been carried out in the case what free fluid surface oscillates in the form of standing wave by vibration. Two sorts of standing waves were considered. First, it is inertia-capillary standing waves due to vibration motion of fluid column as unit. These waves had been discovered under numerical investigation of problem /1/. Analytical model and the characteristic properties of these waves are described in /2/. Secondly, usual capillary waves generated by vibration of growing crystal were also considered. The effects of these surface waves on fluid flow and heat and mass transfer in process of crystal growth had been investigated over the wide ranges of dimensionless parameters for the Prandtl number is less than 1. The Marangoni number was varied from 140 to 2500, the range of cyclic frequency was between 200 and 76000. Transition from laminar thermocapillary convection to regime of flow with high oscillations (turbulent convection) happens very sharply when dimensionless amplitude (scale for linear dimensions is radius of fluid column) of standing wave reached 0.01112/n, where n is number of standing wave periods are along the length of fluid zone. If configuration of standing wave correlates with thermocapillary flow pattern two specific regimes of flow had been discovered. Flow with small oscillations is located in the range of standing wave amplitude between 0.0028 and 0.00418. In this area, radial macrosegregation of dopant is lowered by the factor of 3-6 depending on the Marangoni number. Next is an area with practically stable flow, in particular is identical to laminar flow without vibration. This area ends very sharply in the boundary of turbulent flow. All the mentioned boundaries are independent of the Marangoni number and frequency of oscillation of standing wave. For oscillatory thermocapillary convection (the Marangoni number is more than 2000), amplitude of oscillations for all parameters, including radial macrosegregation, can be reduced by the factor 5 under optimal choosing of vibration parameters. Thus, the study of surface standing waves shown that it is a possibility to reduce both macrosegregation and microsegregation of dopant under crystal growth by the floating zone method in microgravity. The use of magnetic field for elimination of residual oscillations generated by vibration is discussed. It was shown that inertia-capillary waves could be used for measurement of total vibration existing on ISS. The program of experiments for study of surface standing and crystal growth by the floating zone method aboard ISS is suggested. The experiment with inertia-capillary waves had been included in program of scientific investigation on Russian segment of ISS in 1998 but not realized until now. References 1. Feonychev A.I., Kalachinskaya I.S. and Pokhilko V.I. NASA Conference Publication 3338. 1996, pp. 493-498. 2. Feonychev A.I. Inertia-capillary surface waves and their effect on crystal growth in weightlessness (in press, in Russia).

Feonychev, A. I.


Bipedal stance exercise and prostaglandin E2 (PGE 2) and its synergistic effect in increasing bone mass and in lowering the PGE 2 dose required to prevent ovariectomized-induced cancellous bone loss in aged rats  

Microsoft Academic Search

Previous reports have shown that bone loss was partially prevented by bipedal stance “exercise” following ovariectomy (ovx), and it was well documented that prostaglandin E2 (PGE2) had an anabolic effect on the rat skeleton. The aim of this study was to determine whether lower doses of PGE2 could prevent ovx-induced cancellous bone loss with the combination of bipedal stance exercise.

A Mo; W Yao; C Li; X Tian; M Su; Y Ling; Q Zhang; R. B Setterberg; W. S. S Jee



Progression of Cartilage Degradation, Bone Resorption and Pain in Rat Temporomandibular Joint Osteoarthritis Induced by Injection of Iodoacetate  

PubMed Central

Background Osteoarthritis (OA) is an important subtype of temporomandibular disorders. A simple and reproducible animal model that mimics the histopathologic changes, both in the cartilage and subchondral bone, and clinical symptoms of temporomandibular joint osteoarthritis (TMJOA) would help in our understanding of its process and underlying mechanism. Objective To explore whether injection of monosodium iodoacetate (MIA) into the upper compartment of rat TMJ could induce OA-like lesions. Methods Female rats were injected with varied doses of MIA into the upper compartment and observed for up to 12 weeks. Histologic, radiographic, behavioral, and molecular changes in the TMJ were evaluated by light and electron microscopy, MicroCT scanning, head withdrawal threshold test, real-time PCR, immunohistochemistry, and TUNEL assay. Results The intermediate zone of the disc loosened by 1 day post-MIA injection and thinned thereafter. Injection of an MIA dose of 0.5 mg or higher induced typical OA-like lesions in the TMJ within 4 weeks. Condylar destruction presented in a time-dependent manner, including chondrocyte apoptosis in the early stages, subsequent cartilage matrix disorganization and subchondral bone erosion, fibrosis, subchondral bone sclerosis, and osteophyte formation in the late stages. Nociceptive responses increased in the early stages, corresponding to severe synovitis. Furthermore, chondrocyte apoptosis and an imbalance between anabolism and catabolism of cartilage and subchondral bone might account for the condylar destruction. Conclusions Multi-level data demonstrated a reliable and convenient rat model of TMJOA could be induced by MIA injection into the upper compartment. The model might facilitate TMJOA related researches.

Wang, Xue-Dong; Kou, Xiao-Xing; He, Dan-Qing; Zeng, Min-Min; Meng, Zhen; Bi, Rui-Yun; Liu, Yan; Zhang, Jie-Ni; Gan, Ye-Hua; Zhou, Yan-Heng



Immunization against strontium-90 induction of bone tumors with inactivated FBJ virus and irradiated syngeneic strontium-90-induced tumor cells  

SciTech Connect

Three hundred six C57BL/6J female mice were subdivided into a control group left untreated and an experimental group treated intraperitoneally with 1.0 strontium-90/g of body weight at an age of 66 days. Treatments for the groups were as follows: none, 6 injections of formalin-inactivated FBJ viral preparation, 6 injections of active FBJ viral preparation, and 2 injections of 10,000 rad irradiated transplantable osteosarcoma previously induced in C57BL/6J mice by strontium-90. In addition to the above groups, two other groups were treated with respectively 0.032 and 0.10 strontium-90/g body weight in order to obtain information on the dose-response relationship between the injection of strontium-90 and the yield of bone tumors. In the groups not treated with strontium-90, only 1 bone tumor developed; this occurred in the group injected with FBJ virus. The incidence of bone tumors in the groups treated with 1.0 strontium-90 was significantly lower (18.5% or 18.2%) in the two groups that had received injections of inactivated FBJ virus or irradiated isogenic osteosarcoma when compared to the group left uninjected, which developed 43.5% tumors. In contrast, the strontium-90-treated group that also received injections of active FBJ virus developed 63.0% tumors. Only a single bone tumor developed in the groups treated solely with intermediate doses of strontium-90. The results indicate that immunization with inactivated FBJ virus or with irradiated syngeneic strontium-90-induced tumor cells can significantly decrease the development of strontium-90-induced tumors.

Reif, A.E.; Triest, W.E.



Herba epimedii flavonoids suppress osteoclastic differentiation and bone resorption by inducing G2/M arrest and apoptosis.  


Accumulating evidences suggest that Herba epimedii has the potential benefits against osteoporosis. However, previous studies were focused on the crude extract, total flavonoids (TF) and icariin (ICA), and the detailed molecular mechanisms of action and structure-activity relationship (SAR) remain unclear. Herein we aimed to systematically investigate the effects of Herba epimedii flavonoids (HEF) on the activity of osteoclasts, and explore the potential SAR. Both ICA and baohuoside-1 (BS) significantly inhibited the proliferation of RAW 264.7 cells (IC(50) 25 ?M and 67 ?M, respectively). Treatment of ICA resulted in G2/M arrest and apoptosis in RAW 264.7 cells as early as 12 h. Besides, HEF remarkably suppressed vitamin D-induced differentiation of osteoclasts in rabbit bone marrow cells and the bone resorption of rabbit mature osteoclasts in vitro. It is notable that the inhibitory effect of 100 ?M ICA and BS on osteoclast formation is almost 90%; and the inhibition rate on bone resorption is 50% and 80%, respectively. Besides, RANKL-induced osteoclast formation from RAW 264.7 cells and the expression of TRAP, CA II, CTSK and MMP-9 was significantly reduced by the treatment of 25 ?M HEF and 17?-estradiol (ES), and the inhibitory strength increases in the order TF < ES < ICA < BS, which was blocked by ICI182780 suggesting that the regulation of osteoclast activity might be ER dependent. Furthermore, the free hydroxyl group at C-7 of BS played an important role in the SAR for anti-osteoclast action. To conclude, HEF could regulate the formation and activity of osteoclasts by inhibiting the proliferation and differentiation, inducing apoptosis and cell cycle arrest and suppressing bone resorption of osteoclasts. Changes in osteoclast activity are probably mediated predominantly by interaction with nuclear estrogen receptors and via mitochondrial pathway. HEF, especially BS, has great potential for the prevention and treatment of osteoporosis. PMID:22796380

Zhang, Dawei; Zhang, Jinchao; Fong, Chichun; Yao, Xinsheng; Yang, Mengsu



Synergistic inhibition of endochondral bone formation by silencing Hif1? and Runx2 in trauma-induced heterotopic ossification.  


Angiogenesis and osteogenesis are tightly coupled during bone development. We studied the effect of inhibition of Hif1? and Runt-related protein 2 (Runx2) on the formation of heterotopic ossification (HO). We constructed lentivirus vectors expressing Hif1? small interfering RNA (siRNA) and Runx2 siRNA. The inhibition of Hif1? function impaired osteoblast proliferation while osteoblasts differentiated normally. Osteoblasts lacking Runx2 proliferated normally while the differentiation was impaired. The osteoblast differentiation was significantly inhibited by co-Runx2 and Hif1? siRNA treatment. The formation of HO by inhibiting Runx2 and Hif1? in an animal model induced by Achilles tenotomy was investigated. The results showed that lacking of Runx2 and Hif1? could inhibit HO formation. Inhibition of Hif1? prevented HO formation only at the initial step and inhibition of Runx2 worked both at the initial step and after chondrogenesis. Angiogenesis and the expressions of osteogenic genes were downregulated in the Hif1? siRNA group. We found synergistic inhibition of endochondral bone formation by silencing Hif1? and Runx2. Our study provided new insight into the roles of Hif1? and Runx2 during the processes of endochondral bone formation, and had important implications for the new therapeutic methods to inhibit HO or to enhance bone formation. PMID:21629226

Lin, Lin; Shen, Qi; Leng, Huijie; Duan, Xiaoning; Fu, Xin; Yu, Changlong



Prevention of benzene-induced genotoxicity in bone marrow and lung cells: superiority of polyphenolic acetates to polyphenols.  


Previous investigations carried out in our laboratory have highlighted that 7,8-diacetoxy-4-methylcoumarin demonstrates a mechanism-based inhibition of cytochrome P450 (Cyt-P450) activities such as microsome-mediated aflatoxin B1 (AFB1) epoxidation, dealkylation of alkylated resorufin, and toxicokinetics of benzene. 7,8-Diacetoxy-4-methylcoumarin, quercetin pentaacetate, and ellagic acid peracetate were also found to be effective in giving the protection of AFB1-induced genotoxicity in rat's bone marrow and lung cells possibly due to acetylation of Cyt-P450 apoprotein mediated by acetoxy drug: protein transacetylase. Later, this transacetylase was identified as calreticulin, and the acetyltransferase function of calreticulin was appropriately termed calreticulin transacetylase. In this communication, we have focused on the superiority of several classes of polyphenolic acetates to polyphenols in the modification of Cyt-P450-linked mixed function oxidases (MFOs) such as 7-ethoxyresorufin O-deethylase (EROD) and pentoxyresorufin O-dealkylase (PROD). Special attention has also been focused on benzene-induced genotoxicity in bone marrow and lung cells. Results clearly indicated that polyphenolic acetates demonstrated time-dependent inhibition of Cyt-P450-linked MFOs, while parent polyphenols failed to demonstrate the same. Polyphenolic acetates were found to be more superior to polyphenols in preventing benzene-induced micronuclei formation. The pattern of inhibition of Cyt-P450-dependent MFOs and benzene-induced micronuclei formation by polyphenolic acetates was found in tune with their specificities to calreticulin transacetylase. These results further substantiated that inhibition of Cyt-P450-linked MFOs and benzene-induced genotoxicity in bone marrow and lung cells by polyphenolic acetates are mediated by the action of calreticulin transacetylase that catalyzes the acetylation of concerned proteins. PMID:21267547

Kumar, Ajit; Sushama, Anupam; Rohil, Vishwajeet; Manral, Sushma; Gangopadhyay, Sukanya; Prasad, Ashok K; Raj, Hanumantharao G; Parmar, Virender S



Combined Osteotome-Induced Ridge Expansion and Guided Bone Regeneration Simultaneous with Implant Placement: A Biometric Study.  


PURPOSE: To evaluate the long-term outcome of a single-step ridge expansion osteotome procedure and implant placement combined with guided bone regeneration in patients presenting narrow maxillary alveolar ridges. MATERIALS AND METHODS: During the period 1999 to 2010, 41 patients aged 19 to 77 years (18 males; 23 females) suffering from partial or full edentulism associated with horizontal resorption of the maxillary ridges (2.5-5?mm) were treated using the combined ridge expansion and guided bone-regeneration techniques to obtain an improved bony base for implant placement. Implant survival, bone width measurements, clinical and radiologic implant success, and clinical complications were recorded and analyzed. RESULTS: Achievement of primary stability of the implant was impossible at six sites; these were recorded as failures. In the remaining 35 patients, one hundred sixteen endosseous titanium implants were simultaneously placed. Follow-up time varied between 6 and 144 months (mean 52.4); of these, 36% were followed up for periods of time longer than 60 months. Implant diameter and lengths varied between 3.3 to 4.8 and 12 to 16?mm, respectively. In the 35 successful procedures (one hundred sixteen implants), the overall implant survival rate was 100%. An average gain in ridge width was 3.5?±?0.93 (p?bone was 1.91?±?0.6 (p?bone loss was 1.81?mm?±?1.07 (ranging from 0.3 to 4.2?mm), and the mean vertical distal bone loss was 1.74?mm?±?1.12 (ranging from 0.4 to 4.5?mm). In eight patients (32%), at least one implant presented bone loss of ?3?mm. CONCLUSIONS: Within the limitations of this study, we suggest that the combined osteotome-induced ridge expansion and guided bone regeneration simultaneous with implant placement is a reliable procedure with reduced morbidity and may offer an alternative in suitable situations. PMID:23350624

Kolerman, Roni; Nissan, Joseph; Tal, Haim



Bone tumor  


Tumor - bone; Bone cancer; Primary bone tumor; Secondard bone tumor ... malignant) bone tumors include: Chondrosarcoma Ewing's sarcoma Fibrosarcoma Osteosarcomas The cancers that most often spread to the ...


Ovariectomy-induced changes in aged beagles : histomorphometry of rib cortical bone.  

SciTech Connect

Bone loss associated with estrogen depletion is well documented in cancellous bone but less well characterized in cortical bone. The effects of ovariectomy on the aged beagle skeleton were studied by histomorphometric analysis of the cortical bone in sequential rib biopsies. Biopsies were taken from each ovariectomized or sham-operated dog at the time of surgery and at 1, 4, and 8.5 months after surgery. Just prior to each postoperative biopsy, tetracycline, calcein, and xylenol orange, respectively, were administered by a fluorochrome labeling procedure (2d-10d-2d) to provide markers of bone formation. Analysis of sequential rib biopsies provided a means to follow the ovariectomy response over time and to compare each animal against its own baseline. Though ovariectomy did not influence histomorphometric indices at 1 month after surgery, a transient increase in cortical bone formation occurred thereafter, with a sixfold increase over that of sham-operated dogs at 4 months (P < 0.001) and a return to near control levels at 8.5 months. Cortical porosity increased by the fourth month after ovariectomy and remained high at 8.5 months. These data demonstrate for the first time that rib cortical bone is a responsive site for the effects of ovariectomy in aged female dogs.

Wilson, A. K.; Bhattacharyya, M. H.; Miller, S.; Sacco-Gibson, N.; Center for Mechanistic Biology and Biotechnology; Univ. of Utah; Procter & Gamble Pharmaceuticals



Effect of venlafaxine on bone loss associated with ligature-induced periodontitis in Wistar rats  

PubMed Central

Background The present study investigated the effects of venlafaxine, an antidepressant drug with immunoregulatory properties on the inflammatory response and bone loss associated with experimental periodontal disease (EPD). Materials and Methods Wistar rats were subjected to a ligature placement around the second upper left molar. The treated groups received orally venlafaxine (10 or 50 mg/kg) one hour before the experimental periodontal disease induction and daily for 10 days. Vehicle-treated experimental periodontal disease and a sham-operated (SO) controls were included. Bone loss was analyzed morphometrically and histopathological analysis was based on cell influx, alveolar bone, and cementum integrity. Lipid peroxidation quantification and immunohistochemistry to TNF-? and iNOS were performed. Results Experimental periodontal disease rats showed an intense bone loss compared to SO ones (SO = 1.61 ± 1.36; EPD = 4.47 ± 1.98 mm, p < 0.001) and evidenced increased cellular infiltration and immunoreactivity for TNF-? and iNOS. Venlafaxine treatment while at low dose (10 mg/kg) afforded no significant protection against bone loss (3.25 ± 1.26 mm), a high dose (50 mg/kg) caused significantly enhanced bone loss (6.81 ± 3.31 mm, p < 0.05). Venlafaxine effectively decreased the lipid peroxidation but showed no significant change in TNF-? or iNOS immunoreactivity. Conclusion The increased bone loss associated with high dose venlafaxine may possibly be a result of synaptic inhibition of serotonin uptake.



Bone-induced streak artifact suppression in sparse-view CT image reconstruction  

PubMed Central

Background In sparse-view CT imaging, strong streak artifacts may appear around bony structures and they often compromise the image readability. Compressed sensing (CS) or total variation (TV) minimization-based image reconstruction method has reduced the streak artifacts to a great extent, but, sparse-view CT imaging still suffers from residual streak artifacts. We introduce a new bone-induced streak artifact reduction method in the CS-based image reconstruction. Methods We firstly identify the high-intensity bony regions from the image reconstructed by the filtered backprojection (FBP) method, and we calculate the sinogram stemming from the bony regions only. Then, we subtract the calculated sinogram, which stands for the bony regions, from the measured sinogram before performing the CS-based image reconstruction. The image reconstructed from the subtracted sinogram will stand for the soft tissues with little streak artifacts on it. To restore the original image intensity in the bony regions, we add the bony region image, which has been identified from the FBP image, to the soft tissue image to form a combined image. Then, we perform the CS-based image reconstruction again on the measured sinogram using the combined image as the initial condition of the iteration. For experimental validation of the proposed method, we take images of a contrast phantom and a rat using a micro-CT and we evaluate the reconstructed images based on two figures of merit, relative mean square error and total variation caused by the streak artifacts. Results The images reconstructed by the proposed method have been found to have smaller streak artifacts than the ones reconstructed by the original CS-based method when visually inspected. The quantitative image evaluation studies have also shown that the proposed method outperforms the conventional CS-based method. Conclusions The proposed method can effectively suppress streak artifacts stemming from bony structures in sparse-view CT imaging.



Green tea polyphenol protection against 4-nitroquinoline 1-oxide-induced bone marrow lipid peroxidation and genotoxicity in Wistar rats.  


4-Nitroquinoline 1-oxide (4-NQO) a potent oral carcinogen, widely used for induction of oral carcinogenesis, has been found to induce lipid peroxidation in vivo and in vitro. Green tea contains a high content of polyphenols, which are potent antioxidants. Thus green tea polyphenols (GTP) might be expected play a protective role against 4-NQO induced lipid peroxidation and bone marrow toxicity. In the present study, a dose of 200 mg of GTP/kg b.wt/day was given orally for a week, simultaneously animals received 0.2 ml of 0.5% 4-NQO in propylene glycol (5 mg/ml) injected intramuscularly for three times/week. Oxidants and antioxidants such as malendialdehyde (MDA) and thiols, glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) and catalase (CAT) were significantly decreased in 4-NQO induced animals except MDA, and these parameters were brought back to near normalcy on treatment with GTP. The results suggest that GTP treatment offers significant protection against 4-NQO induced lipid peroxidation and bone marrow toxicity and might be a promising potential candidate for prevention of mutations leading to cancer. PMID:23098525

Pandurangan, Ashok Kumar; Periasamy, Srinivasan; Anandasadagopan, Suresh Kumar; Ganapasam, Sudhandiran; Srinivasalu, Shyamala Devi Chennam



Mechanical Strain Using 2D and 3D Bioreactors Induces Osteogenesis: Implications for Bone Tissue Engineering  

NASA Astrophysics Data System (ADS)

Fracture healing is a complicated process involving many growth factors, cells, and physical forces. In cases, where natural healing is not able, efforts have to be undertaken to improve healing. For this purpose, tissue engineering may be an option. In order to stimulate cells to form a bone tissue several factors are needed: cells, scaffold, and growth factors. Stem cells derived from bone marrow or adipose tissues are the most useful in this regard. The differentiation of the cells can be accelerated using mechanical stimulation. The first part of this chapter describes the influence of longitudinal strain application. The second part uses a sophisticated approach with stem cells on a newly developed biomaterial (Sponceram) in a rotating bed bioreactor with the administration of bone morphogenetic protein-2. It is shown that such an approach is able to produce bone tissue constructs. This may lead to production of larger constructs that can be used in clinical applications.

van Griensven, M.; Diederichs, S.; Roeker, S.; Boehm, S.; Peterbauer, A.; Wolbank, S.; Riechers, D.; Stahl, F.; Kasper, C.


Tumor-Induced Osteoclast miRNA Changes as Regulators and Biomarkers of Osteolytic Bone Metastasis.  


Understanding the mechanism by which tumor cells influence osteoclast differentiation is crucial for improving treatment of osteolytic metastasis. Here, we report broad microRNA (miRNA) expression changes in differentiating osteoclasts after exposure to tumor-conditioned media, in part through activation of NF?B signaling by soluble intracellular adhesion molecule (sICAM1) secreted from bone-metastatic cancer cells. Ectopic expression of multiple miRNAs downregulated during osteoclastogenesis suppresses osteoclast differentiation by targeting important osteoclast genes. Intravenous delivery of these miRNAs in vivo inhibits osteoclast activity and reduces osteolytic bone metastasis. Importantly, serum levels of sICAM1 and two osteoclast miRNAs, miR-16 and miR-378, which are elevated in osteoclast differentiation, correlate with bone metastasis burden. These findings establish miRNAs as potential therapeutic targets and clinical biomarkers of bone metastasis. PMID:24135284

Ell, Brian; Mercatali, Laura; Ibrahim, Toni; Campbell, Neil; Schwarzenbach, Heidi; Pantel, Klaus; Amadori, Dino; Kang, Yibin



Gamma Radiation Induces Micronucleated Reticulocytes in 3-D Bone Marrow Bioreactors in Vitro  

PubMed Central

Radiation injury to the bone marrow is potentially lethal due to the potent DNA-damaging effects on cells of the hematopoietic system, including bone marrow stem cell, progenitor, and the precursor cell populations. Investigation of radiation genotoxic effects on bone marrow progenitor/precursor cells has been challenged by the lack of optimal in vitro surrogate organ culture systems, and the overall difficulty to sustain lineage-specific proliferation and differentiation of hematopoiesis in vitro. We report the investigation of radiation genotoxic effects in bone marrow cultures of C57Bl/6 mice established in 3-D bioreactors, which sustain long-term bone marrow cultures. For these studies, genotoxicity is measured by the induction of micronucleated reticulocytes (MN-RET). The kinetics and dose-response relationship of MN-RET induction in response to gamma-radiation of bioreactor-maintained bone marrow cultures are presented. Our data showed that 3-D long-term bone marrow cultures had sustained erythropoiesis capable of generating reticulocytes up to 8 weeks. The peak time-interval of viable cell output and percentage of reticulocytes increased steadily and reached the initial peak between the 14th to 21st days after inoculations. This was followed by a rebound or staying relatively constant until week 8. The percentage of MN-RET reached the maximum between 24 and 32 hours post 1 Gy gamma-ray. There was a near linear MN-RET induction by gamma radiation from 0 Gy to 1.0 Gy, followed by an attenuated increase to 1.5 – 2.0 Gy. The MN-RET response showed a downtrend beyond 2 Gy. Our data suggest that bone marrow culture in the 3-D bioreactor may be a useful organ culture system for the investigation of radiation genotoxic effect in vitro.

Sun, Hongliang; Dertinger, Stephen D.; Hyrien, Ollivier; David Wu, J. H.; Chen, Yuhchyau



Does high serum iron level induce low bone mass in sickle cell anemia ?  

Microsoft Academic Search

Iron overload is quite common in patients suffering from hemoglobinopathies causing arthropathies, endocrinal affection and\\u000a neuropathies. Recently low bone mass was added to the list of complications. This study is conducted to find any correlation\\u000a between serum iron level and low bone mass in sickle cell anemia (SCA). Patients ?18 years of age with sickle cell anemia,\\u000a who attended outpatient

Mir Sadat-AliOsama; Osama Sultan; Haifa Al-Turki; Abdulmohsen AlElq



The effects of photobiomodulation on healing of bone defects in streptozotocin induced diabetic rats  

NASA Astrophysics Data System (ADS)

Previous studies have shown positive effects of Low level laser therapy (LLLT) on the repair of bone defects, but there are only a few that associates bone healing in the presence of a metabolic disorder as Diabetes Melitus and LLLT. The aim of this study was to assess histologically the effect of LLLT (AsGaAl), 780nm, 70mW, CW, Ø~0.4mm, 16J/cm2 per session) on the repair of surgical defects created in the femur of diabetic and non-diabetic Wistar Albinus rats. Surgical bone defects were created in 60 animals divided into four groups of 15 animals each: Group C (non-diabetic - control); Group CL (non-diabetic + LLLT); Group CD (diabetic); Group CDL (diabetic + LLLT). The animals on the irradiated group received 16 J/cm2 per session divided into four points around the defect, being the first irradiation immediately after surgery and repeated every 48h for 14 days. The animals were killed 15, 21 and 30 days after surgery. The results of the present investigation showed histological evidence of improved amount of collagen fibers at early stages of the bone healing (15 days) and increased amount of well organized bone trabeculae at the end of the experimental period (30 days) on irradiated animals, (diabetic and non-diabetic) compared to non irradiated ones. It is concluded that LLLT has a positive biomodulative effect on the healing process of bone defects, even when diabetes mellitus was present.

Martinez Costa Lino, Maíra D.; Bastos de Carvalho, Fabíola; Ferreira Moraes, Michel; Augusto Cardoso, José; Barbosa Pinheiro, Antônio L.; Maria Pedreira Ramalho, Luciana



Prednisolone alone, or in combination with estrogen or dietary calcium deficiency or immobilization, inhibits bone formation but does not induce bone loss in mature rats  

Microsoft Academic Search

Glucocorticoid use has long been recognized as a risk factor for bone loss, resulting in an increased fracture incidence in humans. However, steroid-treated patients often present with other complications that predispose to bone loss, such as immobilization, and little is known about the interaction of these other risk factors for bone loss and glucocorticoids. In the present study, mature female

V. Shen; R. Birchman; X. G. Liang; D. D. Wu; R. Lindsay; D. W. Dempster



The Calcium-Sensing Receptor Mediates Bone Turnover Induced by Dietary Calcium and Parathyroid Hormone in Neonates  

PubMed Central

We have investigated, in neonates, whether the calcium-sensing receptor (CaR) mediates the effects of dietary calcium on bone turnover and/or modulates parathyroid hormone (PTH)–induced bone turnover. Wild-type (WT) pups and pups with targeted deletion of the Pth (Pth–/–) gene or of both Pth and CaR (Pth–/–CaR–/–) genes were nursed by dams on a normal or high-calcium diet. Pups nursed by dams on a normal diet received daily injections of vehicle or of PTH(1–34) (80 µg/kg) for 2 weeks starting from 1 week of age. In pups receiving vehicle and fed by dams on a normal diet, trabecular bone volume, osteoblast number, type 1 collagen–positive area, and mineral apposition rate, as well as the expression of bone-formation-related genes, all were reduced significantly in Pth–/– pups compared with WT pups and were decreased even more dramatically in Pth–/–CaR–/– pups. These parameters were increased in WT and Pth–/– pups but not in Pth–/–CaR–/– pups fed by dams on a high-calcium diet compared with pups fed by dams on a normal diet. These parameters also were increased in WT, Pth–/–, and Pth–/–CaR–/– pups following exogenous PTH treatment; however, the percentage increase was less in Pth–/–CaR–/– pups than in WT and Pth–/– pups. In vehicle-treated pups fed by dams on either the normal or high-calcium diet and in PTH-treated pups fed by dams on a normal diet, the number and surfaces of osteoclasts and the ratio of RANKL/OPG were reduced significantly in Pth–/– pups and less significantly in Pth–/–CaR–/– pups compared with WT pups. These parameters were further reduced significantly in WT and Pth–/– pups from dams fed a high-calcium diet but did not decrease significantly in similarly treated Pth–/–CaR–/– pups, and they increased significantly in PTH-treated pups compared with vehicle-treated, genotype-matched pups fed by dams on the normal diet. These results indicate that in neonates, the CaR mediates alterations in bone turnover in response to changes in dietary calcium and modulates PTH-stimulated bone turnover. © 2011 American Society for Bone and Mineral Research.

Shu, Lei; Ji, Ji; Zhu, Qi; Cao, Guofan; Karaplis, Andrew; Pollak, Martin R; Brown, Edward; Goltzman, David; Miao, Dengshun



Differences in xenobiotic detoxifying activities between bone marrow stromal cells from mice and rats: Implications for benzene-induced hematotoxicity  

SciTech Connect

benzene is a human carcinogen; exposure can result in aplastic anemia and leukemia. Data from animal models are frequently used in benzene risk assessment. In rodent studies, mice are more sensitive to benzene-induced hematotoxicity than rats. Bone marrow stromal cells from mice were significantly more susceptible to the cytotoxicity induced by the benzene metabolites hydroquinone (HQ) and benzoquinone (BQ) than cells from rats. Since cellular gluthathione (GSH) and quinone reductase (QR) are known to play critical roles in modulating HQ-induced cytotoxicity, the GSH content and the QR and glutathione S-transferase (GST) activity in stromal cells from both species was measured. In rat cells, the GSH content and the QR specific activity were 2 and 28 times as much as those from mice, respectively. GSH and QR in both mouse and rat stromal cells were inducible by 1,2-dithiole-3-thione (D3T). D3T pretreatment of both mouse and rat stromal cells resulted in a marked protection against HQ-induced toxicity. Pretreatment of both mouse and rat stromal cells with GSH ethyl ester also provided a dramatic protection against HQ-induced toxicity. Conversely, dicoumarol, an inhibitor of QR, enhanced the HQ-induced toxicity in stromal cells from both mice and rats, indicating an important role for QR in modulating HQ-induced stromal toxicity. Buthionine sulfoximine (BSO), which depleted GSH significantly in both species, potentiated the HQ-induced toxicity in mouse but not in rat stromal cells. Surprisingly, incubation of stromal cells with BSO resulted in a significant induction of QR, especially in rats. Overall, this study demonstrates that the differences in stromal cellular GSH content and QR activity between mice and rats contribute to their respective susceptibility to HQ-induced cytotoxicity in vitro, and may be involved in the greater in vivo sensitivity of mice to benzene-induced hematotoxicity. 51 refs., 9 figs., 1 tab.

Zhu, Hong; Li, Yunbo; Trush, M.A. [Johns Hopkins Univ. School of Hygiene and Public Health, Baltimore, MD (United States)



Reduced gravitational loading does not account for the skeletal effect of botulinum toxin-induced muscle inhibition suggesting a direct effect of muscle on bone.  


Intramuscular injection of botulinum toxin (botox) into rodent hindlimbs has developed as a useful model for exploring muscle-bone interactions. Botox-induced muscle inhibition rapidly induces muscle atrophy and subsequent bone loss, with the latter hypothesized to result from reduced muscular loading of the skeleton. However, botox-induced muscle inhibition also reduces gravitational loading (as evident by reduced ground reaction forces during gait) which may account for its negative skeletal effects. The aim of this study was to investigate the skeletal effect of botox-induced muscle inhibition in cage control and tail suspended mice, with tail suspension being used to control for the reduced gravitational loading associated with botox. Female C57BL/6J mice were injected unilaterally with botox and contralaterally with vehicle, and subsequently exposed to tail suspension or normal cage activities for 6 weeks. Botox-induced muscle inhibition combined with tail suspension had the largest detrimental effect on the skeleton, causing the least gains in midshaft tibial bone mass, cortical area and cortical thickness, greatest gains in midshaft tibial medullary area, and lowest proximal tibial trabecular bone volume fraction. These data indicate botox-induced muscle inhibition has skeletal effects over and above any effect it has in altering gravitational loading, suggesting that muscle has a direct effect on bone. This effect may be relevant in the development of strategies targeting musculoskeletal health. PMID:23388417

Warden, Stuart J; Galley, Matthew R; Richard, Jeffrey S; George, Lydia A; Dirks, Rachel C; Guildenbecher, Elizabeth A; Judd, Ashley M; Robling, Alexander G; Fuchs, Robyn K



Modification of the in vivo four-point loading model for studying mechanically induced bone adaptation.  


We modified the noninvasive, in vivo technique for strain application in the tibiae of rats (Turner et al., Bone 12:73-79, 1991). The original model applies four-point bending to right tibiae via an open-loop, stepper-motor-driven spring linkage. Depending on the magnitude of applied load, the model produces new bone formation at periosteal (Ps) or endocortical surfaces (Ec.S). Due to the spring linkage, however, the range of frequencies at which loads can be applied is limited. The modified system replaces this design with an electromagnetic vibrator. A load transducer in series with the loading points allows calibration, the loaders' position to be adjusted, and cyclic loading completed under load control as a closed servo-loop. Two experiments were conducted to validate the modified system: (1) a strain gauge was applied to the lateral surface of the right tibia of 5 adult female rats and strains measured at applied loads from 10 to 60 N; and (2) the bone formation response was determined in 28 adult female Sprague-Dawley rats. Loading was applied as a haversine wave with a frequency of 2 Hz for 18 sec, every second day for 10 days. Peak bending loads were applied at 33, 40, 52, and 64 N, and a sham-loading group was included at 64 N. Strains in the tibiae were linear between 10 and 60 N, and the average peak strain at the Ps.S at 60 N was 2664 +/- 250 microstrain, consistent with the results of Turner's group. Lamellar bone formation was stimulated at the Ec.S by applied bending, but not by sham loading. Bending strains above a loading threshold of 40 N increased Ec lamellar bone formation rate, bone forming surface, and mineral apposition rate with a dose response similar to that reported by Turner et al. (J Bone Miner Res 9:87-97, 1994). We conclude that the modified loading system offers precision for applied loads of between 0 and 70 N, versatility in the selection of loading rates up to 20 Hz, and a reproducible bone formation response in the rat tibia. Adjustment of the loader also enables study of mechanical usage in murine tibia, an advantage with respect to the increasing variety of transgenic strains available in bone and mineral research. PMID:9737355

Forwood, M R; Bennett, M B; Blowers, A R; Nadorfi, R L



Co-stimulation with bone morphogenetic protein-9 and FK506 induces remarkable osteoblastic differentiation in rat dedifferentiated fat cells.  


Dedifferentiated fat (DFAT) cells, which are isolated from mature adipocytes using the ceiling culture method, exhibit similar characteristics to mesenchymal stem cells, and possess adipogenic, osteogenic, chondrogenic, and myogenic potentials. Bone morphogenetic protein (BMP)-2 and -9, members of the transforming growth factor-? superfamily, exhibit the most potent osteogenic activity of this growth factor family. However, the effects of BMP-2 and BMP-9 on the osteogenic differentiation of DFAT remain unknown. Here, we examined the effects of BMP-2 and BMP-9 on osteoblastic differentiation of rat DFAT (rDFAT) cells in the presence or absence of FK506, an immunosuppressive agent. Co-stimulation with BMP-9 and FK506 induced gene expression of runx2, osterix, and bone sialoprotein, and ALP activity compared with BMP-9 alone, BMP-2 alone and BMP-2+FK506 in rDFAT cells. Furthermore, it caused mineralization of cultures and phosphorylation of smad1/5/8, compared with BMP-9 alone. The ALP activity induced by BMP-9+FK506 was not influenced by addition of noggin, a BMP antagonist. Our data suggest that the combination of BMP-9 and FK506 potently induces osteoblastic differentiation of rDFAT cells. PMID:24064349

Nakamura, Toshiaki; Shinohara, Yukiya; Momozaki, Sawako; Yoshimoto, Takehiko; Noguchi, Kazuyuki



Bone morphogenetic protein-4 induced rat hepatic progenitor cell (WB-F344 cell) differentiation toward hepatocyte lineage.  


Hepatic progenitor cells are local stem cells in the liver and they can be differentiated into either hepatocytes or cholangiocytes depending on different stimulations. These stimulations include extracellular growth factors and intracellular transcription factors. Bone morphogenetic protein 4 (BMP4) is a member of transforming growth factor beta (TGF-beta) superfamily and was first identified as growth factor to induce ectopic bone formation from skeletal muscle. Role of BMP4 in the liver is still unclear especially its role in hepatic progenitor cells (HPCs) differentiation. BMP4 was used to stimulate rat HPCs (WB-F344 cells) and differentiation of WB-F344 cells was investigated by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot analysis. Both adenovirus delivered BMP4 and recombinant BMP4 were able to induce expression of hepatocyte markers such as albumin, TAT-1, and G6Pase but not cholangiocyte markers such as beta4-integrin and CK19. BMP4 induced differentiation of WB-F344 cells toward hepatocytes was mediated by increase in phosphorylation of Smad1 and ERK1/2. Moreover, BMP4 also stimulated expression of transcription factor--C/EBP-alpha, which involved in differentiation of WB-F344 cells toward hepatocytes. BMP4 is able to stimulate WB-F344 cells differentiation toward hepatocyte lineage. PMID:19229878

Fan, Jianghong; Shen, Hong; Dai, Qiaomei; Minuk, Gerald Y; Burzynski, Frank J; Gong, Yuewen



LPS response and endotoxin tolerance in Flt-3L-induced bone marrow-derived dendritic cells.  


Fms-like tyrosine kinase-3 ligand (Flt-3L) stimulates the differentiation of bone marrow cells into dendritic cells (DCs) and was used as an adjuvant therapy in the experimental model of burn wound sepsis. In this study, we describe the phenotypical characteristics of an Flt-3L-dependent DC culture (FLDC) system following LPS stimulation, which induces an inflammatory response, and after a second LPS stimulation, which induces tolerance. Priming of FLDCs with LPS via TLR4 has been shown to induce the activation of all three mitogen-activated protein kinase (MAPK) families and enhance NF-?B complex translocation into the nucleus. Stimulated FLDCs express all maturation markers and exhibit an increase in IL-12p40 production and to a lesser extent, IL-10 production. In contrast, LPS stimulation of tolerized FLDCs was not associated with TLR4 up-regulation and led to MAPK inhibition. The decrease in p38 and JNK activation was correlated with an impairment of IL-12p40 production. Endotoxin tolerance in FLDCs was associated with enhanced ERK1/2 activation, an increase in MKP-1 phosphatase expression, a decrease in NF-?B translocation to the nucleus and an increase in IL-10 production. Overall, DCs generated from bone marrow with Flt-3 ligand have similar characteristics to DC subtypes found in the steady state in vivo, which can acquire endotoxin tolerance in some circumstances. PMID:21802073

Patenaude, Julie; D'Elia, Michele; Côté-Maurais, Guillaume; Bernier, Jacques



Recruitment of a Prostaglandin E Receptor Subtype, EP3-Expressing Bone Marrow Cells Is Crucial in Wound-Induced Angiogenesis  

PubMed Central

E-type prostaglandins have been reported to be proangiogenic in vivo. Thus, we examined prostaglandin receptor signaling relevant to wound-induced angiogenesis. Full-thickness skin wounds were created on the backs of mice, and angiogenesis in wound granulation tissues was estimated. Wound closure and re-epithelization in EP3 receptor knockout mice (EP3?/?) were significantly delayed compared with their wild-type (WT) mice, whereas those in EP1?/?, EP2?/?, and EP4?/? were not delayed. Wound-induced angiogenesis estimated with CD31 immunohistochemistry in EP3?/? mice was significantly inhibited compared with that in WT mice. Immunoreactive vascular endothelial growth factor (VEGF) in wound granulation tissues in EP3?/? mice was markedly less than that in WT mice. Wound closure in WT mice was delayed significantly by VEGF neutralizing antibody compared with control IgG. Wound-induced angiogenesis and wound closure were significantly suppressed in EP3?/? bone marrow transplantation mice compared with those in WT bone marrow transplantation mice. These were accompanied with the reductions in accumulation of VEGF-expressing cells in wound granulation tissues and in mobilization of VEGF receptor 1-expressing leukocytes in peripheral circulation. These results indicate that the recruitment of EP3-expressing cells to wound granulation tissues is critical for surgical wound healing and angiogenesis via up-regulation of VEGF.

Kamoshita, Emi; Ikeda, Yasuhiro; Fujita, Mamoru; Amano, Hideki; Oikawa, Atsuhiko; Suzuki, Tastunori; Ogawa, Yasuhumi; Yamashina, Shohei; Azuma, Sadahiro; Narumiya, Shuh; Unno, Nobuya; Majima, Masataka



7,12-Dimethylbenz[a]anthracene-induced bone marrow toxicity is p53-dependent.  


Polycyclic aromatic hydrocarbons (PAHs) are known immunotoxins and carcinogens. Our laboratory and others have demonstrated that metabolism of these compounds by CYP1B1 is required for carcinogenicity and immunotoxicity to occur. Previously, our laboratory reported significantly decreased bone marrow cellularity in mice following 7,12-dimethlybenz[a]anthracene (DMBA) administration. In addition, we have observed that DMBA causes apoptosis via activation of both caspase-8 and -9 in pre-B cells co-cultured with bone marrow stromal cells in vitro. In this study, we investigated the importance of the p53 protein in the bone marrow response to DMBA. Through the use of p53 gene knockout mice, we demonstrated that the effect of DMBA on bone marrow cellularity is p53-dependent. In addition, apoptosis of primary cultures of progenitor B cells cultured with bone marrow stromal cells and DMBA is also p53-dependent. The results of this study provide evidence for the importance of p53 in the signaling pathways by which PAHs cause immunotoxicity. PMID:12730609

Page, Todd J; O'Brien, Scott; Holston, Karrie; MacWilliams, Peter S; Jefcoate, Colin R; Czuprynski, Charles J



Parathyroid hormone induces bone formation in phosphorylation-deficient PTHR1 knockin mice  

PubMed Central

Activation of G protein-coupled receptors by agonists leads to receptor phosphorylation, internalization of ligand receptor complexes, and desensitization of hormonal response. The role of parathyroid hormone (PTH) receptor 1, PTHR1, is well characterized and known to regulate cellular responsiveness in vitro. However, the role of PTHR1 phosphorylation in bone formation is yet to be investigated. We have previously demonstrated that impaired internalization and sustained cAMP stimulation of phosphorylation-deficient (PD) PTHR1 leads to exaggerated cAMP response to subcutaneous PTH infusion in a PD knockin mouse model. To understand the physiological role of receptor internalization on PTH bone anabolic action, we examined bone parameters of wild-type (WT) and PD knockin female and male mice following PTH treatment. We found a decrease in total and diaphyseal bone mineral density in female but not in male PD mice compared with WT controls at 3–6 mo of age. This effect was attenuated at older age groups. PTH administration displayed increased bone volume and trabecular thickness in the vertebrae and distal femora of both WT and PD animals. These results suggest that PTHR1 phosphorylation does not play a major role in the anabolic action of PTH.

Samra, Tareq A.; Abou-Samra, Abdul B.



Pyruvate dehydrogenase kinase 4 induces bone loss at unloading by promoting osteoclastogenesis.  


Disuse osteoporosis, which occurs commonly in prolonged bed rest and immobilization, is becoming a major problem in modern societies; however, the molecular mechanisms underlying unloading-driven bone loss have not been fully elucidated. The osteocyte network is considered to be an ideal mechanosensor and mechanotransduction system. We searched for the molecules responsible for disuse osteoporosis using BCL2 transgenic mice, in which the osteocyte network was disrupted. Pyruvate dehydrogenase kinase 4 (Pdk4), which inactivates pyruvate dehydrogenase complex (PDC), was upregulated in femurs and tibiae of wild-type mice but not of BCL2 transgenic mice after tail suspension. Bone in Pdk4(-/-) mice developed normally and was maintained. At unloading, however, bone mass was reduced due to enhanced osteoclastogenesis and Rankl expression in wild-type mice but not in Pdk4(-/-) mice. Osteoclast differentiation of Pdk4(-/-) bone marrow-derived monocyte/macrophage lineage cells (BMMs) in the presence of M-CSF and RANKL was suppressed, and osteoclastogenesis was impaired in the coculture of wild-type BMMs and Pdk4(-/-) osteoblasts, in which Rankl expression and promoter activity were reduced. Further, introduction of Pdk4 into Pdk4(-/-) BMMs and osteoblasts enhanced osteoclastogenesis and Rankl expression and activated Rankl promoter. These findings indicate that Pdk4 plays an important role in bone loss at unloading by promoting osteoclastogenesis. PMID:21803180

Wang, Yuying; Liu, Wenguang; Masuyama, Ritsuko; Fukuyama, Ryo; Ito, Masako; Zhang, Quan; Komori, Hisato; Murakami, Tomohiko; Moriishi, Takeshi; Miyazaki, Toshihiro; Kitazawa, Riko; Yoshida, Carolina A; Kawai, Yosuke; Izumi, Shinichi; Komori, Toshihisa



Targeted disruption of the Wnt regulator Kremen induces limb defects and high bone density.  


Kremen1 and Kremen2 (Krm1 and Krm2) are transmembrane coreceptors for Dickkopf1 (Dkk1), an antagonist of Wnt/beta-catenin signaling. The physiological relevance of Kremen proteins in mammals as Wnt modulators is unresolved. We generated and characterized Krm mutant mice and found that double mutants show enhanced Wnt signaling accompanied by ectopic postaxial forelimb digits and expanded apical ectodermal ridges. Triple mutant Krm1(-/-) Krm2(-/-) Dkk1(+/-) mice show enhanced growth of ectopic digits, indicating that Dkk1 and Krm genes genetically interact during limb development. Wnt/beta-catenin signaling also plays a critical role in bone formation. Single Krm mutants show normal bone fo