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Sample records for endosteum

  1. Skeletal cell fate decisions within periosteum and bone marrow during bone regeneration.

    PubMed

    Colnot, Céline

    2009-02-01

    Bone repair requires the mobilization of adult skeletal stem cells/progenitors to allow deposition of cartilage and bone at the injury site. These stem cells/progenitors are believed to come from multiple sources including the bone marrow and the periosteum. The goal of this study was to establish the cellular contributions of bone marrow and periosteum to bone healing in vivo and to assess the effect of the tissue environment on cell differentiation within bone marrow and periosteum. Results show that periosteal injuries heal by endochondral ossification, whereas bone marrow injuries heal by intramembranous ossification, indicating that distinct cellular responses occur within these tissues during repair. [corrected] Next, lineage analyses were used to track the fate of cells derived from periosteum, bone marrow, and endosteum, a subcompartment of the bone marrow. Skeletal progenitor cells were found to be recruited locally and concurrently from periosteum and/or bone marrow/endosteum during bone repair. Periosteum and bone marrow/endosteum both gave rise to osteoblasts, whereas the periosteum was the major source of chondrocytes. Finally, results show that intrinsic and environmental signals modulate cell fate decisions within these tissues. In conclusion, this study sheds light into the origins of skeletal stem cells/progenitors during bone regeneration and indicates that periosteum, endosteum, and bone marrow contain pools of stem cells/progenitors with distinct osteogenic and chondrogenic potentials that vary with the tissue environment.

  2. Cochlear Otosclerosis

    PubMed Central

    Cureoglu, Sebahattin; Baylan, Muzeyyen Yildirim; Paparella, Michael M

    2010-01-01

    Purpose of review The aim of this study is to summarize current advances in research and clinical aspects of cochlear otosclerosis. Recent Findings Recent studies have revealed that otosclerosis is a process of bone remodeling that is unique to only the otic capsule. Even though no obvious bone remodeling is seen in the otic capsule under normal conditions, remodeling starts when some molecular factors trigger the capsule in certain patients who have genetic and/or environmental tendencies. Summary Cochlear otosclerosis is defined as otosclerosis located in the otic capsule involving the cochlear endosteum and causing sensorineural hearing loss or mixed type hearing loss. It has been clearly shown that when otosclerosis is sufficiently severe to involve the cochlear endosteum, it usually fixes the stapes as well. PMID:20693902

  3. Tenascin-C and integrin α9 mediate interactions of prostate cancer with the bone microenvironment.

    PubMed

    San Martin, Rebeca; Pathak, Ravi; Jain, Antrix; Jung, Sung Yun; Hilsenbeck, Susan G; Piňa-Barba, Maria C; Sikora, Andrew G; Pienta, Kenneth J; Rowley, David R

    2017-09-15

    Deposition of the extracellular matrix protein tenascin-C is part of the reactive stroma response, which has a critical role in prostate cancer progression. Here we report that tenascin-C is expressed in the bone endosteum and involved associated with formation of prostate bone metastases. Metastatic cells cultured on osteo-mimetic surfaces coated with tenascin-C exhibited enhanced adhesion and colony formation as mediated by integrin α9β1. Additionally, metastatic cells preferentially migrated and colonized tenascin-C-coated trabecular bone xenografts in a novel system that employed chorioallantoic membranes of fertilized chicken eggs as host. Overall, our studies deepen knowledge about reactive stroma responses in the bone endosteum that accompany prostate cancer metastasis to trabecular bone, with potential implications to therapeutically target this process in patients. Copyright ©2017, American Association for Cancer Research.

  4. Spatial distribution and remodeling of elastic modulus of bone in micro-regime as prediction of early stage osteoporosis.

    PubMed

    Grover, Kartikey; Lin, Liangjun; Hu, Minyi; Muir, Jesse; Qin, Yi-Xian

    2016-01-25

    We assessed the local distribution of bone mechanical properties on a micro-nano-scale and its correlation to strain distribution. Left tibia samples were obtained from 5-month old female Sprague Dawley rats, including baseline control (n=9) and hindlimb suspended (n=9) groups. Elastic modulus was measured by nanoindentation at the dedicated locations. Three additional tibias from control rats were loaded axially to measure bone strain, with 6-10N at 1Hz on a Bose machine for strain measurements. In the control group, the difference of the elastic modulus between periosteum and endosteum was much higher at the anterior and posterior regions (2.6GPa), where higher strain differences were observed (45μɛ). Minimal elastic modulus difference between periosteum and endosteum was observed at the medial region (0.2GPa), where neutral axis of the strain distribution was oriented with lower strain difference (5μɛ). In the disuse group, however, the elastic modulus differences in the anterior posterior regions reduced to 1.2GPa from 2.6GPa in the control group, and increased in the medial region to 2.7GPa from 0.2GPa. It is suggested that the remodeling rate in a region of bone is possibly influenced by the strain gradient from periosteum to endosteum. Such pattern of moduli gradients was compromised in disuse osteopenia, suggesting that the remodeling in distribution of micro-nano-elastic moduli among different regions may serve as a predictor for early stage of osteoporosis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Spatial Distribution and Remodeling of Elastic Modulus of Bone in Micro Regime as Prediction of Early Stage Osteoporosis

    PubMed Central

    Grover, Kartikey; Lin, Liangjun; Hu, Minyi; Muir, Jesse; Qin, Yi-Xian.

    2016-01-01

    We assessed the local distribution of bone mechanical properties on a micro-nano scale and its correlation to strain distribution. Left tibia samples were obtained from 5-month old female Sprague Dawley rats, including baseline control (n=9) and hindlimb suspended (n=9) groups. Elastic modulus was measured by nanoindentation at the dedicated locations. Three additional tibias from control rats were loaded axially to measure bone strain, with 6–10N at 1Hz on a Bose machine for strain measurements. In the control group, the difference of the elastic modulus between periosteum and endosteum was much higher at the anterior and posterior regions (2.6GPa), where higher strain differences were observed (45με). Minimal elastic modulus difference between periosteum and endosteum was observed at the medial region (0.2GPa), where neutral axis of the strain distribution was oriented with lower strain difference (5με). In the disuse group, however, the elastic modulus differences in the anterior posterior regions reduced to 1.2GPa from 2.6GPa in the control group, and increased in the medial region to 2.7GPa from 0.2GPa. It is suggested that the remodeling rate in a region of bone is possibly influenced by the strain gradient from periosteum to endosteum. Such pattern of moduli gradients was compromised in disuse osteopenia, suggesting that the remodeling in distribution of micro-nano elastic moduli among different regions may serve as a predictor for early stage of osteoporosis. PMID:26705110

  6. Changes in osteoblastic activity due to simulated weightless conditions

    NASA Technical Reports Server (NTRS)

    Doty, S. B.; Morey-Holton, E. R.

    1982-01-01

    Using histochemistry and electron microscopy, the reduced bone formation which occurs in the hypokinetic, orthostatically treated adult rat has been studied. The two major changes noted occurred in the osteoblast population, indicated by a reduced alkaline phosphatase activity and reduced numbers of gap junctions between cells. These results were most noticeable in the periosteum and endosteum of the long bones. Changes in osteoblasts lining the surface of trabecular bone were not as evident. These results indicate that the cells lining the surfaces of weight bearing bones are most affected by hypokinesia and this reduction in cellular activity may be a mechanically induced effect.

  7. Inhibition of bone formation during space flight

    NASA Technical Reports Server (NTRS)

    Morey, E. R.; Baylink, D. J.

    1978-01-01

    Parameters of bone formation and resorption were measured in rats orbited for 19.5 days aboard the Soviet Cosmos 782 biological satellite. The most striking effects were on bone formation. During flight, rats formed significantly less periosteal bone than did control rats on the ground. An arrest line at both the periosteum and the endosteum of flight animals suggests that a complete cecessation of bone growth occurred. During a 26-day postflight period, the defect in bone formation was corrected. No significant changes in bone resorption were observed.

  8. Inhibition of bone formation during space flight

    NASA Technical Reports Server (NTRS)

    Morey, E. R.; Baylink, D. J.

    1978-01-01

    Parameters of bone formation and resorption were measured in rats orbited for 19.5 days aboard the Soviet Cosmos 782 biological satellite. The most striking effects were on bone formation. During flight, rats formed significantly less periosteal bone than did control rats on the ground. An arrest line at both the periosteum and the endosteum of flight animals suggests that a complete cecessation of bone growth occurred. During a 26-day postflight period, the defect in bone formation was corrected. No significant changes in bone resorption were observed.

  9. Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs.

    PubMed

    Winkler, Ingrid G; Sims, Natalie A; Pettit, Allison R; Barbier, Valérie; Nowlan, Bianca; Helwani, Falak; Poulton, Ingrid J; van Rooijen, Nico; Alexander, Kylie A; Raggatt, Liza J; Lévesque, Jean-Pierre

    2010-12-02

    In the bone marrow, hematopoietic stem cells (HSCs) reside in specific niches near osteoblast-lineage cells at the endosteum. To investigate the regulation of these endosteal niches, we studied the mobilization of HSCs into the bloodstream in response to granulocyte colony-stimulating factor (G-CSF). We report that G-CSF mobilization rapidly depletes endosteal osteoblasts, leading to suppressed endosteal bone formation and decreased expression of factors required for HSC retention and self-renewal. Importantly, G-CSF administration also depleted a population of trophic endosteal macrophages (osteomacs) that support osteoblast function. Osteomac loss, osteoblast suppression, and HSC mobilization occurred concomitantly, suggesting that osteomac loss could disrupt endosteal niches. Indeed, in vivo depletion of macrophages, in either macrophage Fas-induced apoptosis (Mafia) transgenic mice or by administration of clodronate-loaded liposomes to wild-type mice, recapitulated the: (1) loss of endosteal osteoblasts and (2) marked reduction of HSC-trophic cytokines at the endosteum, with (3) HSC mobilization into the blood, as observed during G-CSF administration. Together, these results establish that bone marrow macrophages are pivotal to maintain the endosteal HSC niche and that the loss of such macrophages leads to the egress of HSCs into the blood.

  10. A NURBS-based technique for subject-specific construction of knee bone geometry.

    PubMed

    Au, Anthony G; Palathinkal, Darren; Liggins, Adrian B; Raso, V James; Carey, Jason; Lambert, Robert G; Amirfazli, A

    2008-10-01

    Subject-specific finite element (FE) models of bones that form the knee joint require rapid and accurate geometry construction. The present study introduces a semi-automatic non-uniform rational B-spline (NURBS) technique to construct knee bone geometries from computed tomography (CT) images using a combination of edge extraction and CAD surface generation. In particular, this technique accurately constructs endosteal surfaces and can accommodate thin cortical bone by estimating the cortical thickness from well-defined surrounding bone. A procedure is also introduced to overcome the bifurcation at the femoral condyles during surface generation by combining transverse and sagittal plane CT data. Available voxel- and NURBS-based subject-specific construction techniques accurately capture periosteal surfaces but are limited in their ability to capture endosteal geometry. In this study, the proposed NURBS-based technique and a typical voxel mesh technique captured periosteal surfaces within an order of magnitude of image resolution. The endosteum of diaphyseal bone was also captured with similar accuracy by both techniques. However, the voxel mesh model failed to accurately capture the metaphyseal and epiphyseal endosteum due to the poor CT contrast of thin cortical bone, resulting in gross overestimation of cortical thickness. The proposed technique considered both the local and global nature of CT images to arrive at a description of cortical bone thickness accurate to within 2 pixel lengths.

  11. Absorbed fractions for alpha-particles in tissues of cortical bone

    NASA Astrophysics Data System (ADS)

    Watchman, Christopher J.; Bolch, Wesley E.

    2009-10-01

    Bone-seeking alpha-particle emitting radionuclides are common health physics hazards. Additionally, they are under consideration as an option for therapeutic molecular radiotherapy applications. Current dose models do not account for energy or bone-site dependence as shown by alpha-particle absorbed fractions given in ICRP Publication 30. Energy-dependent, yet bone-site independent, alpha-particle absorbed fractions have been presented by the models of Stabin and Siegel (2003 Health Phys. 85 294-310). In this work, a chord-based computational model of alpha-particle transport in cortical bone has been developed that explicitly accounts for both the bone-site and particle-energy dependence of alpha-particle absorbed fractions in this region of the skeleton. The model accounts for energy deposition to three targets: cortical endosteum, haversian space tissues and cortical bone. Path length distributions for cortical bone given in Beddoe (1977 Phys. Med. Biol. 22 298-308) provided additional transport regions in the absorbed fraction calculation. Significant variations in absorbed fractions between different skeletal sites were observed. Differences were observed between this model and the absorbed fractions given in ICRP Publication 30, which varied by as much as a factor of 2.1 for a cortical bone surface source irradiating cortical endosteum.

  12. Biocompatibility, bone healing, and safety evaluation in rabbits with an IlluminOss bone stabilization system.

    PubMed

    McSweeney, Amanda L; Zani, Brett G; Baird, Rose; Stanley, James R L; Hayward, Alison; Markham, Peter M; Kopia, Gregory A; Edelman, Elazer R; Rabiner, Robert

    2017-01-30

    Bone healing, biocompatibility, and safety employing the IlluminOss System (IS), comprised of an inflatable balloon filled with photopolymerizable liquid monomer, was evaluated in New Zealand white rabbits. Successful bone healing and callus remodeling over 6 months was demonstrated radiologically and histologically with IS implants in fenestrated femoral cortices. Biocompatibility was demonstrated with IS implants in brushed, flushed femoral intramedullary spaces, eliciting no adverse, local, or systemic responses and with similar biocompatibility to K-wires in contralateral femurs up to 1 year post-implant. Lastly simulated clinical failures demonstrated the safety of IS implants up to 1 year in the presence of liquid or polymerized polymer within the intramedullary space. Polymerized material displayed cortical bone and vasculature effects comparable to mechanical disruption of the endosteum. In the clinically unlikely scenario with no remediation or polymerization, a high dose monomer injection resulted in marked necrosis of cortical bone, as well as associated vasculature, endosteum, and bone marrow. Overall, when polymerized and hardened within bone intramedullary spaces, this light curable monomer system may provide a safe and effective method for fracture stabilization. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

  13. An optical coherence tomography study for imaging the round window niche and the promontorium tympani

    NASA Astrophysics Data System (ADS)

    Just, T.; Lankenau, E.; Hüttmann, G.; Pau, H. W.

    2010-02-01

    An optical coherence tomography study for imaging the round window niche and the promontorium tympani Tympanosclerosis may involve the tympanic membrane, the ossicles, and the oval and round window niche, respectively. The surgical treatment of the obliterated oval window niche is most challenging. Beside stapesplasty, vibroplasty coupling the floating mass transducer (FMT) onto the round window niche and into a new, so-called third window is indicated. In the latter situation, drilling a hole into the promontorium is necessary to couple the FMT close to the membranous endosteum. Damage of the membranous inner ear must be avoided. The question was whether OCT is useful to identify the endosteum and to provide microanatomical information of the round window niche. OCT was carried out on human temporal bone preparations, in which a third window was drilled leaving the membranous labyrinth and the fluid-filled inner ear intact and the overhang of the round window niche was removed. An especially equipped operating microscope with integrated OCT prototype (spectral-domain-OCT) was used. The OCT images and 3D reconstructions demonstrate the usefulness of OCT to measure the drilling cavity, to visualize the inner ear structures, and to obtain microanatomical information of the round and oval window niche. These findings may have an impact on stapes surgery, on cochlea implantation, and on vibroplasty coupling the FMT onto the round and third window. OCTguided drilling allows for more precise identification of the intact inner ear.

  14. Effects of cryosurgery on the healing pattern of rabbit mandibular bone. A triple fluorochrome labelling study.

    PubMed

    Kuylenstierna, R; Nathanson, A; Lundquist, P G

    1981-01-01

    The reparative process of rabbit mandibular bone injured by cryosurgery was studied by a triple fluorochromic method. The regeneration started late, when compared with fracture healing, and reached its maximum some 4-8 weeks after cryosurgery. A normal distribution of fluorochromes was registered after l2 weeks. The regeneration occurred mainly through growth from the marrow cavity region where the cryogenic impact may have stimulated osteogenesis from surviving endosteum and bone marrow. The destroyed periosteum at the site of the probe-tip attachment did not regenerate, although new bone formation of periosteal origin was noticed at the border of the injured cortex. The general distribution of fluorochromes seemed to follow closely the autoradiographic image obtained using 99TcmMDP in a similar experiment, suggesting comparable ways of accumulation in bone tissue.

  15. Mini-implants and miniplates generate sub-absolute and absolute anchorage.

    PubMed

    Consolaro, Alberto

    2014-01-01

    The functional demand imposed on bone promotes changes in the spatial properties of osteocytes as well as in their extensions uniformly distributed throughout the mineralized surface. Once spatial deformation is established, osteocytes create the need for structural adaptations that result in bone formation and resorption that happen to meet the functional demands. The endosteum and the periosteum are the effectors responsible for stimulating adaptive osteocytes in the inner and outer surfaces. Changes in shape, volume and position of the jaws as a result of skeletal correction of the maxilla and mandible require anchorage to allow bone remodeling to redefine morphology, esthetics and function as a result of spatial deformation conducted by orthodontic appliances. Examining the degree of changes in shape, volume and structural relationship of areas where mini-implants and miniplates are placed allows us to classify mini-implants as devices of subabsolute anchorage and miniplates as devices of absolute anchorage.

  16. Osteal macrophages: a new twist on coupling during bone dynamics.

    PubMed

    Pettit, Allison R; Chang, Ming K; Hume, David A; Raggatt, Liza-Jane

    2008-12-01

    Osteoimmunological interactions are central to maintaining bone homeostasis and are key mechanisms in bone pathology. Macrophages are highly adaptable cells with pleiotropic actions. They have important roles in development, homeostasis and both innate and adaptive immunity. Macrophages can have broad ranging effects on bone, particularly in pathologic situations, but they are most commonly considered for their in vitro potential as an osteoclast precursor. We have recently shown that, like most tissues, the endosteum and periosteum contain a population of resident tissue macrophages (OsteoMacs) that impact on the bone formation process and are likely to play important roles in the bone niche. This review discusses the wider impact of macrophages in bone homeostasis and disease and proposes novel roles for OsteoMacs in bone modelling and remodelling.

  17. ELECTRON ABSORBED FRACTIONS IN AN IMAGE-BASED MICROSCOPIC SKELETAL DOSIMETRY MODEL OF CHINESE ADULT MALE.

    PubMed

    Gao, Shenshen; Ren, Li; Qiu, Rui; Wu, Zhen; Li, Chunyan; Li, Junli

    2017-01-10

    Based on the Chinese reference adult male voxel model, a set of microscopic skeletal models of Chinese adult male is constructed through the processes of computed tomography (CT) imaging, bone coring, micro-CT imaging, image segmentation, merging into macroscopic bone model and implementation in Geant4. At the step of image segmentation, a new bone endosteum (BE) segmentation method is realized by sampling. The set of model contains 32 spongiosa samples with voxel size of 19 μm cubes. The microscopic spongiosa bone data for Chinese adult male are provided. Electron absorbed fractions in red bone marrow (RBM) and BE are calculated. Source tissues include the bone marrow (red and yellow), trabecular bone (surfaces and volumes) and cortical bone (surfaces and volumes). Target tissues include RBM and BE. Electron energies range from 10 keV to 10 MeV. Additionally, comparison of the result with other investigations is provided.

  18. Mechatronic feasibility of minimally invasive, atraumatic cochleostomy.

    PubMed

    Williamson, Tom; Du, Xinli; Bell, Brett; Coulson, Chris; Caversaccio, Marco; Proops, David; Brett, Peter; Weber, Stefan

    2014-01-01

    Robotic assistance in the context of lateral skull base surgery, particularly during cochlear implantation procedures, has been the subject of considerable research over the last decade. The use of robotics during these procedures has the potential to provide significant benefits to the patient by reducing invasiveness when gaining access to the cochlea, as well as reducing intracochlear trauma when performing a cochleostomy. Presented herein is preliminary work on the combination of two robotic systems for reducing invasiveness and trauma in cochlear implantation procedures. A robotic system for minimally invasive inner ear access was combined with a smart drilling tool for robust and safe cochleostomy; evaluation was completed on a single human cadaver specimen. Access to the middle ear was successfully achieved through the facial recess without damage to surrounding anatomical structures; cochleostomy was completed at the planned position with the endosteum remaining intact after drilling as confirmed by microscope evaluation.

  19. Bone Niches, Hematopoietic Stem Cells, and Vessel Formation

    PubMed Central

    Tamma, Roberto; Ribatti, Domenico

    2017-01-01

    Bone marrow (BM) is a source of hematopoietic stem cells (HSCs). HSCs are localized in both the endosteum, in the so-called endosteal niche, and close to thin-walled and fenestrated sinusoidal vessel in the center of BM, in the so-called vascular niche. HSCs give rise to all types of mature blood cells through a process finely controlled by numerous signals emerging from the bone marrow niches where HSCs reside. This review will focus on the description of the role of BM niches in the control of the fate of HSCs and will also highlight the role of the BM niches in the regulation of vasculogenesis and angiogenesis. Moreover, alterations of the signals in niche microenvironment are involved in many aspects of tumor progression and vascularization and further knowledge could provide the basis for the development of new therapeutic strategies. PMID:28098778

  20. Titanium implants in rabbit femur: a histologic evaluation.

    PubMed

    Nociti Júnior, F H; Sallum, A W; Sallum, E A; Bozzo, L

    1997-01-01

    The success achieved by Scandinavian researchers in the development of long-term implants has stimulated many dentists to apply them worldwide. However, most of the implants did not have sufficient scientific support. The purpose of this study was to evaluate host tissue response to the insertion of an endosseous dental implant. Twenty adult New Zealand rabbits were used. Histological evaluation was prepared from the femurs. Results showed a hemorrhagic aspect and inflammatory infiltration which was subsequently substituted by granulation tissue, and later, formation of bone tissue. In the cortical bone, the presence of a necrotic area was observed which was later remodelled, and also an intense proliferation of endosteum and periosteum in the regions next to the implant, resulting in a thickening of the cortical bone surface close to the implant. Therefore, it was observed that titanium implants (Carbontec-Special Materials Ltda.) did not interfere with the bone healing process.

  1. The Floating Mass Transducer on the Round Window Versus Attachment to an Ossicular Replacement Prosthesis

    PubMed Central

    Shimizu, Yoshitaka; Puria, Sunil; Goode, Richard L.

    2010-01-01

    Hypothesis The Vibrant Soundbridge Floating Mass Transducer® (FMT) is part of a commercially available implantable hearing device in which the FMT can be placed in the round window niche (RW) or attached to a partial (V-PORP) or total ossicular replacement prosthesis (V-TORP) contacting the stapes head or footplate. The goal is to provide efficient transfer of sound vibration into the cochlea. The hypothesis is that the FMT location on the prosthesis is superior to the RW location. Background No direct comparisons of the three FMT sites have been performed using the same measurement location. Methods A new measurement method called the “Third Window” method (TW) was used in eleven fresh human temporal bones to compare the sites. A small hole was made into the scala tympani of the temporal bones preserving the endosteum. A reflective target was placed on the TW endosteum and displacement of the cochlear fluid was measured using a Polytec HLV-1000 laser Doppler vibrometer. The input to the FMT at all locations was a constant 316 millivolts (mV); the frequency range was 0.5 to 0.8 kHz. Results The V-PORP and V-TORP FMT locations both provided statistically significant better performance above 1.0 kHz than the RW site, but not below that frequency. The V-PORP and V-TORP responses were similar at all test frequencies. Conclusion In this temporal bone model, the FMT provided better higher frequency performance when attached to a PORP or TORP than in the RW niche. PMID:20930654

  2. Periosteal Sharpey's fibers: a novel bone matrix regulatory system?

    PubMed

    Aaron, Jean E

    2012-01-01

    Sharpey's "perforating" fibers (SF) are well known skeletally in tooth anchorage. Elsewhere they provide anchorage for the periosteum and are less well documented. Immunohistochemistry has transformed their potential significance by identifying their collagen type III (CIII) content and enabling their mapping in domains as permeating arrays of fibers (5-25 μ thick), protected from osteoclastic resorption by their poor mineralization. As periosteal extensions they are crucial in early skeletal development and central to intramembranous bone healing, providing unique microanatomical avenues for musculoskeletal exchange, their composition (e.g., collagen type VI, elastin, tenascin) combined with a multiaxial pattern of insertion suggesting a role more complex than attachment alone would justify. A proportion permeate the cortex to the endosteum (and beyond), fusing into a CIII-rich osteoid layer (<2 μ thick) encompassing all resting surfaces, and with which they apparently integrate into a PERIOSTEAL-SHARPEY FIBER-ENDOSTEUM (PSE) structural continuum. This intraosseous system behaves in favor of bone loss or gain depending upon extraneous stimuli (i.e., like Frost's hypothetical "mechanostat"). Thus, the birefringent fibers are sensitive to humoral factors (e.g., estrogen causes retraction, rat femur model), physical activity (e.g., running causes expansion, rat model), aging (e.g., causes fragmentation, pig mandible model), and pathology (e.g., atrophied in osteoporosis, hypertrophied in osteoarthritis, human proximal femur), and with encroaching mineral particles hardening the usually soft parts. In this way the unobtrusive periosteal SF network may regulate bone status, perhaps even contributing to predictable "hotspots" of trabecular disconnection, particularly at sites of tension prone to fatigue, and with the network deteriorating significantly before bone matrix loss.

  3. Americium in the beagle dog: biokinetic and dosimetric model.

    PubMed

    Luciani, A; Polig, E; Lloyd, R D; Miller, S C

    2006-05-01

    A biokinetic model of the systemic distribution of americium in the beagle dog is presented. The model is based on a previous biokinetic model of plutonium. The data sets used for the development of the model were the measurements of excreted activity (urine and feces) and organ burdens (skeleton, liver, and other soft tissues) for different levels of initial injected activity. In developing the model, the compartmental structure of the skeleton of the plutonium model was adopted, and only the numerical values of parameters were adapted. The model well describes the fractions of americium in the skeleton, liver, and soft tissues and the total fraction excreted in urine and feces. The tuning of the liver clearance parameter provides a realistic description of the change in the partitioning between liver and skeleton for different injection levels. The most significant features of the biokinetics and dosimetry of americium and plutonium in beagles are compared. The total fractions of the clearance to the skeleton and the liver are roughly equal to the value for plutonium, but the partitioning of americium between these organs is reversed with respect to the partitioning of plutonium. 241Am doses to liver and skeleton are similar to 239Pu doses, owing to some counteracting factors. For the highest injection level, the liver mass is dependent on the time post injection. For the skeletal tissues, the dose to the cortical endosteum by far exceeds the dose to the trabecular endosteum and the red marrow. The model provides the basis for statistical survival analyses and risk estimates.

  4. Differential β3 and β1 Integrin Expression in Bone Marrow and Cortical Bone of Estrogen Deficient Rats.

    PubMed

    Voisin, Muriel; McNamara, Laoise M

    2015-09-01

    Integrin-based (β3 ) attachments to the extracellular matrix (ECM) on osteocyte cell processes have recently been proposed to play an important role in facilitating osteocyte mechanosensation. However, it is not yet known whether integrin expression is altered in the mechanoregulatory osteocytes during osteoporosis. The objective of this study was to test the hypothesis that the expression of integrin-based mechanosensory complexes (β1 and β3 integrins) is altered as a direct response to estrogen deficiency, in an estrogen deficient animal model of osteoporosis. Four weeks post-operatively, immunohistochemistry was used to detect for β1 and β3 integrin subunits in bone tissue and marrow of ovariectomized (OVX; N = 4) and SHAM (N = 4) operated animals. A tartrate resistant acid phosphatase (TRAP) control stain was performed to quantify the presence of osteoclasts in the bone marrow and bone surfaces. Image analysis was performed to quantify expression patterns in different biological compartments, that is, bone marrow, endosteum, and cortical bone. Our results showed that β1 integrins were ubiquitously expressed throughout the bone and marrow, for both OVX and SHAM groups. β3 integrin subunit expression was lower in bone cells from osteoporotic animals compared to controls, whereas β3 expression in marrow cells did not differ significantly between groups. At the endosteum no difference was observed in β3 integrin subunit expression. As expected, the number of osteoclasts was higher in the OVX group validating an imbalance in bone remodeling. We propose that a reduction in β3 integrin expression in osteocytes might impair mechanosensation by bone cells during estrogen deficiency.

  5. Therapeutic impact of low amplitude high frequency whole body vibrations on the osteogenesis imperfecta mouse bone.

    PubMed

    Vanleene, Maximilien; Shefelbine, Sandra J

    2013-04-01

    Osteogenesis imperfecta (OI) is characterized by extremely brittle bone. Currently, bisphosphonate drugs allow a decrease of fracture by inhibiting bone resorption and increasing bone mass but with possible long term side effects. Whole body mechanical vibrations (WBV) treatment may offer a promising route to stimulate bone formation in OI patients as it has exhibited health benefits on both muscle and bone mass in human and animal models. The present study has investigated the effects of WBV (45Hz, 0.3g, 15minutes/days, 5days/week) in young OI (oim) and wild type female mice from 3 to 8weeks of age. Vibration therapy resulted in a significant increase in the cortical bone area and cortical thickness in the femur and tibia diaphysis of both vibrated oim and wild type mice compared to sham controls. Trabecular bone was not affected by vibration in the wild type mice; vibrated oim mice, however, exhibited significantly higher trabecular bone volume fraction in the proximal tibia. Femoral stiffness and yield load in three point bending were greater in the vibrated wild type mice than in sham controls, most likely attributed to the increase in femur cortical cross sectional area observed in the μCT morphology analyses. The vibrated oim mice showed a trend toward improved mechanical properties, but bending data had large standard deviations and there was no significant difference between vibrated and non-vibrated oim mice. No significant difference of the bone apposition was observed in the tibial metaphyseal trabecular bone for both the oim and wild type vibrated mice by histomorphometry analyses of calcein labels. At the mid diaphysis, the cortical bone apposition was not significantly influenced by the WBV treatment in both the endosteum and periosteum of the oim vibrated mice while a significant change is observed in the endosteum of the vibrated wild type mice. As only a weak impact in bone apposition between the vibrated and sham groups is observed in the

  6. Mesenchymal Stem Cells and Pericytes: To What Extent Are They Related?

    PubMed

    de Souza, Lucas Eduardo Botelho; Malta, Tathiane Maistro; Kashima Haddad, Simone; Covas, Dimas Tadeu

    2016-12-15

    Mesenchymal stem cells (MSCs) were initially identified as progenitors of skeletal tissues within mammalian bone marrow and cells with similar properties were also obtained from other tissues such as adipose and dental pulp. Although MSCs have been extensively investigated, their native behavior and in vivo identity remain poorly defined. Uncovering the in vivo identity of MSCs has been challenging due to the lack of exclusive cell markers, cellular alterations caused by culture methods, and extensive focus on in vitro properties for characterization. Although MSC site of origin influences their functional properties, these mesenchymal progenitors can be found in the perivascular space in virtually all organs from where they were obtained. However, the precise identity of MSCs within the vascular wall is highly controversial. The recurrent concept that MSCs correspond to pericytes in vivo has been supported mainly by their perivascular localization and expression of some molecular markers. However, this view has been a subject of controversy, in part, due to the application of loose criteria to define pericytes and due to the lack of a marker able to unequivocally identify these cells. Furthermore, recent evidences indicate that subpopulations of MSCs can be found at extravascular sites such as the endosteum. In this opinion review, we bring together the advances and pitfalls on the search for the in vivo identity of MSCs and highlight the recent evidences that suggest that perivascular MSCs are adventitial cells, acting as precursors of pericytes and other stromal cells during tissue homeostasis.

  7. Periosteum and bone marrow in bone lengthening: a DEXA quantitative evaluation in rabbits.

    PubMed

    Guichet, J M; Braillon, P; Bodenreider, O; Lascombes, P

    1998-10-01

    We quantitatively studied the role of periosteum and bone marrow-endosteum during lengthening in 18 growing rabbits, comparing four surgical procedures: 1) periosteum and bone marrow preservation, 2) periosteum preservation, bone marrow destruction, 3) periosteum destruction, bone marrow preservation, 4) periosteum and bone marrow destruction. An external fixator was set on one femur, the other serving as a control. Distraction began on day 5 and stopped on day 25 (0.25 mm/12 hours). On day 30, femora were harvested with a layer of muscle. Area, bone mineral content and density were measured by dual-energy x-ray absorptiometry. Procedure 2 showed the highest increase in bone mineral content around the elongated callus (127%) compared to procedures: 1 (81%), 3 (25%) and 4 (-8%, i.e., resorption of bone ends). A statistically significant effect on bone formation was observed when preserving (vs. destroying): 1) periosteum, 2) bone marrow (effect observed only around the distraction gap), 3) periosteum and bone marrow in combination. Periosteum alone forms a larger callus, with more mineral content than bone marrow alone, and destruction of both results in the absence of bone formation around the distraction area. Careful preservation of periosteum is essential to bone healing. Formation of bone with a large mineral content does not require bone marrow preservation, but there is an interaction effect on healing between bone marrow and periosteum.

  8. Role of guided bone regeneration principle in preventing fibrous healing in distraction osteogenesis at high speed: experimental study in rabbit mandibles.

    PubMed

    Elshahat, Ahmed; Inoue, Nozomu; Marti, Guy; Safe, Ikram; Manson, Paul; Vanderkolk, Craig

    2004-11-01

    The formation of fibrous tissues at the distraction gap may result from the accumulation of rapidly migrating fibroblasts at the site of an osteotomy, especially when distraction is rapid. Addition of osteopromotive membranes could theoretically prevent fibroblasts from entering the distraction gap, allowing the osteotomy site to be filled with only osteogenic cells. This study is an attempt to achieve a rapid successful distraction without fibrosis through the use of collagen membranes. Sixteen skeletally mature New Zealand white rabbits were used in this study. They were divided into two groups. One rabbit from each group was excluded from the study because of dislodgement of the distractors. In one group (n = 7), distraction was done as usual. In the other group (n = 7), a collagen membrane surrounded the osteotomy site to be distracted. After a 7-day latency period, distraction started at a rate 2 mm once per day for 5 days. The distractor was left in place for 4 weeks to allow consolidation. Results showed osteogenesis in both groups. Whereas addition of the membrane to distraction increased the quantity of bone formed, absence of the membrane allowed early mineralization (better quality of bone regarding the density). Neither of the two groups showed significant fibrosis or cartilage formation. The endosteum served as a source of blood supply when the periosteum was excluded. The periosteum served as a membrane for guided bone regeneration. Membranes for guided bone regeneration can be used with distraction when the periosteum is lost from trauma or is broken from fast distraction.

  9. Evaluation of injectable silica-embedded nanohydroxyapatite bone substitute in a rat tibia defect model

    PubMed Central

    Xu, Weiguo; Ganz, Cornelia; Weber, Ulf; Adam, Martin; Holzhüter, Gerd; Wolter, Daniel; Frerich, Bernhard; Vollmar, Brigitte; Gerber, Thomas

    2011-01-01

    In clinical practice, vertebral compression fractures occur after trauma and osteoporosis. Kyphoplasty is a minimally invasive procedure using bone filler material for the treatment of such fractures. A full synthetic injectable bone substitute (SIBS) was manufactured by means of spray drying. The aim of this study was to characterize the SIBS and to analyze the remodelling process during degradation of the biomaterial and new bone formation after implantation. SIBS is an aqueous suspension of donut-like microparticles. These microparticles consist of nanocrystallites of synthetic hydroxyapatite embedded in amorphous silica gel. After implantation of SIBS in a proximal tibial diaphyseal defect in 52 rats, grafts were harvested for subsequent analysis on different days. Newly formed bone originating from endosteum was observed on day 6. Hematomas in the medullary space and cortical wounds disappeared on day 12. The wound region was completely replaced by a composite of newly formed cancellous bone, extracellular matrix, and SIBS. At day 63 the cortical defect was fully healed by bone, while newly formed bone in the medullary space almost disappeared and was replaced with bone marrow. In conclusion, SIBS demonstrated a unique structure with osteoinductive and bioresorbable properties, which induced fast bone regeneration. Therefore, a clinical application of SIBS for kyphoplasty is promising. PMID:21845044

  10. Multimodal imaging reveals structural and functional heterogeneity in different bone marrow compartments: functional implications on hematopoietic stem cells.

    PubMed

    Lassailly, Francois; Foster, Katie; Lopez-Onieva, Lourdes; Currie, Erin; Bonnet, Dominique

    2013-09-05

    Intravital microscopy of the calvarium is the only noninvasive method for high-resolution imaging of the bone marrow (BM) and hematopoietic stem cell (HSC) niches. However, it is unclear if the calvarium is representative of all BM compartments. Using the combination of whole body optical imaging, intravital microscopy, and "in vivo fluorescence trapping," a thorough comparison of HSCs and putative HSC niches in the calvaria, epiphyses, and diaphyses, at steady state or after HSC transplantation, can be made. We report substantial heterogeneity between different BM compartments in terms of bone-remodeling activity (BRA), blood volume fraction (BVF), and hypoxia. Although BVF is high in all BM compartments, including areas adjacent to the endosteum, we found that compartments displaying the highest BVF and BRA were preferentially seeded and engrafted upon HSC transplantation. Unexpectedly, the macroanatomical distribution of HSCs at steady state is homogeneous across these 3 areas and independent of these 2 parameters and suggests the existence of "reconstituting niches," which are distinct from "homeostatic niches." Both types of niches were observed in the calvarium, indicating that endochondral ossification, the process needed for the formation of HSC niches during embryogenesis, is dispensable for the formation of HSC niches during adulthood.

  11. Early cortical bone healing around loaded titanium implants: a histological study in the rabbit.

    PubMed

    Slaets, Elke; Naert, Ignace; Carmeliet, Geert; Duyck, Joke

    2009-02-01

    To identify the role of immediate implant loading on the early phases of the bone healing responses. Implants were placed in rabbit tibial diaphyses and left to heal for 3, 7, 14, 28 or 42 days. Half of the animals received an immediate loading protocol of 2.2 N at 3 Hz for 1800 cycles and 5 days/week, whereas the others served as unloaded controls. Histological assessment was combined with histomorphometrical measurements. At early time-points, an endosteal and periosteal new bone formation was found, while the cortex itself contained damaged osteocytes. At later time-points, new bone formation was also found at the cortical level itself. Differences between groups were found mainly in this new bone formation process, with larger reactions for the endosteal and periosteal bone in the loaded group after 28 and 42 days, respectively. At the end-point of the experiment, bone formation at the cortical level was reduced in the loaded group compared with the control group. These results show that the immediate loading protocol caused no differences in the sequential events leading to osseointegration in cortical bone. However, the processes of new bone formation originating from the endosteum and the periosteum lasted longer compared with the unloaded controls.

  12. Use of an absorbable membrane to position biologically inductive materials in the periprosthetic space of cemented joints.

    PubMed

    DiResta, Gene R; Brown, Holly; Aiken, Sean; Doty, Steven; Schneider, Robert; Wright, Timothy; Healey, John H

    2006-01-01

    A device is presented that positions ultrahigh molecular weight polyethylene (UHMWPE) debris against periprosthetic bone surfaces. This can facilitate the study of aseptic loosening associated with cemented joint prostheses by speeding the appearance of this debris within the periprosthetic space. The device, composed of a 100 microm thick bioabsorbable membrane impregnated with 1.4 x 10(9) sub-micron particles of UHMWPE debris, is positioned on the endosteum of the bone prior to the insertion of the cemented orthopedic implant. An in vitro pullout study and an in vivo canine pilot study were performed to investigate its potential to accelerate "time to aseptic loosening" of cemented prosthetic joints. Pullout studies characterized the influence of the membrane on initial implant fixation. The tensile stresses (mean+/-std.dev.) required to withdraw a prosthesis cemented into canine femurs with and without the membrane were 1.15+/-0.3 and 1.54+/-0.01 MPa, respectively; these findings were not significantly different (p > 0.4). The in vivo pilot study, involving five dogs, was performed to evaluate the efficacy of the debris to accelerate loosening in a canine cemented hip arthroplasty. Aseptic loosening and lameness occurred within 12 months, quicker than the 30 months reported in a retrospective clinical review of canine hip arthroplasty.

  13. The Hematopoietic Niche in Myeloproliferative Neoplasms

    PubMed Central

    Schmitt-Graeff, Annette H.; Nitschke, Roland; Zeiser, Robert

    2015-01-01

    Specialized microanatomical areas of the bone marrow provide the signals that are mandatory for the maintenance and regulation of hematopoietic stem cells (HSCs) and progenitor cells. A complex microenvironment adjacent to the marrow vasculature (vascular niche) and close to the endosteum (endosteal niche) harbors multiple cell types including mesenchymal stromal cells and their derivatives such as CAR cells expressing high levels of chemokines C-X-C motif ligand 12 and early osteoblastic lineage cells, endothelial cells, and megakaryocytes. The characterization of the cellular and molecular networks operating in the HSC niche has opened new perspectives for the understanding of the bidirectional cross-talk between HSCs and stromal cell populations in normal and malignant conditions. A structural and functional remodeling of the niche may contribute to the development of myeloproliferative neoplasms (MPN). Malignant HSCs may alter the function and survival of MSCs that do not belong to the neoplastic clone. For example, a regression of nestin+ MSCs by apoptosis has been attributed to neuroglial damage in MPN. Nonneoplastic MSCs in turn can promote aggressiveness and drug resistance of malignant cells. In the future, strategies to counteract the pathological interaction between the niche and neoplastic HSCs may offer additional treatment strategies for MPN patients. PMID:26696752

  14. Osseointegration in hip prostheses: experimental study in sheep.

    PubMed

    Doria, C; De Santis, V; Falcone, G; Proietti, L; De Santis, E

    2003-01-01

    Sixteen 2- to 3-year-old sheep were submitted to a hemiarthroplasty of the hip joint with a specially designed femoral component. The proximal two thirds of the stem had a circumferential, plasma-sprayed, porous coating with hydroxyapatite. The animals where killed a 15, 30, 60, 90, 120, 180, 200, 270, 360, and 540 days after surgery. Femurs were submitted to plain radiographs, computerised tomography (CT) scan, and dual energy X-ray absorptiometry (DEXA). Cross-sections were obtained at four different levels and studied using scanning electron microscopy. In the coated portion of the stem, apposition of woven immature bone was evident at 15-30 days and mature lamellar bone by 30 days. With time, the gap between the endosteum and the coated surface was filled by bridges of lamellar bone with a marked trabecular orientation. In the distal uncoated portion of the stem, the implant was initially surrounded by fibrous tissue that, with time, transformed into lamellar bone.

  15. Use of multiple acoustic wave modes for assessment of long bones: Model study

    PubMed Central

    Tatarinov, Alexey; Sarvazyan, Noune; Sarvazyan, Armen

    2010-01-01

    Multiple acoustic wave mode method has been proposed as a new modality in axial bone QUS. The new method is based on measurement of ultrasound velocity at different ratio of wavelength to the bone thickness, and taking into account both bulk and guided waves. It allows assessment of changes in both the material properties related to porosity and mineralization as well as the cortical thickness influenced by resorption from inner layers, which are equally important in diagnostics of osteoporosis and other bone osteopenia. Developed method was validated in model studies using a dual-frequency (100 and 500 kHz) ultrasound device. Three types of bone phantoms for long bones were developed and tested: (1) tubular specimens from polymer materials to model combined changes of material stiffness and cortical wall thickness; (2) layered specimens to model porosity in compact bone progressing from endosteum towards periosteum; (3) animal bone specimens with both cortical and trabecular components. Observed changes of the ultrasound velocity of guided waves at 100 kHz followed gradual changes in the thickness of the intact cortical layer. On the other hand, the bulk velocity at 500 kHz remained nearly constant at the different cortical layer thickness but was affected by the material stiffness. Similar trends were observed in phantoms and in fragments of animal bones. PMID:15982472

  16. Characterization of the major parathyroid hormone target cell in the endosteal metaphysis of rat long bones

    SciTech Connect

    Rouleau, M.F.; Mitchell, J.; Goltzman, D. )

    1990-10-01

    The majority of in vivo competitive binding of parathyroid hormone (PTH) in the endosteal metaphysis of rat long bones was recently shown to be localized in the intertrabecular tissue to a cell that is distinct from a differentiated osteoblast. In the present report we have further characterized this cell, termed a parathyroid hormone target (PT) cell, by light and electron microscopy using radioautography and histochemical techniques. These studies demonstrate that the PT cell is a mononuclear cell with a large cell body located at times between clusters of differentiated osteoblasts, as well as in other regions of the intertrabecular tissue. Its long cytoplasmic processes extend from the bone matrix through the intertrabecular region toward vascular structures, interdigitating with various cells of the endosteum. A distinctive tubular structure originating in the Golgi system and often associated with long mitochondria and glycogen particles extends throughout the cytoplasmic processes of the PT cell. Based on its capacity to incorporate ({sup 3}H)thymidine, the PT cell appears to divide rather slowly. The identification of occasional hybrid cells with ultrastructural features of both the PT cell and the differentiated osteoblast and the presence of histochemical evidence for alkaline phosphatase activity suggest that the PT cell is of the osteoblast lineage. These studies therefore morphologically define a major osseous target cell for PTH that, although of the osteoblast lineage, is not a differentiated osteoblast and provide in vivo evidence that characteristics of the 'osteoblast phenotype' are not restricted to a sole osseous cell type.

  17. The Promotional Effect of Mesenchymal Stem Cell Homing on Bone Tissue Regeneration.

    PubMed

    Zhou, Qi; Yang, Chengzhe; Yang, Pishan

    2017-01-01

    Background & Objective: Bone defects caused by bone fractures, malformations, postoperation on tumor and even periodontitis have became serious clinical problems. Although the exact origin of osteoblast precursors is still obscure, mesenchymal stem cells (MSCs) that originate from local bone marrow, periosteum, endosteum, mineralized bone or systemic circulation play key roles in osteoblastic differentiation and secretion of multiple factors during spontaneous healing of bone trauma or defect. Substantial evidences have shown that systemically infused MSCs can home and participate in bone tissue repair or regeneration. Applying pharmacological molecules to promote MSC homing or to mobilize MSCs in bone marrow niche to increase the amount of MSCs in the peripheral blood has been demonstrated to be important strategies to enhance MSC homing. However, there are some systemic conditions which influence MSC homing. In this paper, we review both systemic and local homing of MSCs during bone regeneration, and discuss strategies for enhancing the recruitment of MSCs to the injured bone tissues. Systemic influences of MSC homing are also discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  18. Hematopoietic Stem Cells in Neural-crest Derived Bone Marrow.

    PubMed

    Jiang, Nan; Chen, Mo; Yang, Guodong; Xiang, Lusai; He, Ling; Hei, Thomas K; Chotkowski, Gregory; Tarnow, Dennis P; Finkel, Myron; Ding, Lei; Zhou, Yanheng; Mao, Jeremy J

    2016-12-21

    Hematopoietic stem cells (HSCs) in the endosteum of mesoderm-derived appendicular bones have been extensively studied. Neural crest-derived bones differ from appendicular bones in developmental origin, mode of bone formation and pathological bone resorption. Whether neural crest-derived bones harbor HSCs is elusive. Here, we discovered HSC-like cells in postnatal murine mandible, and benchmarked them with donor-matched, mesoderm-derived femur/tibia HSCs, including clonogenic assay and long-term culture. Mandibular CD34 negative, LSK cells proliferated similarly to appendicular HSCs, and differentiated into all hematopoietic lineages. Mandibular HSCs showed a consistent deficiency in lymphoid differentiation, including significantly fewer CD229 + fractions, PreProB, ProB, PreB and B220 + slgM cells. Remarkably, mandibular HSCs reconstituted irradiated hematopoietic bone marrow in vivo, just as appendicular HSCs. Genomic profiling of osteoblasts from mandibular and femur/tibia bone marrow revealed deficiencies in several HSC niche regulators among mandibular osteoblasts including Cxcl12. Neural crest derived bone harbors HSCs that function similarly to appendicular HSCs but are deficient in the lymphoid lineage. Thus, lymphoid deficiency of mandibular HSCs may be accounted by putative niche regulating genes. HSCs in craniofacial bones have functional implications in homeostasis, osteoclastogenesis, immune functions, tumor metastasis and infections such as osteonecrosis of the jaw.

  19. Granulocyte Colony-Stimulating Factor Induces Osteoblast Inhibition by B Lymphocytes and Osteoclast Activation by T Lymphocytes during Hematopoietic Stem/Progenitor Cell Mobilization.

    PubMed

    Li, Sidan; Li, Tianshou; Chen, Yongbing; Nie, Yinchao; Li, Changhong; Liu, Lanting; Li, Qiaochuan; Qiu, Lugui

    2015-08-01

    In the bone marrow (BM), hematopoietic stem and progenitor cells (HSPCs) reside in specialized niches near osteoblast cells at the endosteum. HSPCs that egress to peripheral blood are widely used for transplant, and mobilization is most commonly performed with recombinant human granulocyte colony-stimulating factor (G-CSF). However, the cellular targets of G-CSF that initiate the mobilization cascade and bone remodeling are not completely understood. Here, we examined whether T and B lymphocytes modulate the bone niche and influence HSPC mobilization. We used T and B defective mice to show that G-CSF-induced mobilization of HSPCs correlated with B lymphocytes but poorly with T lymphocytes. In addition, we found that defective B lymphocytes prevent G-CSF-mediated osteoblast disruption, and further study showed BM osteoblasts were reduced coincident with mobilization, induced by elevated expression of dickkopf1 of BM B lymphocytes. BM T cells were also involved in G-CSF-induced osteoclast activation by regulating the Receptor Activator of Nuclear Factor-κ B Ligand/Osteoprotegerin (RANKL/OPG) axis. These data provide evidence that BM B and T lymphocytes play a role in G-CSF-induced HSPC mobilization by regulating bone remodeling.

  20. Current insights on the regenerative potential of the periosteum: molecular, cellular, and endogenous engineering approaches.

    PubMed

    Colnot, Céline; Zhang, Xinping; Knothe Tate, Melissa L

    2012-12-01

    While century old clinical reports document the periosteum's remarkable regenerative capacity, only in the past decade have scientists undertaken mechanistic investigations of its regenerative potential. At a Workshop at the 2012 Annual Meeting of Orthopaedic Research Society, we reviewed the molecular, cellular, and tissue scale approaches to elucidate the mechanisms underlying the periosteum's regenerative potential as well as translational therapies engineering solutions inspired by its remarkable regenerative capacity. The entire population of osteoblasts within periosteum, and at endosteal and trabecular bone surfaces within the bone marrow, derives from the embryonic perichondrium. Periosteal cells contribute more to cartilage and bone formation within the callus during fracture healing than do cells of the bone marrow or endosteum, which do not migrate out of the marrow compartment. Furthermore, a current healing paradigm regards the activation, expansion, and differentiation of periosteal stem/progenitor cells as an essential step in building a template for subsequent neovascularization, bone formation, and remodeling. The periosteum comprises a complex, composite structure, providing a niche for pluripotent cells and a repository for molecular factors that modulate cell behavior. The periosteum's advanced, "smart" material properties change depending on the mechanical, chemical, and biological state of the tissue. Understanding periosteum development, progenitor cell-driven initiation of periosteum's endogenous tissue building capacity, and the complex structure-function relationships of periosteum as an advanced material are important for harnessing and engineering ersatz materials to mimic the periosteum's remarkable regenerative capacity. Copyright © 2012 Orthopaedic Research Society.

  1. Feasibility Study of a Hand Guided Robotic Drill for Cochleostomy

    PubMed Central

    Brett, Peter; Zoka-Assadi, Masoud; Reid, Andrew; Proops, David

    2014-01-01

    The concept of a hand guided robotic drill has been inspired by an automated, arm supported robotic drill recently applied in clinical practice to produce cochleostomies without penetrating the endosteum ready for inserting cochlear electrodes. The smart tactile sensing scheme within the drill enables precise control of the state of interaction between tissues and tools in real-time. This paper reports development studies of the hand guided robotic drill where the same consistent outcomes, augmentation of surgeon control and skill, and similar reduction of induced disturbances on the hearing organ are achieved. The device operates with differing presentation of tissues resulting from variation in anatomy and demonstrates the ability to control or avoid penetration of tissue layers as required and to respond to intended rather than involuntary motion of the surgeon operator. The advantage of hand guided over an arm supported system is that it offers flexibility in adjusting the drilling trajectory. This can be important to initiate cutting on a hard convex tissue surface without slipping and then to proceed on the desired trajectory after cutting has commenced. The results for trials on phantoms show that drill unit compliance is an important factor in the design. PMID:25110684

  2. Effects of local administration of growth hormone in peri-implant bone: an experimental study with implants in rabbit tibiae.

    PubMed

    Tresguerres, Isabel F; Blanco, Luis; Clemente, Celia; Tresguerres, Jesús A F

    2003-01-01

    The objective of this study was to evaluate the qualitative and quantitative differences that could appear in newly formed peri-implant bone around Screw-Vent implants placed in rabbit tibiae when treated with local administration of growth hormone (GH). Eight New Zealand rabbits were randomly divided into 2 groups: the experimental group, which received 4 IU of GH in the form of lyophilized powder added to the ostectomy site before implant placement, and the control group, which did not receive GH before implant placement. Animals were sacrificed 2 weeks later, and histologic sections were obtained for histomorphometry and observation under light microscopy. The sections in the GH-treated group presented enhanced growth of new trabeculae from the periosteal tissue, and the bone-to-implant contact in the experimental group was significantly greater (P < .05). Local administration of GH stimulated a more dramatic effect than that seen previously with systemic GH administration, prompting growth from both the periosteum and endosteum. Local administration of GH at the time of implant placement could enhance peri-implant bone reaction.

  3. Uncemented primary press-fit total hip arthroplasty: a 3 to 6 years of experience.

    PubMed

    Vidyadhara, S; Rao, S K

    2007-04-01

    To analyse the 3 to 6 years' clinicoradiological outcome of 45 uncemented total hip arthroplasties performed in 37 patients using cementless Spotorno stem and St Nabor cup. The main indications for surgery were avascular necrosis of the femoral head and rheumatoid arthritis. Younger patients with good bone quality and a trumpet-shaped femur were eligible. A single surgeon performed all the operations using a posterolateral approach. Patients were reviewed at 6 weeks, 3 months, 6 months, and yearly thereafter. The clinical status was recorded using the Harris Hip Score. All radiographs were analysed by 2 independent blinded observers on 2 separate occasions. The mean follow-up period was 49 months and the mean Harris Hip Score at the latest follow-up was 94. Osseointegration in the form of trabeculae running from the endosteum to the prosthesis surface along with tropism of the calcar was evident in 73% of the hips. None of the remaining hips showed any continuous radio-opaque lines suggestive of a lack of bone ongrowth. Patients with endosteal condensation had better Harris Hip Scores. Intra-operative stability of the implants could fairly predict outcome. Initial clinicoradiological results of uncemented total hip arthroplasty are promising in younger patients with good bone quality and a trumpet-shaped femur.

  4. Optical Coherence Tomography Guided Laser Cochleostomy: Towards the Accuracy on Tens of Micrometer Scale

    PubMed Central

    Weller, Marcel; Wieser, Wolfgang; Huber, Robert; Raczkowsky, Jörg; Schipper, Jörg; Wörn, Heinz; Klenzner, Thomas

    2014-01-01

    Lasers have been proven to be precise tools for bone ablation. Applying no mechanical stress to the patient, they are potentially very suitable for microsurgery on fragile structures such as the inner ear. However, it remains challenging to control the laser-bone ablation without injuring embedded soft tissue. In this work, we demonstrate a closed-loop control of a short-pulsed CO2 laser to perform laser cochleostomy under the monitoring of an optical coherence tomography (OCT) system. A foresighted detection of the bone-endosteum-perilymph boundary several hundred micrometers before its exposure has been realized. Position and duration of the laser pulses are planned based on the residual bone thickness distribution. OCT itself is also used as a highly accurate tracking system for motion compensation between the target area and the optics. During ex vivo experimental evaluation on fresh porcine cochleae, the ablation process terminated automatically when the thickness of the residual tissue layer uniformly reached a predefined value. The shape of the resulting channel bottom converged to the natural curvature of the endosteal layer without injuring the critical structure. Preliminary measurements in OCT scans indicated that the mean absolute accuracy of the shape approximation was only around 20 μm. PMID:25295253

  5. Outcome of 47 consecutive sinus lift operations using aragonitic calcium carbonate associated with autologous platelet-rich plasma: clinical, histologic, and histomorphometrical evaluations.

    PubMed

    Papa, Francesco; Cortese, Antonio; Sagliocco, Raffaele; Farella, Mauro; Banzi, Claudio; Maltarello, Maria Cristina; Pellegrini, Camilla; D'Agostino, Elio; Aimola, Pierpaolo; Claudio, Pier Paolo

    2009-11-01

    The reconstruction of the maxillary bone frequently represents a real challenge for maxillofacial surgeons especially regarding the best choice of a suitable material to produce the required bone augmentation. In this study, we summarize our clinical experience on 47 sinus lifts with lateral approach using a mixture of aragonitic calcium carbonate and autologous platelet-rich plasma compared with that of a previous published study in which bovine bone (LADDEC) and autologous bone were used in 50 sinus lift operations (Br J Oral Maxillofac Surg 2005;43:309-313). We subjected 34 patients to sinus lift operation, for a total of 47 sinus lifts, using natural coral as osteoconductive material. This material, combined with autologous platelet-rich plasma, was placed onto the maxillary sinus floor, after carefully lifting the endosteum. Cases were clinically, radiographically, and histologically analyzed. Histomorphometrical analysis, tests of microhardness, and x-ray microanalysis were conducted comparing the various sample to controls obtained from the same patients. Histomorphometrical analysis, microhardness test, and x-ray microanalysis demonstrated that the newly formed bone showed morphologic and structural characteristics that were similar for all the grafting materials compared (bovine bone, autologous bone, and coral). Although all the grafting materials did yield good results of maturation of the newly formed bone, best results were achieved using autologous bone.

  6. Early B-lymphocyte precursor cells in mouse bone marrow: Subosteal localization of B220+ cells during postirradiation regeneration

    SciTech Connect

    Jacobsen, K.; Tepper, J.; Osmond, D.G. )

    1990-05-01

    The localization of early B-lymphocyte precursor cells in the bone marrow of young mice has been studied during recovery from sublethal whole body gamma-irradiation (150 rad). Initial studies by double immunofluorescence labeling of the B-lineage-associated cell surface glycoprotein, B220, and of mu heavy chains in bone marrow cell suspensions, demonstrated a sequential wave of regeneration of early B precursor cells, pre-B cells, and B cells. Early B precursor cells expressing B220 but not mu chains were enriched at 1-3 days following irradiation. After in vivo administration of 125I-labeled monoclonal antibody 14.8 to detect B220+ cells in situ, light and electron microscope radioautography of femoral bone marrow sections revealed concentrations of labeled B220+ cells located peripherally near the cortical bone at 1-3 days following irradiation, increasing in numbers in more central areas by 5-7 days. Proliferative B220+ precursor cells were found within layers of bone-lining cells and in a subosteal area characterized by a prominent electron-dense extracellular matrix, often associated with stromal reticular cells. The results demonstrate that the precursor cells that are active in the bone marrow early in the recovery of B lymphopoiesis after gamma-irradiation are located both within and near the endosteum of the surrounding bone. The distinctive extracellular matrix and stromal cell associations noted in this region may contribute to a supportive local microenvironment for early hemopoietic progenitor cells.

  7. Endosteal-like extracellular matrix expression on melt electrospun written scaffolds.

    PubMed

    Muerza-Cascante, Maria Lourdes; Shokoohmand, Ali; Khosrotehrani, Kiarash; Haylock, David; Dalton, Paul D; Hutmacher, Dietmar W; Loessner, Daniela

    2016-12-22

    Tissue engineering technology platforms constitute a unique opportunity to integrate cells and extracellular matrix (ECM) proteins into scaffolds and matrices that mimic the natural microenvironment in vitro. The development of tissue-engineered 3D models that mimic the endosteal microenvironment enables researchers to discover the causes and improve treatments for blood and immune-related diseases. The aim of this study was to establish a physiologically relevant in vitro model using 3D printed scaffolds to assess the contribution of human cells to the formation of a construct that mimics human endosteum. Melt electrospun written scaffolds were used to compare the suitability of primary human osteoblasts (hOBs) and placenta-derived mesenchymal stem cells (plMSCs) in (non-)osteogenic conditions and with different surface treatments. Using osteogenic conditions, hOBs secreted a dense ECM with enhanced deposition of endosteal proteins, such as fibronectin and vitronectin, and osteogenic markers, such as osteopontin and alkaline phosphatase, compared to plMSCs. The expression patterns of these proteins were reproducibly identified in hOBs derived from three individual donors. Calcium phosphate-coated scaffolds induced the expression of osteocalcin by hOBs when maintained in osteogenic conditions. The tissue-engineered endosteal microenvironment supported the growth and migration of primary human haematopoietic stem cells (HSCs) when compared to HSCs maintained using tissue culture plastic. This 3D testing platform represents an endosteal bone-like tissue and warrants future investigation for the maintenance and expansion of human HSCs.

  8. The assessment of human exposure to radionuclides from a uranium mill tailings release and mine dewatering effluent.

    PubMed

    Ruttenber, A J; Kreiss, K; Douglas, R L; Buhl, T E; Millard, J

    1984-07-01

    This study provides an assessment of human exposure to radiation from a river system contaminated by radionuclides of the 238U decay series released through a dam break at a uranium mill tailings pond and by the continuous discharge of dewatering effluent from 2 uranium mines. The in vivo analyses of radionuclides in 6 Navajo Indians who lived near the river indicate no detectable elevations above background concentrations. Dose estimates for inhalation of suspended river sediment indicate a maximum annual 50-yr dose commitment of 204 mrem to the endosteum. Estimates of doses (50-yr dose commitments) from the ingestion of livestock range between 1 mrem (to liver) and 79 mrem (to bone) suggest that the major contribution to human exposure is from mine dewatering effluent that has been continuously released into the river system for many years. Although the estimated exposures do not exceed existing state or federal regulations, their magnitude justifies further measurement of radionuclides in animals and in the natural environment and the consideration of strategies to reduce radiation exposure to humans and animals.

  9. Mesenchymal Stem Cells in Bone Regeneration

    PubMed Central

    Knight, M. Noelle; Hankenson, Kurt D.

    2013-01-01

    Significance Mesenchymal stem cells (MSCs) play a key role in fracture repair by differentiating to become bone-forming osteoblasts and cartilage-forming chondrocytes. Cartilage then serves as a template for additional bone formation through the process of endochondral ossification. Recent Advances Endogenous MSCs that contribute to healing are primarily derived from the periosteum, endosteum, and marrow cavity, but also may be contributed from the overlying muscle or through systemic circulation, depending on the type of injury. A variety of growth factor signaling pathways, including BMP, Wnt, and Notch signaling, influence MSC proliferation and differentiation. These MSCs can be therapeutically manipulated to promote differentiation. Furthermore, MSCs can be harvested, cultivated, and delivered to promote bone healing. Critical Issues Pharmacologically manipulating the number and differentiation capacity of endogenous MSCs is one potential therapeutic approach to improve healing; however, ideal agents to influence signaling pathways need to be developed and additional therapeutics that activate endogenous MSCs are needed. Whether isolated and purified, MSCs participate directly in the healing process or serve a bystander effect and indirectly influence healing is not well defined. Future Directions Studies must focus on better understanding the regulation of endogenous MSCs durings fracture healing. This will reveal novel molecules and pathways to therapeutically target. Similarly, while animal models have demonstrated efficacy in the delivery of MSCs to promote healing, more research is needed to understand ideal donor cells, cultivation methods, and delivery before stem cell therapy approaches can be utilized to repair bone. PMID:24527352

  10. Secreted frizzled-related protein 1 modulates glucocorticoid attenuation of osteogenic activities and bone mass.

    PubMed

    Wang, Feng-Sheng; Lin, Chun-Liang; Chen, Yeung-Jen; Wang, Ching-Jen; Yang, Kuender D; Huang, Yu-Ting; Sun, Yi-Chih; Huang, Hui-Chen

    2005-05-01

    Prolonged glucocorticoid treatment is known to cause osteoporosis or aseptic necrosis. Secreted frizzled-related proteins 1 (SFRP1) and low-density lipoprotein-related protein 5 (LRP5), a Wnt protein antagonist and a coreceptor, have been found to regulate skeletogenesis. Whereas recent studies have reported that excess glucocorticoid promotes bone loss, the biological role of SFRP1 and LRP5 in regulating glucocorticoid attenuation of bone formation is not fully understood. We showed that a supraphysiological level of glucocorticoid enhanced SFRP1 but not LRP5 expression of primary mesenchymal cell cultures in vitro and osteoblasts at metaphyseal trabecular endosteum and chondrocytes at calcified cartilage in vivo. Glucocorticoid augmentation of SFRP1 expression was transcriptionally mediated. The inhibitory action of glucocorticoid on osteogenic differentiation appeared to be regulated by SFRP1 mediation of beta-catenin destabilization because knocking down SFRP1 by RNA interference abrogated the supraphysiological level of glucocorticoid attenuation of osteogenesis. Recombinant human SFRP1 reduced the promoting effect of physiological level of glucocorticoid on cytosolic beta-catenin accumulation, runt-related transcription factor-2 activation, and osteogenic activities. Glucocorticoid and recombinant human SFRP1 significantly increased osteochondral cell apoptosis associated with reduced mineral density, biomechanical properties, trabecular bone volume, and midshaft cortical bone areas in rat femurs. These findings suggest that SFRP1 modulates glucocorticoid-induced bone loss. Regulation of Wnt/SFRP signal transduction can be used in the future as an alternative strategy for the prevention of glucocorticoid-induced osteoporosis.

  11. The effects of early postoperative radiation on vascularized bone grafts

    SciTech Connect

    Evans, H.B.; Brown, S.; Hurst, L.N. )

    1991-06-01

    The effects of early postoperative radiation were assessed in free nonvascularized and free vascularized rib grafts in the canine model. The mandibles of one-half of the dogs were exposed to a cobalt 60 radiation dose of 4080 cGy over a 4-week period, starting 2 weeks postoperatively. The patency of vascularized grafts was confirmed with bone scintigraphy. Histological studies, including ultraviolet microscopy with trifluorochrome labeling, and histomorphometric analyses were performed. Osteocytes persist within the cortex of the vascularized nonradiated grafts to a much greater extent than in nonvascularized, nonradiated grafts. Cortical osteocytes do not persist in either vascularized or nonvascularized grafts subjected to radiation. New bone formation is significantly retarded in radiated grafts compared with nonradiated grafts. Periosteum and endosteum remained viable in the radiated vascularized grafts, producing both bone union and increased bone turnover, neither of which were evident to any significant extent in nonvascularized grafts. Bone union was achieved in vascularized and non-vascularized nonradiated bone. In the radiated group of dogs, union was only seen in the vascularized bone grafts.

  12. Osseointegration and osseoconductivity of hydroxyapatite of different microporosities.

    PubMed

    Rosa, A L; Beloti, M M; Oliveira, P T; Van Noort, R

    2002-11-01

    The aim of this study was to determine the relationship between changes in microporosity and the osseointegration and the osseoconductivity of hydroxyapatite (HAp). HAp cylinders were manufactured by a combination of uniaxial powder pressing and different sintering conditions, with different percentages of microporosity: HAp-I with 3.96+/-0.75% microporosity, HAp-II with 15.66+/-1.60% microporosity, and HAp-III with 29.72+/-0.69% microporosity. These HAp cylinders were surgically implanted in rabbit femurs. After 8 and 12 weeks, the femurs were removed, fixed, sectioned, ground, and stained by Stevenel's blue/Van Gieson for light microscopy and histomorphometry. Some ground sections were routinely processed for SEM. The osseointegration and the osseoconductivity were determined by means of image analysis and the data were submitted to ANOVA. In all cases the cortical bone was repaired and the HAp facing the medullary canal was lined with endosteum, which in some areas exhibited thin bone tissue formation. SEM observations showed no differences in the morphology of tissue-HAp interfaces for the three different porosities of HAp. There were no statistical differences between the groups related to either osseointegration or osseoconductivity. These results suggest that neither osseointegration nor osseoconductivity of HAp are influenced by changes in HAp microporosity.

  13. Hematopoietic Stem Cells in Neural-crest Derived Bone Marrow

    PubMed Central

    Jiang, Nan; Chen, Mo; Yang, Guodong; Xiang, Lusai; He, Ling; Hei, Thomas K.; Chotkowski, Gregory; Tarnow, Dennis P.; Finkel, Myron; Ding, Lei; Zhou, Yanheng; Mao, Jeremy J.

    2016-01-01

    Hematopoietic stem cells (HSCs) in the endosteum of mesoderm-derived appendicular bones have been extensively studied. Neural crest-derived bones differ from appendicular bones in developmental origin, mode of bone formation and pathological bone resorption. Whether neural crest-derived bones harbor HSCs is elusive. Here, we discovered HSC-like cells in postnatal murine mandible, and benchmarked them with donor-matched, mesoderm-derived femur/tibia HSCs, including clonogenic assay and long-term culture. Mandibular CD34 negative, LSK cells proliferated similarly to appendicular HSCs, and differentiated into all hematopoietic lineages. Mandibular HSCs showed a consistent deficiency in lymphoid differentiation, including significantly fewer CD229 + fractions, PreProB, ProB, PreB and B220 + slgM cells. Remarkably, mandibular HSCs reconstituted irradiated hematopoietic bone marrow in vivo, just as appendicular HSCs. Genomic profiling of osteoblasts from mandibular and femur/tibia bone marrow revealed deficiencies in several HSC niche regulators among mandibular osteoblasts including Cxcl12. Neural crest derived bone harbors HSCs that function similarly to appendicular HSCs but are deficient in the lymphoid lineage. Thus, lymphoid deficiency of mandibular HSCs may be accounted by putative niche regulating genes. HSCs in craniofacial bones have functional implications in homeostasis, osteoclastogenesis, immune functions, tumor metastasis and infections such as osteonecrosis of the jaw. PMID:28000662

  14. Periosteum: biology, regulation, and response to osteoporosis therapies.

    PubMed

    Allen, Matthew R; Hock, Janet M; Burr, David B

    2004-11-01

    Periosteum contains osteogenic cells that regulate the outer shape of bone and work in coordination with inner cortical endosteum to regulate cortical thickness and the size and position of a bone in space. Induction of periosteal expansion, especially at sites such as the lumbar spine and femoral neck, reduces fracture risk by modifying bone dimensions to increase bone strength. The cell and molecular mechanisms that selectively and specifically activate periosteal expansion, as well as the mechanisms by which osteoporosis drugs regulate periosteum, remain poorly understood. We speculate that an alternate strategy to protect human bones from fracture may be through targeting of the periosteum, either using current or novel agents. In this review, we highlight current concepts of periosteal cell biology, including their apparent differences from endosteal osteogenic cells, discuss the limited data regarding how the periosteal surface is regulated by currently approved osteoporosis drugs, and suggest one potential means through which targeting periosteum may be achieved. Improving our understanding of mechanisms controlling periosteal expansion will likely provide insights necessary to enhance current and develop novel interventions to further reduce the risk of osteoporotic fractures.

  15. The periosteal microcirculation in health and disease: An update on clinical significance.

    PubMed

    Szabó, Andrea; Janovszky, Ágnes; Pócs, Levente; Boros, Mihály

    2017-03-01

    Apart from its nutritive functions, the periosteum critically affects bone regeneration via its stem/osteoprogenitor cell content. Normal healing after bone fractures, trauma-orthopedic interventions and invasive dental procedures is critically linked to the reestablishment of the periosteal microcirculation, but the reconstruction, replacement or repair of lost tissues may also be performed with autologous periosteum. Besides the initiation of cell differentiation during bone repair and remodeling processes, the periosteum together with the endosteum plays significant roles in the pathogenesis of both hormone-related and trauma-induced osteoporotic alterations in the bone metabolism. Nevertheless, the axial bones, and in particular the jawbones, and the appendicular bones display differences not only in their blood supply and fracture healing characteristics, but also in respect of the development of osteoporosis and their reactions to treatment modalities (i.e. bisphosphonates). These reactions may also be linked to the differences in periosteal microcirculatory reactions. The present overview summarizes the relevant data of microcirculatory studies focusing on the periosteal reactions in different anatomical locations together with the optimal background methodologies, study models and the most significant observations.

  16. PDGFB-based stem cell gene therapy increases bone strength in the mouse.

    PubMed

    Chen, Wanqiu; Baylink, David J; Brier-Jones, Justin; Neises, Amanda; Kiroyan, Jason B; Rundle, Charles H; Lau, Kin-Hing William; Zhang, Xiao-Bing

    2015-07-21

    Substantial advances have been made in the past two decades in the management of osteoporosis. However, none of the current medications can eliminate the risk of fracture and rejuvenate the skeleton. To this end, we recently reported that transplantation of hematopoietic stem/progenitor cells (HSCs) or Sca1(+) cells engineered to overexpress FGF2 results in a significant increase in lamellar bone matrix formation at the endosteum; but this increase was attended by the development of secondary hyperparathyroidism and severe osteomalacia. Here we switch the therapeutic gene to PDGFB, another potent mitogen for mesenchymal stem cells (MSCs) but potentially safer than FGF2. We found that modest overexpression of PDGFB using a relatively weak phosphoglycerate kinase (PGK) promoter completely avoided osteomalacia and secondary hyperparathyroidism, and simultaneously increased trabecular bone formation and trabecular connectivity, and decreased cortical porosity. These effects led to a 45% increase in the bone strength. Transplantation of PGK-PDGFB-transduced Sca1(+) cells increased MSC proliferation, raising the possibility that PDGF-BB enhances expansion of MSC in the vicinity of the hematopoietic niche where the osteogenic milieu propels the differentiation of MSCs toward an osteogenic destination. Our therapy should have potential clinical applications for patients undergoing HSC transplantation, who are at high risk for osteoporosis and bone fractures after total body irradiation preconditioning. It could eventually have wider application once the therapy can be applied without the preconditioning.

  17. Yield optimisation and molecular characterisation of uncultured CD271+ mesenchymal stem cells in the Reamer Irrigator Aspirator waste bag.

    PubMed

    Churchman, Sarah M; Kouroupis, Dimitrios; Boxall, Sally A; Roshdy, Tarek; Tan, Hiang B; McGonagle, Dennis; Giannoudis, Peter V; Jones, Elena A

    2013-12-13

    Bone reconstruction requires the use of autografts from patients' iliac crest (IC); for large-volume defects bone void fillers and autologous mesenchymal stem cells (MSCs) are often added. The Reamer/Irrigator/Aspirator (RIA) device provides the means of harvesting large amounts of autograft and additionally yields a waste bag containing MSCs, which is currently discarded. The aim of this study was to enumerate and characterise native MSCs from RIA waste bag and compare them to 'gold-standard' donor-matched MSCs from IC bone marrow (BM). IC-BM from age matched trauma patients was used as control. In RIA waste bags the median MSC yield established using a colony-forming fibroblast assay was 314333 (range 5 x 104-1.4 x 106), equivalent to approximately one litre of IC-BM aspirate. CD271+ cells were present at high levels in RIA waste bags, had MSC surface phenotype (CD90+CD73+CD105+CD34>sup>-CD61-CD19-CD31-CD33-) and expressed genes associated with multipotentiality, osteogenesis, adipogenesis and angiogenic support. RIA- CD271+ MSCs were transcriptionally similar to donor-matched IC-CD271+ MSCs (76 % transcripts); with the majority of bone-related and Wnt pathway molecules being expressed at comparable levels. Lower-level expression of MCAM/CD146 and 5/13 hypoxia-related molecules was found in RIA-CD271+ MSCs, potentially reflecting their native residence in a more hypoxic environment of the endosteum and bone cortex. These data suggest that long bones contain very large numbers of MSCs, transcriptionally-similar to IC-BM MSCs; they can be procured by reaming using the RIA device and used, following concentration, as autologous and potentially allogeneic bone repair therapy.

  18. Stem cell niches and other factors that influence the sensitivity of bone marrow to radiation-induced bone cancer and leukaemia in children and adults

    PubMed Central

    Richardson, Richard B

    2011-01-01

    Purpose: This paper reviews and reassesses the internationally accepted niches or ‘targets’ in bone marrow that are sensitive to the induction of leukaemia and primary bone cancer by radiation. Conclusions: The hypoxic conditions of the 10 μm thick endosteal/osteoblastic niche where preleukemic stem cells and hematopoietic stem cells (HSC) reside provides a radioprotective microenvironment that is 2-to 3-fold less radiosensitive than vascular niches. This supports partitioning the whole marrow target between the low haematological cancer risk of irradiating HSC in the endosteum and the vascular niches within central marrow. There is a greater risk of induced bone cancer when irradiating a 50 μm thick peripheral marrow adjacent to the remodelling/reforming portion of the trabecular bone surface, rather than marrow next to the quiescent bone surface. This choice of partitioned bone cancer target is substantiated by the greater radiosensitivity of: (i) Bone with high remodelling rates, (ii) the young, (iii) individuals with hypermetabolic benign diseases of bone, and (iv) the epidemiology of alpha-emitting exposures. Evidence is given to show that the absence of excess bone-cancer in atomic-bomb survivors may be partially related to the extremely low prevalence among Japanese of Paget's disease of bone. Radiation-induced fibrosis and the wound healing response may be implicated in not only radiogenic bone cancers but also leukaemia. A novel biological mechanism for adaptive response, and possibility of dynamic targets, is advocated whereby stem cells migrate from vascular niches to stress-mitigated, hypoxic niches. PMID:21204614

  19. Dioxin-induced up-regulation of the active form of vitamin D is the main cause for its inhibitory action on osteoblast activities, leading to developmental bone toxicity

    SciTech Connect

    Nishimura, Noriko Nishimura, Hisao; Ito, Tomohiro; Miyata, Chie; Izumi, Keiko; Fujimaki, Hidekazu; Matsumura, Fumio

    2009-05-01

    Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) is known to cause bone toxicity, particularly during animal development, although its action mechanism to cause this toxicity has yet to be elucidated. Mouse pups were exposed to TCDD via dam's milk that were administered orally with 15 {mu}g TCDD/kg b.w. on postnatal day 1. Here we report that TCDD causes up-regulation of vitamin D 1{alpha}-hydroxylase in kidney, resulting in a 2-fold increase in the active form of vitamin D, 1,25-dihydroxyvitamin D{sub 3}, in serum. This action of TCDD is not caused by changes in parathyroid hormone, a decrease in vitamin D degrading enzyme, vitamin D 24-hydroxylase, or alterations in serum Ca{sup 2+} concentration. Vitamin D is known to affect bone mineralization. Our data clearly show that TCDD-exposed mice exhibit a marked decrease in osteocalcin and collagen type 1 as well as alkaline phosphatase gene expression in tibia by postnatal day 21, which is accompanied with a mineralization defect in the tibia, lowered activity of osteoblastic bone formation, and an increase in fibroblastic growth factor-23, a sign of increased vitamin D effect. Despite these significant effects of TCDD on osteoblast activities, none of the markers of osteoclast activities was found to be affected. Histomorphometry confirmed that osteoblastic activity, but not bone resorption activity, was altered by TCDD. A prominent lesion commonly observed in these TCDD-treated mice was impaired bone mineralization that is characterized by an increased volume and thickness of osteoids lining both the endosteum of the cortical bone and trabeculae. Together, these data suggest that the impaired mineralization resulting from reduction of the osteoblastic activity, which is caused by TCDD-induced up-regulation of vitamin D, is responsible for its bone developmental toxicity.

  20. Mesenchymal progenitors residing close to the bone surface are functionally distinct from those in the central bone marrow.

    PubMed

    Siclari, Valerie A; Zhu, Ji; Akiyama, Kentaro; Liu, Fei; Zhang, Xianrong; Chandra, Abhishek; Nah, Hyun-Duck; Shi, Songtao; Qin, Ling

    2013-04-01

    Long bone is an anatomically complicated tissue with trabecular-rich metaphyses at two ends and cortical-rich diaphysis at the center. The traditional flushing method isolates only mesenchymal progenitor cells from the central region of long bones and these cells are distant from the bone surface. We propose that mesenchymal progenitors residing in endosteal bone marrow that is close to the sites of bone formation, such as trabecular bone and endosteum, behave differently from those in the central bone marrow. In this report, we separately isolated endosteal bone marrow using a unique enzymatic digestion approach and demonstrated that it contained a much higher frequency of mesenchymal progenitors than the central bone marrow. Endosteal mesenchymal progenitors express common mesenchymal stem cell markers and are capable of multi-lineage differentiation. However, we found that mesenchymal progenitors isolated from different anatomical regions of the marrow did exhibit important functional differences. Compared with their central marrow counterparts, endosteal mesenchymal progenitors have superior proliferative ability with reduced expression of cell cycle inhibitors. They showed greater immunosuppressive activity in culture and in a mouse model of inflammatory bowel disease. Aging is a major contributing factor for trabecular bone loss. We found that old mice have a dramatically decreased number of endosteal mesenchymal progenitors compared with young mice. Parathyroid hormone (PTH) treatment potently stimulates bone formation. A single PTH injection greatly increased the number of endosteal mesenchymal progenitors, particularly those located at the metaphyseal bone, but had no effect on their central counterparts. In summary, endosteal mesenchymal progenitors are more metabolically active and relevant to physiological bone formation than central mesenchymal progenitors. Hence, they represent a biologically important target for future mesenchymal stem cell studies.

  1. Stem cell niches and other factors that influence the sensitivity of bone marrow to radiation-induced bone cancer and leukaemia in children and adults.

    PubMed

    Richardson, Richard B

    2011-04-01

    This paper reviews and reassesses the internationally accepted niches or 'targets' in bone marrow that are sensitive to the induction of leukaemia and primary bone cancer by radiation. The hypoxic conditions of the 10 μm thick endosteal/osteoblastic niche where preleukemic stem cells and hematopoietic stem cells (HSC) reside provides a radioprotective microenvironment that is 2- to 3-fold less radiosensitive than vascular niches. This supports partitioning the whole marrow target between the low haematological cancer risk of irradiating HSC in the endosteum and the vascular niches within central marrow. There is a greater risk of induced bone cancer when irradiating a 50 μm thick peripheral marrow adjacent to the remodelling/reforming portion of the trabecular bone surface, rather than marrow next to the quiescent bone surface. This choice of partitioned bone cancer target is substantiated by the greater radiosensitivity of: (i) Bone with high remodelling rates, (ii) the young, (iii) individuals with hypermetabolic benign diseases of bone, and (iv) the epidemiology of alpha-emitting exposures. Evidence is given to show that the absence of excess bone-cancer in atomic-bomb survivors may be partially related to the extremely low prevalence among Japanese of Paget's disease of bone. Radiation-induced fibrosis and the wound healing response may be implicated in not only radiogenic bone cancers but also leukaemia. A novel biological mechanism for adaptive response, and possibility of dynamic targets, is advocated whereby stem cells migrate from vascular niches to stress-mitigated, hypoxic niches.

  2. Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice.

    PubMed

    Zhou, Xin; von der Mark, Klaus; Henry, Stephen; Norton, William; Adams, Henry; de Crombrugghe, Benoit

    2014-12-01

    One of the crucial steps in endochondral bone formation is the replacement of a cartilage matrix produced by chondrocytes with bone trabeculae made by osteoblasts. However, the precise sources of osteoblasts responsible for trabecular bone formation have not been fully defined. To investigate whether cells derived from hypertrophic chondrocytes contribute to the osteoblast pool in trabecular bones, we genetically labeled either hypertrophic chondrocytes by Col10a1-Cre or chondrocytes by tamoxifen-induced Agc1-CreERT2 using EGFP, LacZ or Tomato expression. Both Cre drivers were specifically active in chondrocytic cells and not in perichondrium, in periosteum or in any of the osteoblast lineage cells. These in vivo experiments allowed us to follow the fate of cells labeled in Col10a1-Cre or Agc1-CreERT2 -expressing chondrocytes. After the labeling of chondrocytes, both during prenatal development and after birth, abundant labeled non-chondrocytic cells were present in the primary spongiosa. These cells were distributed throughout trabeculae surfaces and later were present in the endosteum, and embedded within the bone matrix. Co-expression studies using osteoblast markers indicated that a proportion of the non-chondrocytic cells derived from chondrocytes labeled by Col10a1-Cre or by Agc1-CreERT2 were functional osteoblasts. Hence, our results show that both chondrocytes prior to initial ossification and growth plate chondrocytes before or after birth have the capacity to undergo transdifferentiation to become osteoblasts. The osteoblasts derived from Col10a1-expressing hypertrophic chondrocytes represent about sixty percent of all mature osteoblasts in endochondral bones of one month old mice. A similar process of chondrocyte to osteoblast transdifferentiation was involved during bone fracture healing in adult mice. Thus, in addition to cells in the periosteum chondrocytes represent a major source of osteoblasts contributing to endochondral bone formation in vivo.

  3. Development of skeletal system for mesh-type ICRP reference adult phantoms

    NASA Astrophysics Data System (ADS)

    Yeom, Yeon Soo; Wang, Zhao Jun; Tat Nguyen, Thang; Kim, Han Sung; Choi, Chansoo; Han, Min Cheol; Kim, Chan Hyeong; Lee, Jai Ki; Chung, Beom Sun; Zankl, Maria; Petoussi-Henss, Nina; Bolch, Wesley E.; Lee, Choonsik

    2016-10-01

    The reference adult computational phantoms of the international commission on radiological protection (ICRP) described in Publication 110 are voxel-type computational phantoms based on whole-body computed tomography (CT) images of adult male and female patients. The voxel resolutions of these phantoms are in the order of a few millimeters and smaller tissues such as the eye lens, the skin, and the walls of some organs cannot be properly defined in the phantoms, resulting in limitations in dose coefficient calculations for weakly penetrating radiations. In order to address the limitations of the ICRP-110 phantoms, an ICRP Task Group has been recently formulated and the voxel phantoms are now being converted to a high-quality mesh format. As a part of the conversion project, in the present study, the skeleton models, one of the most important and complex organs of the body, were constructed. The constructed skeleton models were then tested by calculating red bone marrow (RBM) and endosteum dose coefficients (DCs) for broad parallel beams of photons and electrons and comparing the calculated values with those of the original ICRP-110 phantoms. The results show that for the photon exposures, there is a generally good agreement in the DCs between the mesh-type phantoms and the original voxel-type ICRP-110 phantoms; that is, the dose discrepancies were less than 7% in all cases except for the 0.03 MeV cases, for which the maximum difference was 14%. On the other hand, for the electron exposures (⩽4 MeV), the DCs of the mesh-type phantoms deviate from those of the ICRP-110 phantoms by up to ~1600 times at 0.03 MeV, which is indeed due to the improvement of the skeletal anatomy of the developed skeleton mesh models.

  4. Osteal tissue macrophages are intercalated throughout human and mouse bone lining tissues and regulate osteoblast function in vitro and in vivo.

    PubMed

    Chang, Ming K; Raggatt, Liza-Jane; Alexander, Kylie A; Kuliwaba, Julia S; Fazzalari, Nicola L; Schroder, Kate; Maylin, Erin R; Ripoll, Vera M; Hume, David A; Pettit, Allison R

    2008-07-15

    Resident macrophages are an integral component of many tissues and are important in homeostasis and repair. This study examines the contribution of resident tissue macrophages to bone physiology. Using immunohistochemistry, we showed that a discrete population of resident macrophages, OsteoMacs, was intercalated throughout murine and human osteal tissues. OsteoMacs were distributed among other bone lining cells within both endosteum and periosteum. Furthermore, OsteoMacs were coisolated with osteoblasts in murine bone explant and calvarial preparations. OsteoMacs made up 15.9% of calvarial preparations and persisted throughout standard osteoblast differentiation cultures. Contrary to previous studies, we showed that it was OsteoMacs and not osteoblasts within these preparations that responded to pathophysiological concentrations of LPS by secreting TNF. Removal of OsteoMacs from calvarial cultures significantly decreased osteocalcin mRNA induction and osteoblast mineralization in vitro. In a Transwell coculture system of enriched osteoblasts and macrophages, we demonstrated that macrophages were required for efficient osteoblast mineralization in response to the physiological remodeling stimulus, elevated extracellular calcium. Notably, OsteoMacs were closely associated with areas of bone modeling in situ, forming a distinctive canopy structure covering >75% of mature osteoblasts on diaphyseal endosteal surfaces in young growing mice. Depletion of OsteoMacs in vivo using the macrophage-Fas-induced apoptosis (MAFIA) mouse caused complete loss of osteoblast bone-forming surface at this modeling site. Overall, we have demonstrated that OsteoMacs are an integral component of bone tissues and play a novel role in bone homeostasis through regulating osteoblast function. These observations implicate OsteoMacs, in addition to osteoclasts and osteoblasts, as principal participants in bone dynamics.

  5. Short-term aluminum administration in the rat. Effects on bone formation and relationship to renal osteomalacia.

    PubMed Central

    Goodman, W G; Gilligan, J; Horst, R

    1984-01-01

    Aluminum may be pathogenic in the osteomalacia observed in some patients receiving hemodialysis. To study the early effects of Al on bone growth, bone formation, mineralization, and resorption were measured during short-term Al exposure in the tibial cortex of pair-fed control (C, n = 10), aluminum-treated (AL, n = 9), subtotally nephrectomized control (NX-C, n = 7), and subtotally nephrectomized aluminum-treated (NX-AL, n = 8) rats using double tetracycline labeling of bone. Animals received 2 mg/d of elemental Al intraperitoneally for 5 d/wk over 4 wk. Total bone and matrix (osteoid) formation, periosteal bone and matrix formation, and periosteal bone and matrix apposition fell by 20% in AL from C, P less than 0.05 for all values, and by 40% in NX-AL from NX-C, P less than 0.01 for all values. Moreover, each measurement was significantly less in NX-AL than in AL, P less than 0.05 for all values. Osteoid width did not increase following aluminum administration in either AL or NX-AL. Resorption surface increased from control values in both AL and NX-AL; also, resorptive activity at the endosteum was greater in NX-AL than in NX-C, P less than 0.05. Thus, aluminum impairs new bone and matrix formation but does not cause classic osteomalacia in the cortical bone of rats whether renal function is normal or reduced. These findings may represent either a different response to aluminum administration in cortical bone as contrasted to trabecular bone or an early phase in the development of osteomalacia. Aluminum may increase bone resorption and contribute to osteopenia in clinical states associated with aluminum accumulation in bone. PMID:6690476

  6. Intra-Bone Marrow Transplantation of Endosteal Bone Marrow Cells Facilitates Allogeneic Hematopoietic and Stromal Cells Engraftment Dependent on Early Expression of CXCL-12.

    PubMed

    Chen, Chen; Su, Yingjun; Chen, Jianwu; Zhang, Dongliang; Song, Yajuan; Guo, Shuzhong

    2015-09-16

    Hematopoietic stem cell transplantation (HSCT) has been considered as an effective approach at inducing allogeneic hematopoietic reconstitution and immune tolerance. However, it remains critical to find the optimal HSCT delivery method and robust sources of hematopoietic stem cells (HSCs). We introduced a new method by infusing allogeneic endosteal bone marrow cells (BMCs) harvested from long bones endosteum through intra-bone marrow transplantation (IBBMT) into irradiated mice. Recipient mice that were transplanted with central BMCs or through intravenous bone marrow transplantation (IVBMT) were used as controls (n=6 per group). We compared the new method with each control group for allogeneic HSCs homing pattern, peripheral blood chimerism level, skin allograft survival time, and donor stromal cell percentage in recipient BM. AMD3100 was injected to determine whether chemokine stromal cell-derived factor-1 (CXCL-12) was critical for the new method. More allogeneic HSCs homed into spleen and bone marrow for the new method as compared to each control group. IBBMT of endosteal BMCs led to a higher peripheral blood chimerism and skin allograft survival. At 18 weeks, donor stromal cell percentage in recipient BMCs was higher for the new method than in each control group. By AMD3100 blockade at day 1, peripheral blood chimerism level and donor stromal cell percentage were significantly reduced as compared to the control group without AMD3100 blockade. Our study suggests that IBBMT of endosteal BMCs is an effective approach for HSCT in inducing allogeneic hematopoietic reconstitution. The advantage is dependent upon the early expression of CXCL-12 after bone marrow transplantation.

  7. Mesenchymal Progenitors Residing Close to the Bone Surface Are Functionally Distinct from Those in the Central Bone Marrow

    PubMed Central

    Siclari, Valerie A.; Zhu, Ji; Akiyama, Kentaro; Liu, Fei; Zhang, Xianrong; Chandra, Abhishek; Nah-Cederquist, Hyun-Duck; Shi, Songtao; Qin, Ling

    2013-01-01

    Long bone is an anatomically complicated tissue with trabecular-rich metaphyses at two ends and cortical-rich diaphysis at the center. The traditional flushing method only isolates mesenchymal progenitor cells from the central region of long bones and these cells are distant from the bone surface. We propose that mesenchymal progenitors residing in endosteal bone marrow that is close to the sites of bone formation, such as trabecular bone and endosteum, behave differently from those in the central bone marrow. In this report, we separately isolated endosteal bone marrow using a unique enzymatic digestion approach and demonstrated that it contained a much higher frequency of mesenchymal progenitors than the central bone marrow. Endosteal mesenchymal progenitors express traditional mesenchymal stem cell markers and are capable of multi-lineage differentiation. However, we found that mesenchymal progenitors isolated from different anatomical regions of the marrow did exhibit important functional differences. Compared to their central marrow counterparts, endosteal mesenchymal progenitors have superior proliferative ability with reduced expression of cell cycle inhibitors. They showed greater immunosuppressive activity in culture and in a mouse model of inflammatory bowel disease. Aging is a major contributing factor for trabecular bone loss. We found that old mice have a dramatically decreased number of endosteal mesenchymal progenitors compared to young mice. Parathyroid hormone (PTH) treatment potently stimulates bone formation. A single PTH injection greatly increased the number of endosteal mesenchymal progenitors, particularly those located at the metaphyseal bone, but had no effect on their central counterparts. In summary, endosteal mesenchymal progenitors are more metabolically active and relevant to physiological bone formation than central mesenchymal progenitors. Hence, they represent a biologically important target for future mesenchymal stem cell studies

  8. Removal of SOST or blocking its product sclerostin rescues defects in the periodontitis mouse model

    PubMed Central

    Ren, Yinshi; Han, Xianglong; Ho, Sunita P.; Harris, Stephen E.; Cao, Zhengguo; Economides, Aris N.; Qin, Chunlin; Ke, Huazhu; Liu, Min; Feng, Jian Q.

    2015-01-01

    Understanding periodontal ligament (PDL) biology and developing an effective treatment for bone and PDL damage due to periodontitis have been long-standing aims in dental medicine. Here, we first demonstrated by cell lineage tracing and mineral double-labeling approaches that murine PDL progenitor cells display a 2- and 3-fold higher mineral deposition rate than the periosteum and endosteum at the age of 4 weeks, respectively. We next proved that the pathologic changes in osteocytes (Ocys; changes from a spindle shape to round shape with a >50% reduction in the dendrite number/length, and an increase in SOST) are the key pathologic factors responsible for bone and PDL damage in periostin-null mice (a periodontitis animal model) using a newly developed 3-dimensional FITC-Imaris technique. Importantly, we proved that deleting the Sost gene (a potent inhibitor of WNT signaling) or blocking sclerostin function by using the mAb in this periodontitis model significantly restores bone and PDL defects (n = 4–5; P < 0.05). Together, identification of the key contribution of the PDL in normal alveolar bone formation, the pathologic changes of the Ocys in periodontitis bone loss, and the novel link between sclerostin and Wnt signaling in the PDL will aid future drug development in the treatment of patients with periodontitis.—Ren, Y., Han, X., Ho, S. P., Harris, S. E., Cao, Z., Economides, A. N., Qin, C., Ke, H., Liu, M., Feng, J. Q. Removal of SOST or blocking its product sclerostin rescues defects in the periodontitis mouse model. PMID:25757567

  9. Col2-Cre and tamoxifen-inducible Col2-CreER target different cell populations in the knee joint

    PubMed Central

    Nagao, Masashi; Cheong, Chan Wook; Olsen, Bjorn

    2015-01-01

    Objective Collagen type 2 (Col2)-Cre or tamoxifen-inducible Col2-CreER transgenic mouse lines have been used for studies to explore the cellular and molecular pathogenesis of osteoarthritis (OA). The purpose of this study is to investigate whether the targeted cells are the same or different in the two mouse lines. Methods We crossed tamoxifen inducible Col2-CreER and Col2-Cre mice with Rosa tdTomato reporter mice and analyzed the labeling patterns at different time points. Results In the Col2-CreER mice, 90.8 [95% confidence interval (CI) (88.3, 93.2)] and 82.8 (77.4, 88.3) % of the articular surface cells are Tomato positive when tamoxifen was administered at 2 and 2.5 weeks of age and strong activity was observed even 4.5 months after injection. However, 46.0 (32.8, 59.1) and 22.2 (11.7, 32.6) % of the surface cells were Tomato positive when tamoxifen was administered at 3 and 4 weeks of age, respectively. Little to no Tomato activity in the articular surface cells was observed when tamoxifen was administered at 8 weeks of age. At any stage of tamoxifen injection, the Tomato activity was detected in growth plate and epiphyseal bone in addition to articular chondrocytes, but little in endothelium and not in the synovium and ligament. In contrast, the targeted tissues in the Col2-Cre mouse line were articular cartilage, growth plate, meniscus, endosteum, ligament, bone and synovium. Conclusions This study demonstrates that the pattern of targeted cells in the inducible Col2-CreER mice are partially overlapping with but different from that of targeted cells in Col2-Cre mice and the pattern varies dependent on when tamoxifen is administered. PMID:26256767

  10. Non-ototoxic local delivery of bisphosphonate to the mammalian cochlea

    PubMed Central

    Kang, Woo Seok; Sun, Shuting; Nguyen, Kim; Kashemirov, Boris; McKenna, Charles E.; Hacking, S. Adam; Quesnel, Alicia M.; Sewell, William F.; McKenna, Michael J.; Jung, David H.

    2015-01-01

    Hypothesis Local delivery of bisphosphonates results in superior localization of these compounds for the treatment of cochlear otosclerosis, without ototoxicity. Background Otosclerosis is a common disorder of abnormal bone remodeling within the human otic capsule. It is a frequent cause of conductive hearing loss from stapes fixation. Large lesions that penetrate the cochlear endosteum and injure the spiral ligament result in sensorineural hearing loss. Nitrogen-containing bisphosphonates (e.g., zoledronate) are potent inhibitors of bone remodeling with proven efficacy in the treatment of metabolic bone diseases, including otosclerosis. Local delivery to the cochlea may allow for improved drug targeting, higher local concentrations, and the avoidance of systemic complications. In this study, we utilize a fluorescently labeled bisphosphonate compound (6-FAM-ZOL) to determine drug localization and concentration within the otic capsule. Various methods for delivery are compared. Ototoxicity is evaluated by ABR and DPOAEs. Methods 6-FAM-ZOL was administered to guinea pigs via intraperitoneal injection, placement of alginate beads onto the round window membrane (RWM), or microfluidic pump infusion via a cochleostomy. Hearing was evaluated. Specimens were embedded into resin blocks, ground to a mid-modiolar section, and quantitatively imaged using fluorescence microscopy. Results There was a dose-dependent increase in fluorescent signal following systemic 6-FAM-ZOL treatment. Local delivery via the RWM or a cochleostomy increased delivery efficiency. No significant ototoxicity was observed following either systemic or local 6-FAM-ZOL delivery. Conclusions These findings establish important pre-clinical parameters for the treatment of cochlear otosclerosis in humans. PMID:25996080

  11. A polyethylene-high proportion hydroxyapatite implant and its investigation in vivo.

    PubMed

    Sarsilmaz, F; Orhan, N; Unsaldi, E; Durmus, A S; Colakoglu, N

    2007-01-01

    An implant from hydroxyapatite and polyethylene (HA+PE) composite was investigated for the usability in large bone defects. With this aim, the implants were manufactured in blocks by hot compacting the mixture of 80% HA and 20% PE weight ratio. Powders were machined in a lathe in the dimensions of diaphysis of the radius of the mongrel dogs. Then a defect, 1.5 cm in length, was made in the diaphysis of the radius with an operation performed under general anaesthesia in 16 healthy mongrel dogs. The defects were filled with implant as a block. The dogs were observed radiologically in 15-day intervals and examined clinically in certain intervals. The bone samples were taken out from four dogs for the histopatological examinations at the end of the 2nd, 4th, 6th and 12th months, respectively. Clinical examinations indicated the occurrence of slight lameness in all cases at the first month of experiment, but lameness completely disappeared in a further examination. Progressive resorption and new bone formation began in the implants from the first month, but complete resorption was not observed in any case at the end of 12-month period. SEM and optical microscope examinations revealed fibroblast cell with its clear cytoplasmic extensions and osteoblast cells in endosteum in the inner region. Bone formation increasing and extending to the pores of implant in time and blood vessels with lamellar structure and Haversian system were observed. As a result, it was indicated that HA+PE composite implants could be applied with confidence and are useful in treatment of large bone defects in long bone of dogs.

  12. A theoretical simulation of hematopoietic stem cells during oxygen fluctuations: prediction of bone marrow responses during hemorrhagic shock.

    PubMed

    Antoniou, Eliana S; Sund, Steve; Homsi, Emile N; Challenger, Leonard F; Rameshwar, Pranela

    2004-11-01

    The bone marrow (BM) responds to various diseases, including infections and hemorrhagic shock, by generating immune and blood cells. These cells are derived from a finite number of lymphohematopoietic stem cells (LHSC) close to the endosteal region of the BM. This study presumes that studies on LHSC involving proteomics, computational biology, and genomics could be aided by mathematical models. A theoretical model is developed to predict the responses of proliferating (P) nonproliferating (N) BM cells during acute blood loss when the Po2 in the BM is decreased. Hematopoietic responses were simulated for otherwise healthy individuals who have been subjected to various degrees of blood loss, as represented by 3%, 5%, and 20% O2. The model is robust and could predict hematopoietic activity in the area close to the endosteum during low Po2 as for acute blood loss. Steady-state hematopoiesis at oxygen saturation (80%) in healthy individuals could not be simulated with the equations. Functional assays tested the model with an in vitro assay of the most primitive LHSC (modified long-term culture-initiating cell assay, LTC-IC). The LTC-IC assay showed that 1%, 3% - 5%, and 20% O2 mediate significant increases in the proliferation of the most primitive BM progenitors, as compared with 80% O2. Thus, the functional studies show that the theoretical model is robust and could be used to gain insights into the biology of LHSC during different degrees of blood loss. The utility of such a model in surgical trauma is discussed.

  13. An image-based skeletal dosimetry model for the ICRP reference adult female-internal electron sources.

    PubMed

    O'Reilly, Shannon E; DeWeese, Lindsay S; Maynard, Matthew R; Rajon, Didier A; Wayson, Michael B; Marshall, Emily L; Bolch, Wesley E

    2016-12-21

    An image-based skeletal dosimetry model for internal electron sources was created for the ICRP-defined reference adult female. Many previous skeletal dosimetry models, which are still employed in commonly used internal dosimetry software, do not properly account for electron escape from trabecular spongiosa, electron cross-fire from cortical bone, and the impact of marrow cellularity on active marrow self-irradiation. Furthermore, these existing models do not employ the current ICRP definition of a 50 µm bone endosteum (or shallow marrow). Each of these limitations was addressed in the present study. Electron transport was completed to determine specific absorbed fractions to both active and shallow marrow of the skeletal regions of the University of Florida reference adult female. The skeletal macrostructure and microstructure were modeled separately. The bone macrostructure was based on the whole-body hybrid computational phantom of the UF series of reference models, while the bone microstructure was derived from microCT images of skeletal region samples taken from a 45 years-old female cadaver. The active and shallow marrow are typically adopted as surrogate tissue regions for the hematopoietic stem cells and osteoprogenitor cells, respectively. Source tissues included active marrow, inactive marrow, trabecular bone volume, trabecular bone surfaces, cortical bone volume, and cortical bone surfaces. Marrow cellularity was varied from 10 to 100 percent for active marrow self-irradiation. All other sources were run at the defined ICRP Publication 70 cellularity for each bone site. A total of 33 discrete electron energies, ranging from 1 keV to 10 MeV, were either simulated or analytically modeled. The method of combining skeletal macrostructure and microstructure absorbed fractions assessed using MCNPX electron transport was found to yield results similar to those determined with the PIRT model applied to the UF adult male skeletal dosimetry model. Calculated

  14. An image-based skeletal dosimetry model for the ICRP reference adult female—internal electron sources

    NASA Astrophysics Data System (ADS)

    O'Reilly, Shannon E.; DeWeese, Lindsay S.; Maynard, Matthew R.; Rajon, Didier A.; Wayson, Michael B.; Marshall, Emily L.; Bolch, Wesley E.

    2016-12-01

    An image-based skeletal dosimetry model for internal electron sources was created for the ICRP-defined reference adult female. Many previous skeletal dosimetry models, which are still employed in commonly used internal dosimetry software, do not properly account for electron escape from trabecular spongiosa, electron cross-fire from cortical bone, and the impact of marrow cellularity on active marrow self-irradiation. Furthermore, these existing models do not employ the current ICRP definition of a 50 µm bone endosteum (or shallow marrow). Each of these limitations was addressed in the present study. Electron transport was completed to determine specific absorbed fractions to both active and shallow marrow of the skeletal regions of the University of Florida reference adult female. The skeletal macrostructure and microstructure were modeled separately. The bone macrostructure was based on the whole-body hybrid computational phantom of the UF series of reference models, while the bone microstructure was derived from microCT images of skeletal region samples taken from a 45 years-old female cadaver. The active and shallow marrow are typically adopted as surrogate tissue regions for the hematopoietic stem cells and osteoprogenitor cells, respectively. Source tissues included active marrow, inactive marrow, trabecular bone volume, trabecular bone surfaces, cortical bone volume, and cortical bone surfaces. Marrow cellularity was varied from 10 to 100 percent for active marrow self-irradiation. All other sources were run at the defined ICRP Publication 70 cellularity for each bone site. A total of 33 discrete electron energies, ranging from 1 keV to 10 MeV, were either simulated or analytically modeled. The method of combining skeletal macrostructure and microstructure absorbed fractions assessed using MCNPX electron transport was found to yield results similar to those determined with the PIRT model applied to the UF adult male skeletal dosimetry model. Calculated

  15. Development of the voxel computational phantoms of pediatric patients and their application to organ dose assessment

    NASA Astrophysics Data System (ADS)

    Lee, Choonik

    A series of realistic voxel computational phantoms of pediatric patients were developed and then used for the radiation risk assessment for various exposure scenarios. The high-resolution computed tomographic images of live patients were utilized for the development of the five voxel phantoms of pediatric patients, 9-month male, 4-year female, 8-year female, 11-year male, and 14-year male. The phantoms were first developed as head and torso phantoms and then extended into whole body phantoms by utilizing computed tomographic images of a healthy adult volunteer. The whole body phantom series was modified to have the same anthropometrics with the most recent reference data reported by the international commission on radiological protection. The phantoms, named as the University of Florida series B, are the first complete set of the pediatric voxel phantoms having reference organ masses and total heights. As part of the dosimetry study, the investigation on skeletal tissue dosimetry methods was performed for better understanding of the radiation dose to the active bone marrow and bone endosteum. All of the currently available methodologies were inter-compared and benchmarked with the paired-image radiation transport model. The dosimetric characteristics of the phantoms were investigated by using Monte Carlo simulation of the broad parallel beams of external phantom in anterior-posterior, posterior-anterior, left lateral, right lateral, rotational, and isotropic angles. Organ dose conversion coefficients were calculated for extensive photon energies and compared with the conventional stylized pediatric phantoms of Oak Ridge National Laboratory. The multi-slice helical computed tomography exams were simulated using Monte Carlo simulation code for various exams protocols, head, chest, abdomen, pelvis, and chest-abdomen-pelvis studies. Results have found realistic estimates of the effective doses for frequently used protocols in pediatric radiology. The results were very

  16. Constitutively expressed COX-2 in osteoblasts positively regulates Akt signal transduction via suppression of PTEN activity.

    PubMed

    Li, Ching-Ju; Chang, Je-Ken; Wang, Gwo-Jaw; Ho, Mei-Ling

    2011-02-01

    Cyclooxygenase-2 (COX-2) is thought to be an inducible enzyme, but increasing reports indicate that COX-2 is constitutively expressed in several organs. The status of COX-2 expression in bone and its physiological role remains undefined. Non-selective non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, which commonly suppress COX-2 activity, were reported to suppress osteoblast proliferation via Akt/FOXO3a/p27(Kip1) signaling, suggesting that COX-2 may be the key factor of the suppressive effects of NSAIDs on proliferation. Although Akt activation correlates with PTEN deficiency and cell viability, the role of COX-2 on PTEN/Akt regulation remains unclear. In this study, we hypothesized that COX-2 may be constitutively expressed in osteoblasts and regulate PTEN/Akt-related proliferation. We examined the localization and co-expression of COX-2 and p-Akt in normal mouse femurs and in cultured mouse (mOBs) and human osteoblasts (hOBs). Our results showed that osteoblasts adjacent to the trabeculae, periosteum and endosteum in mouse femurs constitutively expressed COX-2, while COX-2 co-expressed with p-Akt in osteoblasts sitting adjacent to trabeculae in vivo, and in mOBs and hOBs in vitro. We further used COX-2 siRNA to test the role of COX-2 in Akt signaling in hOBs; COX-2 silencing significantly inhibited PTEN phosphorylation, enhanced PTEN activity, and suppressed p-Akt level and proliferation. However, replenishment of the COX-2 enzymatic product, PGE2, failed to reverse COX-2-dependent Akt phosphorylation. Furthermore, transfection with recombinant human COX-2 (rhCOX-2) significantly reversed COX-2 siRNA-suppressed PTEN phosphorylation, but this effect was reduced when the enzymatic activity of rhCOX-2 was blocked. This finding indicated that the effect of COX-2 on PTEN/Akt signaling is not related to PGE2 but still dependent on COX-2 enzymatic activity. Conversely, COX-1 silencing did not affect PTEN/Akt signaling. Our findings provide

  17. Biomechanical and biophysical environment of bone from the macroscopic to the pericellular and molecular level.

    PubMed

    Ren, Li; Yang, Pengfei; Wang, Zhe; Zhang, Jian; Ding, Chong; Shang, Peng

    2015-10-01

    (IFF) within the lacunar-canalicular system and at the endosteum, the piezoelectricity at the deformed bone surface, and the streaming potential accompanying the IFF. Their generation mechanisms and the regulation effect on bone adaptation are presented. The IFF-induced chemotransport effect, shear stress, and fluid drag on the pericellular matrix are meaningful and noteworthy. Furthermore, we firmly believe that bone adaptation is regulated by the combination of bone biomechanical and biophysical environment, not only the commonly considered matrix strain, fluid shear stress, and hydrostatic pressure, but also the piezoelectricity and streaming potential. Especially, it is necessary to incorporate bone matrix piezoelectricity and streaming potential to explain how osteoblasts (bone formation cells) and osteoclasts (bone resorption cells) can differentiate among different types of loads. Specifically, the regulation effects and the related mechanisms of the biomechanical and biophysical environments on bone need further exploration, and the incorporation of experimental research with theoretical simulations is essential. Copyright © 2015. Published by Elsevier Ltd.

  18. Expression and functional proteomic analyses of osteocytes from Xenopus laevis tested under mechanical stress conditions: preliminary observations on an appropriate new animal model.

    PubMed

    Bertacchini, Jessika; Benincasa, Marta; Checchi, Marta; Cavani, Francesco; Smargiassi, Alberto; Ferretti, Marzia; Palumbo, Carla

    2017-09-19

    Hitherto, the role of the osteocyte as transducer of mechanical stimuli into biological signals is far from settled. In this study, we used an appropriate model represented by the cortex of Xenopus laevis long bone diaphysis lacking (unlike the mammalian one) of vascular structures and containing only osteocytes inside the bone matrix. These structural features allow any change of protein profile that might be observed upon different experimental conditions, such as bone adaptation to stress/mechanical loading, to be ascribed specifically to osteocytes. The study was conducted by combining ultrastructural observations and two-dimensional electrophoresis for proteomic analysis. The osteocyte population was extracted from long bones of lower limbs of amphibian skeletons after different protocols (free and forced swimming). The experiments were performed on 210 frogs subdivided into five trials, each including free swimming frogs (controls) and frogs submitted to forced swimming (stressed). The stressed groups were obliged to swim (on movable spheres covering the bottom of a pool on a vibrating plate) continuously for 8 h, and killed 24 h later along with the control groups. Long bones free of soft tissues (periosteum, endosteum and bone marrow), as well as muscles of posterior limbs, were processed and analyzed for proteins differentially expressed or phosphorylated between the two sample groups. The comparative analysis showed that protein phosphorylation profiles differ between control and stressed groups. In particular, we found in long bones of stressed samples that both Erk1/2 and Akt are hyperphosphorylated; moreover, the different phosphorylation of putative Akt substrates (recognized by specific Akt phosphosubstrates-antibody) in stressed vs. control samples clearly demonstrated that Akt signaling is boosted by forced swimming (leading to an increase of mechanical stress) of amphibian long bones. In parallel, we found in posterior limb muscles that the

  19. Accounting for beta-particle energy loss to cortical bone via paired-image radiation transport (PIRT)

    SciTech Connect

    Shah, Amish P.; Rajon, Didier A.; Patton, Phillip W.; Jokisch, Derek W.; Bolch, Wesley E.

    2005-05-01

    Current methods of skeletal dose assessment in both medical physics (radionuclide therapy) and health physics (dose reconstruction and risk assessment) rely heavily on a single set of bone and marrow cavity chord-length distributions in which particle energy deposition is tracked within an infinite extent of trabecular spongiosa, with no allowance for particle escape to cortical bone. In the present study, we introduce a paired-image radiation transport (PIRT) model which provides a more realistic three-dimensional (3D) geometry for particle transport in the skeletal site at both microscopic and macroscopic levels of its histology. Ex vivo CT scans were acquired of the pelvis, cranial cap, and individual ribs excised from a 66-year male cadaver (BMI of 22.7 kg m{sup -2}). For the three skeletal sites, regions of trabecular spongiosa and cortical bone were identified and segmented. Physical sections of interior spongiosa were taken and subjected to microCT imaging. Voxels within the resulting microCT images were then segmented and labeled as regions of bone trabeculae, endosteum, active marrow, and inactive marrow through application of image processing algorithms. The PIRT methodology was then implemented within the EGSNRC radiation transport code whereby electrons of various initial energies are simultaneously tracked within both the ex vivo CT macroimage and the CT microimage of the skeletal site. At initial electron energies greater than 50-200 keV, a divergence in absorbed fractions to active marrow are noted between PIRT model simulations and those estimated under existing techniques of infinite spongiosa transport. Calculations of radionuclide S values under both methodologies imply that current chord-based models may overestimate the absorbed dose to active bone marrow in these skeletal sites by 0% to 27% for low-energy beta emitters ({sup 33}P, {sup 169}Er, and {sup 177}Lu), by {approx}4% to 49% for intermediate-energy beta emitters ({sup 153}Sm, {sup 186

  20. Skeletal dosimetry based on µCT images of trabecular bone: update and comparisons

    NASA Astrophysics Data System (ADS)

    Kramer, R.; Cassola, V. F.; Vieira, J. W.; Khoury, H. J.; de Oliveira Lira, C. A. B.; Robson Brown, K.

    2012-06-01

    Two skeletal dosimetry methods using µCT images of human bone have recently been developed: the paired-image radiation transport (PIRT) model introduced by researchers at the University of Florida (UF) in the US and the systematic-periodic cluster (SPC) method developed by researchers at the Federal University of Pernambuco in Brazil. Both methods use µCT images of trabecular bone (TB) to model spongiosa regions of human bones containing marrow cavities segmented into soft tissue volumes of active marrow (AM), trabecular inactive marrow and the bone endosteum (BE), which is a 50 µm thick layer of marrow on all TB surfaces and on cortical bone surfaces next to TB as well as inside the medullary cavities. With respect to the radiation absorbed dose, the AM and the BE are sensitive soft tissues for the induction of leukaemia and bone cancer, respectively. The two methods differ mainly with respect to the number of bone sites and the size of the µCT images used in Monte Carlo calculations and they apply different methods to simulate exposure from radiation sources located outside the skeleton. The PIRT method calculates dosimetric quantities in isolated human bones while the SPC method uses human bones embedded in the body of a phantom which contains all relevant organs and soft tissues. Consequently, the SPC method calculates absorbed dose to the AM and to the BE from particles emitted by radionuclides concentrated in organs or from radiation sources located outside the human body in one calculation step. In order to allow for similar calculations of AM and BE absorbed doses using the PIRT method, the so-called dose response functions (DRFs) have been developed based on absorbed fractions (AFs) of energy for electrons isotropically emitted in skeletal tissues. The DRFs can be used to transform the photon fluence in homogeneous spongiosa regions into absorbed dose to AM and BE. This paper will compare AM and BE AFs of energy from electrons emitted in skeletal

  1. Marrow toxicity of 33P-versus 32P-orthophosphate: implications for therapy of bone pain and bone metastases.

    PubMed

    Goddu, S M; Bishayee, A; Bouchet, L G; Bolch, W E; Rao, D V; Howell, R W

    2000-05-01

    theoretical dosimetry model of the mouse femur was developed, and the absorbed doses to the femoral marrow, bone, and endosteum were calculated using the EGS4 Monte Carlo code. When the animals were irradiated with exponentially decreasing dose rates of 137Cs gamma rays, initial dose rates required to achieve 37% survival were 1.9, 0.98, 0.88, and 0.79 cGy/h for dose rate decrease half-times of 62, 255, and 425 h and infinity, respectively. The D37 values were 144 +/- 15, 132 +/- 12, 129 +/- 3, and 133 +/- 10 cGy, respectively, compared with a value of 103 cGy for acute irradiation. When 32P and 33P were administered, the injected activities required to achieve 37% survival were 313 and 2,820 kBq, respectively. Theoretical dosimetry calculations show that 33P offers a 3- to 6-fold therapeutic advantage over 32P, depending on the source and target regions assumed. The low-energy beta-particle emitter 33P appears to offer a substantial dosimetric advantage over energetic beta-particle emitters (e.g., 32p, 89Sr, 186Re) for irradiating bone and minimizing marrow toxicity. This suggests that low-energy beta or conversion electron emitters may offer a substantial advantage for alleviation of bone pain as well as for specifically irradiating metastatic disease in bone.

  2. Considerations in the selection of radiopharmaceuticals for palliation of bone pain from metastatic osseous lesions.

    PubMed

    Bouchet, L G; Bolch, W E; Goddu, S M; Howell, R W; Rao, D V

    2000-04-01

    Bone pain is a common complication for terminal patients with bone metastases from prostate, lung, breast, and other malignancies. A multidisciplinary approach in treating bone pain is generally required, 1 which includes a combination of analgesic drug therapy, radiation therapy, hormonal therapy, and chemotherapy. Over the years, treatment of bone pain using bone-seeking radiopharmaceuticals has been explored extensively. Pharmaceuticals labeled with energetic 1-particle emitters such as 32p, 89Sr, 153Sm, and 186Re, in addition to the low-energy electron emitter 117mSn, have been studied for this purpose. Bone-marrow toxicity as a consequence of chronic irradiation by the energetic , particles is a general problem associated with this form of treatment. It is therefore desirable to identify radiochemicals that minimize the dose to the bone marrow and at the same time deliver therapeutic doses to the bone. New S values (mean absorbed dose per unit cumulated activity) for target regions of human bone and marrow were used to ascertain the capacity of various radiochemicals to deliver a high bone dose while minimizing the marrow dose. The relative dosimetric advantage of a given radiopharmaceutical compared with a reference radiochemical was quantitated as a dosimetric relative advantage factor (RAF). Several radionuclides that emit energetic 1 particles (32p, 89Sr, 153Sm, 186Re, and 177Lu) and radionuclides that emit low-energy electrons or beta particles (169Er, 117mSn, and 33p) were evaluated. For these calculations, ratios of the cumulated activity in the bone relative to cumulated activity in the marrow alpha equal to 10 and 100 were used. When the radiopharmaceutical was assumed to be uniformly distributed in the endosteum and alpha was taken as 100 for both the reference and test radiochemicals, the RAF values compared with the reference radionuclide 32p were 1.0, 1.2, 1.4, 1.6, 1.7, 1.9, and 2.0 for 89Sr, 186Re, 153Sm, 177Lu, 169Er, 117mSn, and 33P