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1

Differential Gene Expression from Microarray Analysis Distinguishes Woven and Lamellar Bone Formation in the Rat Ulna following Mechanical Loading  

PubMed Central

Formation of woven and lamellar bone in the adult skeleton can be induced through mechanical loading. Although much is known about the morphological appearance and structural properties of the newly formed bone, the molecular responses to loading are still not well understood. The objective of our study was to use a microarray to distinguish the molecular responses between woven and lamellar bone formation induced through mechanical loading. Rat forelimb loading was completed in a single bout to induce the formation of woven bone (WBF loading) or lamellar bone (LBF loading). A set of normal (non-loaded) rats were used as controls. Microarrays were performed at three timepoints after loading: 1 hr, 1 day and 3 days. Confirmation of microarray results was done for a select group of genes using quantitative real-time PCR (qRT-PCR). The micorarray identified numerous genes and pathways that were differentially regulated for woven, but not lamellar bone formation. Few changes in gene expression were evident comparing lamellar bone formation to normal controls. A total of 395 genes were differentially expressed between formation of woven and lamellar bone 1 hr after loading, while 5883 and 5974 genes were differentially expressed on days 1 and 3, respectively. Results suggest that not only are the levels of expression different for each type of bone formation, but that distinct pathways are activated only for woven bone formation. A strong early inflammatory response preceded an increase in angiogenic and osteogenic gene expression for woven bone formation. Furthermore, at later timepoints there was evidence of bone resorption after WBF loading. In summary, the vast coverage of the microarray offers a comprehensive characterization of the early differences in expression between woven and lamellar bone formation. PMID:22216249

McKenzie, Jennifer A.; Bixby, Elise C.; Silva, Matthew J.

2011-01-01

2

Rapid Establishment of Chemical and Mechanical Properties During Lamellar Bone Formation  

SciTech Connect

The development of prophylaxes and treatments of bone diseases that can effectively increase the strength of bone as a structure necessitates a better understanding of the time course by which chemical properties define the stiffness of the material during primary and secondary mineralization. It was hypothesized that these processes would be relatively slow in the actively growing skeleton. Seven-week-old Sprague-Dawley female rats (n = 8) were injected with multiple fluorochrome labels over a time span of 3 weeks and killed. Chemical and mechanical properties of the tibial mid-diaphysis were spatially characterized between the endocortical and periosteal surface by in situ infrared microspectroscopy and nanoindentation. The phosphate-to-protein ratio of bone 2-6 days old was 20% smaller at the periosteal surface and 22% smaller at the endocortical surface (P < 0.05 each) compared to older intracortical regions. The ratios of carbonate to protein, crystallinity, type A/type B carbonate, collagen cross-linking, and bone elastic modulus did not differ significantly between bone 2-6, 10-14, and 8-22 days old and intracortical regions. Intracortical properties of 10-week-old rats, except for the carbonate-to-protein ratio which was 23% smaller (P < 0.01), were not significantly different from intracortical matrix properties of young adult rats (5 months, n = 4). Spatially, the phosphate-to-protein ratio (R{sup 2} = 0.33) and the phosphate-to-carbonate ratio (R{sup 2} = 0.55) were significantly correlated with bone material stiffness, while the combination of all chemical parameters raised the R{sup 2} value to 0.83. These data indicate that lamellar bone has the ability to quickly establish its mechanical and chemical tissue properties during primary and secondary mineralization even when the skeleton experiences rapid growth.

Busa,B.; Miller, L.; Rubin, C.; Qin, Y.; Judex, S.

2005-01-01

3

Patterned silk film scaffolds for aligned lamellar bone tissue engineering  

PubMed Central

Various porous biomaterial scaffolds have been utilized for bone tissue engineering; however, they are often limited in their ability to replicate the structural hierarchy and mechanics of native cortical bone. In this study, the alignment and osteogenic differentiation of human mesenchymal stem cells (MSCs) on patterned silk films (PF) was investigated as a bottom-up, biomimetic approach toward engineering cortical bone lamellae. Screening films cast with nine different micro and nano scale groove patterns showed that cellular alignment was mediated by an interplay between the width and depth of the patterns. MSCs were differentiated in osteogenic medium for four weeks on the PF that induced the highest degree of alignment, while flat films (FF) served as controls. Gene expression analysis and calcium quantification indicated that the PF supported osteogenic differentiation while also inducing robust lamellar alignment of cells and matrix deposition. A secondary alignment effect was noted on the PF where a new layer of aligned cells grew over the first layer, but rotated obliquely to the underlying pattern direction and first layer orientation. This layering and rotation of the aligned MSCs resembled the characteristic structural organization observed in native lamellar bone. The ability to control multilayered lamellar structural hierarchy from the interplay between a patterned 2D surface and cells suggests intriguing options for future biomaterial scaffolds designed to mimic native tissue structures. PMID:23070941

Tien, Lee W.; Gil, Eun Seok; Park, Sang-Hyug; Mandal, Biman B.; Kaplan, David L.

2013-01-01

4

Kinetics of lamellar formation on sparsely stripped patterns  

NASA Astrophysics Data System (ADS)

Chemical epitaxy based on the self-assembly of block copolymers is viewed as a promising technique to achieve ordered patterns on a large scale. Herein, we study the kinetics of lamellar formation of block copolymers under the direction of sparsely stripped patterns using cell dynamics simulations of the time-dependent Ginzburg-Landau theory. First, a scaling law is unveiled with the ordering time of lamellae, tp, with respect to the multiples between the periods of lamellae and stripe patterns, which is consistent with the power law evolution of the correlation length existing in the bulk phase of lamellae. Second, the tolerative windows of perfect order, with deviation from integer multiples, are also estimated from the aspect of kinetics. The results of the ordering time and tolerative windows are of great interest for relevant experiments or applications. Finally, a two-stage evolution is explored during the pattern formation of chemical epitaxy by probing into the evolution of defects, which is of fundamental interest for us to understand the coarsening kinetics of block copolymers under the direction of chemical patterns.

Xie, Nan; Li, Weihua; Zhang, Hongdong; Qiu, Feng; Shi, An-Chang

2013-11-01

5

Microfibril Orientation Dominates the Microelastic Properties of Human Bone Tissue at the Lamellar Length Scale  

PubMed Central

The elastic properties of bone tissue determine the biomechanical behavior of bone at the organ level. It is now widely accepted that the nanoscale structure of bone plays an important role to determine the elastic properties at the tissue level. Hence, in addition to the mineral density, the structure and organization of the mineral nanoparticles and of the collagen microfibrils appear as potential key factors governing the elasticity. Many studies exist on the role of the organization of collagen microfibril and mineral nanocrystals in strongly remodeled bone. However, there is no direct experimental proof to support the theoretical calculations. Here, we provide such evidence through a novel approach combining several high resolution imaging techniques: scanning acoustic microscopy, quantitative scanning small-Angle X-ray scattering imaging and synchrotron radiation computed microtomography. We find that the periodic modulations of elasticity across osteonal bone are essentially determined by the orientation of the mineral nanoparticles and to a lesser extent only by the particle size and density. Based on the strong correlation between the orientation of the mineral nanoparticles and the collagen molecules, we conclude that the microfibril orientation is the main determinant of the observed undulations of microelastic properties in regions of constant mineralization in osteonal lamellar bone. This multimodal approach could be applied to a much broader range of fibrous biological materials for the purpose of biomimetic technologies. PMID:23472132

Rupin, Fabienne; Raum, Kay; Peyrin, Françoise; Burghammer, Manfred; Saïed, Amena; Laugier, Pascal

2013-01-01

6

Homogenized stiffness matrices for mineralized collagen fibrils and lamellar bone using unit cell finite element models.  

PubMed

Mineralized collagen fibrils have been usually analyzed like a two-phase composite material where crystals are considered as platelets that constitute the reinforcement phase. Different models have been used to describe the elastic behavior of the material. In this work, it is shown that when Halpin-Tsai equations are applied to estimate elastic constants from typical constituent properties, not all crystal dimensions yield a model that satisfy thermodynamic restrictions. We provide the ranges of platelet dimensions that lead to positive definite stiffness matrices. On the other hand, a finite element model of a mineralized collagen fibril unit cell under periodic boundary conditions is analyzed. By applying six canonical load cases, homogenized stiffness matrices are numerically calculated. Results show a monoclinic behavior of the mineralized collagen fibril. In addition, a 5-layer lamellar structure is also considered where crystals rotate in adjacent layers of a lamella. The stiffness matrix of each layer is calculated applying Lekhnitskii transformations, and a new finite element model under periodic boundary conditions is analyzed to calculate the homogenized 3D anisotropic stiffness matrix of a unit cell of lamellar bone. Results are compared with the rule-of-mixtures showing in general good agreement. PMID:23793930

Vercher, Ana; Giner, Eugenio; Arango, Camila; Tarancón, José E; Fuenmayor, F Javier

2014-04-01

7

Multilamellar vesicle formation from a planar lamellar phase under shear flow.  

PubMed

The formation of multilamellar vesicles (MLVs) from the lamellar phase of nonionic surfactant system C12E5/D2O under shear flow is studied by time-resolved small angle neutron and light scattering during shear flow. A novel small angle neutron scattering sample environment enables the tracking of the lamellae alignment in the velocity-velocity gradient (1-2) plane during MLV formation, which was tracked independently using flow small angle light scattering commensurate with rheology. During the lamellar-to-multilamellar vesicle transition, the primary Bragg peak from the lamellar ordering was observed to tilt, and this gradually increased with time, leading to an anisotropic pattern with a primary axis oriented at ?25° relative to the flow direction. This distorted pattern persists under flow after MLV formation. A critical strain and critical capillary number based on the MLV viscosity are demonstrated for MLV formation, which is shown to be robust for other systems as well. These novel measurements provide fundamentally new information about the flow orientation of lamellae in the plane of flow that cannot be anticipated from the large body of previous literature showing nearly isotropic orientation in the 2,3 and 1,3 planes of flow. These observations are consistent with models for buckling-induced MLV formation but suggest that the instability is three-dimensional, thereby identifying the mechanism of MLV formation in simple shear flow. PMID:24983325

Gentile, Luigi; Behrens, Manja A; Porcar, Lionel; Butler, Paul; Wagner, Norman J; Olsson, Ulf

2014-07-22

8

Lamellar Bone is an Incremental Tissue Reconciling Enamel Rhythms, Body Size, and Organismal Life History  

Microsoft Academic Search

Mammalian enamel formation is periodic, including fluctuations attributable to the daily biological clock as well as longer-period\\u000a oscillations that enigmatically correlate with body mass. Because the scaling of bone mass to body mass is an axiom of vertebrate\\u000a hard tissue biology, we consider that long-period enamel formation rhythms may reflect corresponding and heretofore unrecognized\\u000a rhythms in bone growth. The principal

Timothy G. Bromage; Rodrigo S. Lacruz; Russell Hogg; Haviva M. Goldman; Shannon C. McFarlin; Johanna Warshaw; Wendy Dirks; Alejandro Perez-Ochoa; Igor Smolyar; Donald H. Enlow; Alan Boyde

2009-01-01

9

Formation of the lamellar phase of alkyl-benzenesulphonates from surfactant\\/water\\/electrolyte solutions  

Microsoft Academic Search

In the phase diagram of sodium 1?-(4)-alkylbenzenesulfonate (4SDBS)\\/water\\/Mg(NO3)2 in the diluted surfactant regime, the appearance of three regions exhibiting various micro-structures of isotropic phases\\u000a is shown. The visualization of the dynamics of the lamellar phase formation from the saturated viscous isotropic surfactant\\/electrolyte\\u000a solution was done by the light microscopy operated with differential interference contrast (DIC) using video camera. The first

?. Težak; N. Jalšenjak; N. Ljubeši?

10

Peripheral Leptin Regulates Bone Formation  

PubMed Central

Substantial evidence does not support the prevailing view that leptin, acting through a hypothalamic relay, decreases bone accrual by inhibiting bone formation. To clarify the mechanisms underlying regulation of bone architecture by leptin, we evaluated bone growth and turnover in wild type (WT) mice, leptin receptor-deficient db/db mice, leptin-deficient ob/ob mice and ob/ob mice treated with leptin. We also performed hypothalamic leptin gene therapy to determine the effect of elevated hypothalamic leptin levels on osteoblasts. Finally, to determine the effects of loss of peripheral leptin signaling on bone formation and energy metabolism, we used bone marrow (BM) from WT or db/db donor mice to reconstitute the hematopoietic and mesenchymal stem cell compartments in lethally irradiated WT recipient mice. Decreases in bone growth, osteoblast-lined bone perimeter and bone formation rate were observed in ob/ob mice and greatly increased in ob/ob mice following subcutaneous administration of leptin. Similarly, hypothalamic leptin gene therapy increased osteoblast-lined bone perimeter in ob/ob mice. In spite of normal osteoclast-lined bone perimeter, db/db mice exhibited a mild but generalized osteopetrotic-like (calcified cartilage encased by bone) skeletal phenotype and greatly reduced serum markers of bone turnover. Tracking studies and histology revealed quantitative replacement of BM cells following BM transplantation. WT mice engrafted with db/db BM did not differ in energy homeostasis from untreated WT mice or WT mice engrafted with WT BM. Bone formation in WT mice engrafted with WT BM did not differ from WT mice, whereas bone formation in WT mice engrafted with db/db cells did not differ from the low rates observed in untreated db/db mice. In summary, our results indicate that leptin, acting primarily through peripheral pathways, increases osteoblast number and activity. PMID:22887758

Turner, Russell T.; Kalra, Satya P.; Wong, Carmen P.; Philbrick, Kenneth A.; Lindenmaier, Laurence B.; Boghossian, Stephane; Iwaniec, Urszula T.

2012-01-01

11

Physiological variables affecting surface film formation by native lamellar body-like pulmonary surfactant particles.  

PubMed

Pulmonary surfactant (PS) is a surface active complex of lipids and proteins that prevents the alveolar structures from collapsing and reduces the work of breathing by lowering the surface tension at the alveolar air-liquid interface (ALI). Surfactant is synthesized by the alveolar type II (AT II) cells, and it is stored in specialized organelles, the lamellar bodies (LBs), as tightly packed lipid bilayers. Upon secretion into the alveolar lining fluid, a large fraction of these particles retain most of their packed lamellar structure, giving rise to the term lamellar body like-particles (LBPs). Due to their stability in aqueous media, freshly secreted LBPs can be harvested from AT II cell preparations. However, when LBPs get in contact with an ALI, they quickly and spontaneously adsorb into a highly organized surface film. In the present study we investigated the adsorptive capacity of LBPs at an ALI under relevant physiological parameters that characterize the alveolar environment in homeostatic or in pathological conditions. Adsorption of LBPs at an ALI is highly sensitive to pH, temperature and albumin concentration and to a relatively lesser extent to changes in osmolarity or Ca(2+) concentrations in the physiological range. Furthermore, proteolysis of LBPs significantly decreases their adsorptive capacity confirming the important role of surfactant proteins in the formation of surface active films. PMID:24582711

Hobi, Nina; Siber, Gerlinde; Bouzas, Virginia; Ravasio, Andrea; Pérez-Gil, Jesus; Haller, Thomas

2014-07-01

12

Dilatational band formation in bone  

PubMed Central

Toughening in hierarchically structured materials like bone arises from the arrangement of constituent material elements and their interactions. Unlike microcracking, which entails micrometer-level separation, there is no known evidence of fracture at the level of bone’s nanostructure. Here, we show that the initiation of fracture occurs in bone at the nanometer scale by dilatational bands. Through fatigue and indentation tests and laser confocal, scanning electron, and atomic force microscopies on human and bovine bone specimens, we established that dilatational bands of the order of 100 nm form as ellipsoidal voids in between fused mineral aggregates and two adjacent proteins, osteocalcin (OC) and osteopontin (OPN). Laser microdissection and ELISA of bone microdamage support our claim that OC and OPN colocalize with dilatational bands. Fracture tests on bones from OC and/or OPN knockout mice (OC?/?, OPN?/?, OC-OPN?/?;?/?) confirm that these two proteins regulate dilatational band formation and bone matrix toughness. On the basis of these observations, we propose molecular deformation and fracture mechanics models, illustrating the role of OC and OPN in dilatational band formation, and predict that the nanometer scale of tissue organization, associated with dilatational bands, affects fracture at higher scales and determines fracture toughness of bone. PMID:23129653

Poundarik, Atharva A.; Diab, Tamim; Sroga, Grazyna E.; Ural, Ani; Boskey, Adele L.; Gundberg, Caren M.; Vashishth, Deepak

2012-01-01

13

Three-dimensional structure of human lamellar bone: the presence of two different materials and new insights into the hierarchical organization.  

PubMed

Lamellar bone is the most common bone type in humans. The predominant components of individual lamellae are plywood-like arrays of mineralized collagen fibrils aligned in different directions. Using a dual-beam electron microscope and the Serial Surface View (SSV) method we previously identified a small, but significantly different layer in rat lamellar bone, namely a disordered layer with collagen fibrils showing little or no preferred orientation. Here we present a 3D structural analysis of 12 SSV volumes (25 complete lamellae) from femora of 3 differently aged human individuals. We identify the ordered and disordered motifs in human bone as in the rat, with several significant differences. The ordered motif shows two major preferred orientations, perpendicular to the long axis of the bone, and aligned within 10-20° of the long axis, as well as fanning arrays. At a higher organizational level, arrays of ordered collagen fibrils are organized into 'rods' around 2 to 3?m in diameter, and the long axes of these 'rods' are parallel to the lamellar boundaries. Human bone also contains a disordered component that envelopes the rods and fills in the spaces between them. The disordered motif is especially well-defined between adjacent layers of rods. The disordered motif and its interfibrillar substance stain heavily with osmium tetroxide and Alcian blue indicating the presence of another organic component in addition to collagen. The canalicular network is confined to the disordered material, along with voids and individual collagen fibrils, some of which are also aligned more or less perpendicular to the lamellar boundaries. The organization of the ordered fibril arrays into rods enveloped in the continuous disordered structure was not observed in rat lamellar bone. We thus conclude that human lamellar bone is comprised of two distinct materials, an ordered material and a disordered material, and contains an additional hierarchical level of organization composed of arrays of ordered collagen fibrils, referred to as rods. This new structural information on human lamellar bone will improve our understanding of structure-mechanical function relations, mechanisms of mechano-sensing and the characterizations of bone pathologies. PMID:24211799

Reznikov, Natalie; Shahar, Ron; Weiner, Steve

2014-02-01

14

Microstructure-microhardness relations in parallel-fibered and lamellar bone  

Microsoft Academic Search

Understanding the mechanical function of bone material in relation to its structure is a fascinating but very complicated problem to resolve. Part of the complexity arises from the hierarchical structural organization of bone. Microhardness measurements, initially on relatively simply structured parallel-fibered bone, show a marked anisotropy in three orthogonal directions. This may, in part, be due to the highly anisotropic

V. Ziv; H. D. Wagner; S. Weiner

1996-01-01

15

Elastic properties of human cortical and trabecular lamellar bone measured by nanoindentation  

Microsoft Academic Search

An experimental investigation was undertaken to measure the intrinsic elastic properties of several of the microstructural components of human vertebral trabecular bone and tibial cortical bone by the nanoindentation method. Specimens from two thoracic vertebrae (T-12) and two tibiae were obtained from frozen, unembalmed human male cadavers aged 57 and 61 years. After drying and mounting in epoxy resin, nanoindentation

Jae-Young Rho; Ting Y. Tsui; George M. Pharr

1997-01-01

16

Evidence for arrested bone formation during spaceflight  

NASA Technical Reports Server (NTRS)

Addressing the question of whether the bone formed in space is unusual, the morphology of bone made at the tibial diaphysis of rats before, during, and after spaceflight is studied. Evidence of arrest lines in the bone formed in space is reported suggesting that bone formation ceases along portions of the periosteum during spaceflight. Visualized by microradiography, the arrest lines are shown to be less mineralized than the surrounding bone matrix. When viewed by scanning electron microscopy, it is seen that bone fractures more readily at the site of an arrest line. These observations are seen as suggesting that arrest lines are a zone of weakness and that their formation may result in decreased bone strength in spite of normalization of bone formation after flight. The occurrence, location, and morphology of arrest lines are seen as suggesting that they are a visible result of the phenomenon of arrested bone formation.

Turner, R. T.; Bobyn, J. D.; Duvall, P.; Morey, E. R.; Baylink, D. J.; Spector, M.

1982-01-01

17

Inhibition of bone formation during space flight  

NASA Technical Reports Server (NTRS)

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.

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

1978-01-01

18

Shell Formation and Bone Strength Laying Hens  

E-print Network

Shell Formation and Bone Strength in Laying Hens Effects of Age, Daidzein and Exogenous Estrogen Cover aquarelle: E. Spörndly-Nees #12;Shell Formation and Bone Strength in Laying Hens Effects of Age as well as an economical problem. Parallel with reduced shell quality the bone strength declines

19

Recombinant Human Bone Morphogenetic Protein Induces Bone Formation  

Microsoft Academic Search

We have purified and characterized active recombinant human bone morphogenetic protein (BMP) 2A. Implantation of the recombinant protein in rats showed that a single BMP can induce bone formation in vivo. A dose-response and time-course study using the rat ectopic bone formation assay revealed that implantation of 0.5-115 mug of partially purified recombinant human BMP-2A resulted in cartilage by day

Elizabeth A. Wang; Vicki Rosen; Josephine S. D'Alessandro; Marc Bauduy; Paul Cordes; Tomoko Harada; David I. Israel; Rodney M. Hewick; Kelvin M. Kerns; Peter Lapan; Deborah H. Luxenberg; David McQuid; Ioannis K. Moutsatsos; John Nove; John M. Wozney

1990-01-01

20

Hierarchical Formation of Fibrillar and Lamellar Self-Assemblies from Guanosine-Based Motifs  

PubMed Central

Here we investigate the supramolecular polymerizations of two lipophilic guanosine derivatives in chloroform by light scattering technique and TEM experiments. The obtained data reveal the presence of several levels of organization due to the hierarchical self-assembly of the guanosine units in ribbons that in turn aggregate in fibrillar or lamellar soft structures. The elucidation of these structures furnishes an explanation to the physical behaviour of guanosine units which display organogelator properties. PMID:20798860

Neviani, Paolo; Sarazin, Dominique; Schmutz, Marc; Blanck, Christian; Giuseppone, Nicolas; Spada, Gian Piero

2010-01-01

21

Space flight and bone formation  

NASA Technical Reports Server (NTRS)

Major physiological changes which occur during spaceflight include bone loss, muscle atrophy, cardiovascular and immune response alterations. When trying to determine the reason why bone loss occurs during spaceflight, one must remember that all these other changes in physiology and metabolism may also have impact on the skeletal system. For bone, however, the role of normal weight bearing is a major concern and we have found no adequate substitute for weight bearing which can prevent bone loss. During the study of this problem, we have learned a great deal about bone physiology and increased our knowledge about how normal bone is formed and maintained. Presently, we do not have adequate ground based models which can mimic the tissue loss that occurs in spaceflight but this condition closely resembles the bone loss seen with osteoporosis. Although a normal bone structure will respond to application of mechanical force and weight bearing by forming new bone, a weakened osteoporotic bone may have a tendency to fracture. The study of the skeletal system during weightless conditions will eventually produce preventative measures and form a basis for protecting the crew during long term space flight. The added benefit from these studies will be methods to treat bone loss conditions which occur here on earth.

Doty, St B.

2004-01-01

22

Skeletal Self-Repair: Stress Fracture Healing by Rapid Formation and Densification of Woven Bone  

PubMed Central

Stress fractures of varying severity were created using a rat model of skeletal fatigue loading. Periosteal woven bone formed in proportion to the level of bone damage, resulting in the rapid recovery of whole-bone strength independent of stress fracture severity. Introduction A hard periosteal callus is a hallmark of stress fracture healing. The factors that regulate the formation of this woven bone callus are poorly understood. Our objective was to produce stress fractures of varying severity and to assess the woven bone response and recovery of bone strength. Materials and Methods We used the forelimb compression model to create stress fractures of varying severity in 192 adult rats. Forelimbs were loaded in fatigue until the displacement reached 30, 45, 65 or 85% of fracture. The osteogenic responses of loaded and contralateral control ulnae were assessed 7 and 14 days after loading using pQCT, microCT, mechanical testing, histomorphometry, and Raman spectroscopy. Results Loading stimulated the formation of periosteal woven bone that was maximal near the ulnar mid-shaft and transitioned to lamellar bone away from the mid-shaft. Woven bone area increased in a dose-response manner with increasing fatigue displacement. Whole-bone strength was partially recovered at 7 days and fully recovered at 14 days, regardless of initial stress fracture severity. The density of the woven bone increased by 80% from 7 to 14 days, due in part to a 30% increase in the mineral:collagen ratio of the woven bone tissue. Conclusion Functional healing of a stress fracture, as evidenced by recovery of whole-bone strength, occurred within 2 weeks, regardless of stress fracture severity. Partial recovery of strength in the first week was attributed to the rapid formation of a collar of woven bone that was localized to the site of bone damage and whose size depended on the level of initial damage. Complete recovery of strength in the second week was due to woven bone densification. For the first time we have shown that woven bone formation occurs as a dose-dependent response following damaging mechanical loading of bone. PMID:17576168

Uthgenannt, Brian A.; Kramer, Michael H.; Hwu, Joyce A.; Wopenka, Brigitte; Silva, Matthew J.

2013-01-01

23

MicroRNAs involved in bone formation.  

PubMed

During skeletal development, mesenchymal progenitor cells undergo a multistage differentiation process in which they proliferate and become bone- and cartilage-forming cells. This process is tightly regulated by multiple levels of regulatory systems. The small non-coding RNAs, microRNAs (miRNAs), post-transcriptionally regulate gene expression. Recent studies have demonstrated that miRNAs play significant roles in all stages of bone formation, suggesting the possibility that miRNAs can be novel therapeutic targets for skeletal diseases. Here, we review the role and mechanism of action of miRNAs in bone formation. We discuss roles of specific miRNAs in major types of bone cells, osteoblasts, chondrocytes, osteoclasts, and their progenitors. Except a few, the current knowledge about miRNAs in bone formation has been obtained mainly by in vitro studies; further validation of these findings in vivo is awaited. We also discuss about several miRNAs of particular interest in the light of future therapies of bone diseases. PMID:25108446

Papaioannou, Garyfallia; Mirzamohammadi, Fatemeh; Kobayashi, Tatsuya

2014-12-01

24

[BMP signaling and bone formation].  

PubMed

Bone morphogenetic proteins (BMPs) bind to two types of membrane receptors. Type II receptor phosphorylates type I receptor, then the phosphorylated type I receptor phosphorylates downstream effectors, such as Smads. Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by progressive heterotopic ossification in skeletal muscle tissue. ALK2, a BMP type I receptor has been mutated in patients with FOP. The mutant ALK2 phosphorylates Smads in the absence of BMPs. In FOP, muscle injury may enhance BMP signaling via Smads to induce acute heterotopic ossification. Inhibitors of the BMP-Smad pathway will be useful to develop novel treatments for FOP. PMID:23103811

Katagiri, Takenobu

2012-11-01

25

Novel Regulators of Bone Formation: Molecular Clones and Activities  

Microsoft Academic Search

Protein extracts derived from bone can initiate the process that begins with cartilage formation and ends in de novo bone formation. The critical components of this extract, termed bone morphogenetic protein (BMP), that direct cartilage and bone formation as well as the constitutive elements supplied by the animal during this process have long remained unclear. Amino acid sequence has been

John M. Wozney; Vicki Rosen; Anthony J. Celeste; Lisa M. Mitsock; Matthew J. Whitters; Ronald W. Kriz; Rodney M. Hewick; Elizabeth A. Wang

1988-01-01

26

Increased bone formation in osteocalcin-deficient mice  

Microsoft Academic Search

VERTEBRATES constantly remodel bone. The resorption of preexisting bone by osteoclasts and the formation of new bone by osteoblasts is strictly coordinated to maintain bone mass within defined limits. A few molecular determinants of bone remodelling that affect osteoclast activity1-3 have been characterized, but the molecular determinants of osteoblast activity are unknown. To investigate the role of osteocalcin, the most

Patricia Ducy; Christelle Desbois; Brendan Boyce; Gerald Pinero; Beryl Story; Colin Dunstan; Erica Smith; Jeffrey Bonadio; Steven Goldstein; Caren Gundberg; Allan Bradley; Gerard Karsenty

1996-01-01

27

Erythropoietin Couples Hematopoiesis with Bone Formation  

PubMed Central

Background It is well established that bleeding activates the hematopoietic system to regenerate the loss of mature blood elements. We have shown that hematopoietic stem cells (HSCs) isolated from animals challenged with an acute bleed regulate osteoblast differentiation from marrow stromal cells. This suggests that HSCs participate in bone formation where the molecular basis for this activity is the production of BMP2 and BMP6 by HSCs. Yet, what stimulates HSCs to produce BMPs is unclear. Methodology/Principal Findings In this study, we demonstrate that erythropoietin (Epo) activates Jak-Stat signaling pathways in HSCs which leads to the production of BMPs. Critically, Epo also directly activates mesenchymal cells to form osteoblasts in vitro, which in vivo leads to bone formation. Importantly, Epo first activates osteoclastogenesis which is later followed by osteoblastogenesis that is induced by either Epo directly or the expression of BMPs by HSCs to form bone. Conclusions/Significance These data for the first time demonstrate that Epo regulates the formation of bone by both direct and indirect pathways, and further demonstrates the exquisite coupling between hematopoesis and osteopoiesis in the marrow. PMID:20523730

Ziegler, Anne M.; Pedersen, Elisabeth A.; Wang, Jianhua; Wang, Zhuo; Song, Junhui; Wang, Jingcheng; Lee, Clara H.; Sud, Sudha; Pienta, Kenneth J.; Krebsbach, Paul H.; Taichman, Russell S.

2010-01-01

28

Experimental adipocere formation: implications for adipocere formation on buried bone.  

PubMed

Adipocere, or grave wax (adipo = fat, cere = wax), is a distinctive decomposition product composed primarily of fatty acids (FA) and their alkali salts. FA result from the bacterial enzymatic hydrolysis of body fats. Reactions with ammonia and alkali metals originating from body fluids and pore waters of the depositional environment produce alkali salts of FA (soap). Adipocere formation is generally associated with burial of corpses with ample adipose tissue available. No indications that adipocere can form on defleshed remains have been presented in the literature. At the termination of a long-term bone diagenesis experiment, several samples were found to possess growths of an unknown compound. Gas chromatography-mass spectrometry confirmed that the growths are adipocere. The results herein reveal that adipocere can indeed form on defleshed bones under the right conditions and that even residual adipose and lipids in defleshed bones are sufficient to produce adipocere growth on the surfaces of bone. PMID:22211839

Moses, Randolph J

2012-05-01

29

The Relation between Bone and Stone Formation  

PubMed Central

Hypercalciuria is the most common metabolic abnormality found in patients with calcium-containing kidney stones. Patients with hypercalciuria often excrete more calcium than they absorb, indicating a net loss of total body calcium. The source of this additional urine calcium is almost certainly the skeleton, the largest repository of calcium in the body. Hypercalciuric stone formers exhibit decreased bone mineral density (BMD) which is correlated with the increase in urine calcium excretion. The decreased BMD also correlates with an increase in markers of bone turnover, as well as increased fractures. In humans, it is difficult to determine the cause of the decreased BMD in hypercalciuric stone formers. To study the effect of hypercalciuria on bone we utilized our genetic hypercalciuric stone-forming (GHS) rats which were developed through successive inbreeding of the most hypercalciuric Sprague-Dawley rats. GHS rats excrete significantly more urinary calcium than similarly fed controls and all the GHS rats form kidney stones while control rats do not. The hypercalciuria is due to a systemic dysregulation of calcium homeostasis, with increased intestinal calcium absorption, enhanced bone mineral resorption and decreased renal tubule calcium reabsorption associated with an increase in vitamin D receptors in all these target tissues. We recently found that GHS rats fed an ample calcium diet have reduced BMD and their bones are more fracture prone, indicating an intrinsic disorder of bone not secondary to diet. Using this model, we should better understand the pathogenesis of hypercalciuria and stone formation in humans to ultimately improve bone health of patients with kidney stones. PMID:23247537

Krieger, Nancy S.; Bushinsky, David A.

2012-01-01

30

In situ micropillar compression reveals superior strength and ductility but an absence of damage in lamellar bone  

NASA Astrophysics Data System (ADS)

Ageing societies suffer from an increasing incidence of bone fractures. Bone strength depends on the amount of mineral measured by clinical densitometry, but also on the micromechanical properties of the hierarchical organization of bone. Here, we investigate the mechanical response under monotonic and cyclic compression of both single osteonal lamellae and macroscopic samples containing numerous osteons. Micropillar compression tests in a scanning electron microscope, microindentation and macroscopic compression tests were performed on dry ovine bone to identify the elastic modulus, yield stress, plastic deformation, damage accumulation and failure mechanisms. We found that isolated lamellae exhibit a plastic behaviour, with higher yield stress and ductility but no damage. In agreement with a proposed rheological model, these experiments illustrate a transition from a ductile mechanical behaviour of bone at the microscale to a quasi-brittle response driven by the growth of cracks along interfaces or in the vicinity of pores at the macroscale.

Schwiedrzik, Jakob; Raghavan, Rejin; Bürki, Alexander; Lenader, Victor; Wolfram, Uwe; Michler, Johann; Zysset, Philippe

2014-07-01

31

Regulation of bone resorption and formation by purines and pyrimidines  

E-print Network

Regulation of bone resorption and formation by purines and pyrimidines Astrid Hoebertz1 , Timothy R, signalling through P2 receptors, might play important roles in the regulation of bone and cartilage cells Osteoblasts (bone-forming cells) Osteoclasts (bone-resorbing cells) Origin Derived from precursors

Burnstock, Geoffrey

32

Bone formation in vitro by stromal cells obtained from bone marrow of young adult rats  

Microsoft Academic Search

Cells from fetal or neonatal skeleton can synthesize bone-like tissue in vitro. In contrast, formation of bone-like tissue in vitro by cells derived from adult animals has rarely been reported and has not been achieved using cells from bone marrow. We have explored development of bone-like tissue in vitro by bone marrow stromal cells. Marrow stromal cells obtained from 40–43-day-old

C. Maniatopoulos; J. Sodek; A. H. Melcher

1988-01-01

33

Bone Balance within a Cortical BMU: Local Controls of Bone Resorption and Formation  

PubMed Central

Maintaining bone volume during bone turnover by a BMU is known as bone balance. Balance is required to maintain structural integrity of the bone and is often dysregulated in disease. Consequently, understanding how a BMU controls bone balance is of considerable interest. This paper develops a methodology for identifying potential balance controls within a single cortical BMU. The theoretical framework developed offers the possibility of a directed search for biological processes compatible with the constraints of balance control. We first derive general control constraint equations and then introduce constitutive equations to identify potential control processes that link key variables that describe the state of the BMU. The paper describes specific local bone volume balance controls that may be associated with bone resorption and bone formation. Because bone resorption and formation both involve averaging over time, short-term fluctuations in the environment are removed, leaving the control systems to manage deviations in longer-term trends back towards their desired values. The length of time for averaging is much greater for bone formation than for bone resorption, which enables more filtering of variability in the bone formation environment. Remarkably, the duration for averaging of bone formation may also grow to control deviations in long-term trends of bone formation. Providing there is sufficient bone formation capacity by osteoblasts, this leads to an extraordinarily robust control mechanism that is independent of either osteoblast number or the cellular osteoid formation rate. A complex picture begins to emerge for the control of bone volume. Different control relationships may achieve the same objective, and the ‘integration of information’ occurring within a BMU may be interpreted as different sets of BMU control systems coming to the fore as different information is supplied to the BMU, which in turn leads to different observable BMU behaviors. PMID:22844401

Smith, David W.; Gardiner, Bruce S.; Dunstan, Colin

2012-01-01

34

Formation of lamellar cross bridges in the annulus fibrosus of the intervertebral disc is a consequence of vascular regression.  

PubMed

Cross bridges are radial structures within the highly organized lamellar structure of the annulus fibrosus of the intervertebral disc that connect two or more non-consecutive lamellae. Their origin and function are unknown. During fetal development, blood vessels penetrate deep within the AF and recede during postnatal growth. We hypothesized that cross bridges are the pathways left by these receding blood vessels. Initially, the presence of cross bridges was confirmed in cadaveric human discs aged 25 and 53 years. Next, L1-L2 intervertebral discs (n=4) from sheep ranging in age from 75 days fetal gestation to adult were processed for paraffin histology. Mid-sagittal sections were immunostained for endothelial cell marker PECAM-1. The anterior and posterior AF were imaged using differential interference contrast microscopy, and the following parameters were quantified: total number of distinct lamellae, total number of cross bridges, percentage of cross bridges staining positive for PECAM-1, cross bridge penetration depth (% total lamellae), and PECAM-1 positive cross bridge penetration depth. Cross bridges were first observed at 100 days fetal gestation. The overall number peaked in neonates then remained relatively unchanged. The percentage of PECAM-1 positive cross bridges declined progressively from almost 100% at 100 days gestation to less than 10% in adults. Cross bridge penetration depth peaked in neonates then remained unchanged at subsequent ages. Depth of PECAM-1 positive cross bridges decreased progressively after birth. Findings were similar for both the anterior and posterior. The AF lamellar architecture is established early in development. It later becomes disrupted as a consequence of vascularization. Blood vessels then recede, perhaps due to increasing mechanical stresses in the surrounding matrix. In this study we present evidence that the pathways left by receding blood vessels remain as lamellar cross bridges. It is unclear whether the presence of cross bridges in the aging and degenerating intervertebral disc would be advantageous or detrimental, and this question should be addressed by future studies. PMID:21504791

Smith, Lachlan J; Elliott, Dawn M

2011-05-01

35

Formation of lamellar cross bridges in the annulus fibrosus of the intervertebral disc is a consequence of vascular regression  

PubMed Central

Cross bridges are radial structures within the highly organized lamellar structure of the annulus fibrosus of the intervertebral disc that connect two or more non-consecutive lamellae. Their origin and function are unknown. During fetal development, blood vessels penetrate deep within the AF and recede during postnatal growth. We hypothesized that cross bridges are the pathways left by these receding blood vessels. Initially, the presence of cross bridges was confirmed in cadaveric human discs aged 25 and 53 years. Next, L1-L2 intervertebral discs (n=4) from sheep ranging in age from 75 days fetal gestation to adult were processed for paraffin histology. Mid-sagittal sections were immunostained for endothelial cell marker PECAM-1. The anterior and posterior AF were imaged using differential interference contrast microscopy, and the following parameters were quantified: total number of cross bridges; percentage of cross bridges staining positive for PECAM-1; cross bridge penetration depth (% total lamellae); and PECAM-1 positive cross bridge penetration depth. Cross bridges were first observed at 100 days fetal gestation. The overall number peaked in neonates then remained relatively unchanged. The percentage of PECAM-1 positive cross bridges declined progressively from almost 100% at 100 days gestation to less than 10% in adults. Cross bridge penetration depth peaked in neonates then remained unchanged at subsequent ages. Depth of PECAM-1 positive cross bridges decreased progressively after birth. Findings were similar for both the anterior and posterior. The AF lamellar architecture is established early in development. It later becomes disrupted as a consequence of vascularization. Blood vessels then recede, perhaps due to increasing mechanical stresses in the surrounding matrix. In this study we present evidence that the pathways left by receding blood vessels remain as lamellar cross bridges. It is unclear whether the presence of cross bridges in the aging and degenerating intervertebral disc would be advantages or detrimental, and this question should be addressed by future studies. PMID:21504791

Smith, Lachlan J; Elliott, Dawn M

2011-01-01

36

MgCHA particles dispersion in porous PCL scaffolds: in vitro mineralization and in vivo bone formation.  

PubMed

In this work, we focus on the in vitro and in vivo response of composite scaffolds obtained by incorporating Mg,CO3 -doped hydroxyapatite (HA) particles in poly(?-caprolactone) (PCL) porous matrices. After a complete analysis of chemical and physical properties of synthesized particles (i.e. SEM/EDS, DSC, XRD and FTIR), we demonstrate that the Mg,CO3 doping influences the surface wettability with implications upon cell-material interaction and new bone formation mechanisms. In particular, ion substitution in apatite crystals positively influences the early in vitro cellular response of human mesenchymal stem cells (hMSCs), i.e. adhesion and proliferation, and promotes an extensive mineralization of the scaffold in osteogenic medium, thus conforming to a more faithful reproduction of the native bone environment than undoped HA particles, used as control in PCL matrices. Furthermore, we demonstrate that Mg,CO3 -doped HA in PCL scaffolds support the in vivo cellular response by inducing neo-bone formation as early as 2?months post-implantation, and abundant mature bone tissue at the sixth month, with a lamellar structure and completely formed bone marrow. Together, these results indicate that Mg(2+) and CO3 (2-) ion substitution in HA particles enhances the scaffold properties, providing the right chemical signals to combine with morphological requirements (i.e. pore size, shape and interconnectivity) to drive osteogenic response in scaffold-aided bone regeneration. PMID:22730225

Guarino, Vincenzo; Scaglione, Silvia; Sandri, Monica; Alvarez-Perez, Marco A; Tampieri, Anna; Quarto, Rodolfo; Ambrosio, Luigi

2014-04-01

37

The impact of skeletal unloading on bone formation  

NASA Technical Reports Server (NTRS)

Skeletal unloading leads to decreased bone formation and decreased bone mass. Bone resorption is uncoupled from bone formation, contributing to the bone loss. During space flight bone is lost principally from the bones most loaded in the 1 g environment. Determining the mechanism(s) by which loading of bone is sensed and translated into a signal(s) controlling bone formation remains the holy grail in this field. It seems likely that matrix/cell interactions will underlie much of the mechanocoupling. Integrins are a prime mediator of such interactions. The role for systemic hormones such as PTH, GH and 1,25(OH)2D compared to locally produced factors such as IGF-I, PTHrP, BMPs and TGF beta in modulating the cellular response to load remains unclear. Our studies demonstrate that skeletal unloading leads to resistance to the anabolic actions of IGF-I on bone as a result of failure of IGF-I to activate its own signaling pathways. This is associated with a reduction in integrin expression, suggesting crosstalk between these two pathways. As the mechanism(s) by which bone responds to changes in mechanical load with changes in bone formation is further elucidated, applications of this knowledge to other etiologies of osteoporosis are likely to develop. Skeletal unloading provides a perturbation in bone mineral homeostasis that can be used to understand the mechanisms by which bone mineral homeostasis is maintained, and that such understanding will lead to effective treatment for disuse osteoporosis in addition to preventive measures for the bone loss that accompanies space travel.

Bikle, Daniel D.; Sakata, Takeshi; Halloran, Bernard P.

2003-01-01

38

Inhibition of cortical and trabecular bone formation in the long bones of immobilized monkeys  

NASA Technical Reports Server (NTRS)

Tetracycline derivatives are administered on three separate occasions to label the sites of bone formation. Determinations are made of the tetracycline-labeling frequency and mineral apposition rate of osteons and trabecular bone surfaces in the humerus and femur. The inhibition of bone formation induced by immobilization is found to be more pronounced in trabecular bone. The immobilized monkeys exhibit a moderate, but statistically nonsignificant, reduction in the percentage of osteons forming bone. Conversely, the dramatic decline in the percentage of trabecular surfaces undergoing bone formation in the monkeys is found to be highly significant. The diminished rate of mineral apposition in osteons is seen as suggesting that osteoblastic activity is impaired in cortical bone during immobilization.

Wronski, T. J.; Morey, E. R.

1983-01-01

39

Deep anterior lamellar Keratoplasty  

PubMed Central

Keratoconus is a disease causing increased steepening of the cornea resulted in irregular astigmatism. Treatment options are Glasses, Hard contact lenses, Cross linking, Intracorneal Segments insertion, Refractive surgery (Gilda et al., 2008), or Keratoplasty. Lamellar Keratoplasty (LKP) can be a better choice to manage cases of moderate and some cases of severe Keratoconus without deep scarring and severe thinning, also in cases of corneal scarring not involving the deeper layers of the cornea. LKP is a corneal graft technique consisting of transplantation of partial-thickness donor tissue, devoid of endothelium, Descemet membrane (DM), and rear stroma into a recipient healthy stromal bed after dissection of pathologic anterior stroma. However, deep lamellar Keratoplasty (DLKP) is a surgical method that completely removes pathologic corneal stroma tissue down to the DM, followed by transplantation of donor cornea without endothelium over the host bed. DLKP has a number of advantages over penetrating Keratoplasty (PKP). Because it does not violate the intraocular structures of the eye, it diminishes or eliminates the chance of postoperative glaucoma, cataract formation, retinal detachment, cystoids macular edema, expulsive choroidal hemorrhage and epithelial ingrowths. Furthermore, this procedure avoids the replacement of host endothelium with donor endothelium and thus precludes endothelial graft rejection, with comparable visual outcomes and low rate of chronic endothelial cell loss compared to PKP. PMID:23960861

Al-Kharashi, Soliman A.; Al-Obailan, Majed M.; Almohaimeed, Mansour; Al-Torbak, Abdullah A.

2009-01-01

40

In Vitro and In Vivo effects of ipriflavone on bone formation and bone biomechanics  

Microsoft Academic Search

Ipriflavone (IP) positively affects bone density in postmenopausal osteoporosis, primarily by inhibiting bone resorption.\\u000a Using in vitro models of human osteoblast differentiation, we have observed that IP and some of its metabolites stimulate the expression\\u000a of bone sialoprotein, decorin, and type I collagen, and facilitate the deposition of mineralized matrix. This suggests that\\u000a IP may stimulate bone formation in addition

R. Civitelli

1997-01-01

41

Bone formation is not impaired by hibernation (disuse) in black bears Ursus americanus  

Microsoft Academic Search

Disuse by bed rest, limb immobilization or space flight causes rapid bone loss by arresting bone formation and accelerating bone resorption. This net bone loss increases the risk of fracture upon remobilization. Bone loss also occurs in hibernating ground squirrels, golden hamsters, and little brown bats by arresting bone formation and accelerating bone resorption. There is some histological evidence to

Seth W. Donahue; Michael R. Vaughan; Laurence M. Demers; Henry J. Donahue

2003-01-01

42

Lanthanum carbonate stimulates bone formation in a rat model of renal insufficiency with low bone turnover.  

PubMed

Control of phosphate is important in the management of chronic kidney disease with mineral and bone disorder (CKD-MBD), for which lanthanum carbonate, a non-calcium phosphate-binding agent, has recently been introduced; however, it remains to be determined whether it has any beneficial or deleterious effect on bone remodeling. In the present study, the effects of lanthanum carbonate were examined in an animal model that mimics low turnover bone disease in CKD, i.e., thyroparathyroidectomized (TPTX) and 5/6 nephrectomized (NX) rats undergoing a constant infusion of parathyroid hormone (PTH) and thyroxine injections (TPTX-PTH-5/6NX). Bone histomorphometry at the second lumbar vertebra and tibial metaphysis revealed that both bone formation and resorption were markedly suppressed in the TPTX-PTH-5/6NX model compared with the sham-operated control group, and treatment with lanthanum carbonate was associated with the stimulation of bone formation but not an acceleration of bone resorption. Lanthanum treatment caused a robust stimulation of bone formation with an activation of osteoblasts on the endosteal surface of femoral diaphysis, leading to an increase in cortical bone volume. Thus, lanthanum carbonate has the potential to stimulate bone formation in cases of CKD-MBD with suppressed bone turnover. PMID:24126694

Fumoto, Toshio; Ito, Masako; Ikeda, Kyoji

2014-09-01

43

Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency  

PubMed Central

Postmenopausal bone loss stems from the inability of osteoblastic activity to match the increase in osteoclastic bone resorption induced by estrogen deficiency. However, the mechanism that uncouples osteoblast from osteoclast activities remains unexplained. We show that ovariectomy enhances the production of the osteoclastogenic cytokine IL-7, and that its neutralization in vivo prevents ovariectomy-induced bone loss. Surprisingly, serum osteocalcin levels, a biochemical marker of bone formation, suggested that the bone-sparing effects of IL-7 neutralization were due not only to inhibition of bone resorption, but also to stimulation of bone formation. Consistent with these data, addition of IL-7 to neonatal calvarial organ cultures blocked new bone formation, and injection of IL-7 into mice in vivo inhibited bone formation as measured by calcein incorporation into long bones. The antianabolic effects of IL-7 were consistent with an observed downregulation of the osteoblast-specific transcription factor core-binding factor ?1/Runx2. Thus, because it targets both the osteoclast and the osteoblast pathways, IL-7 is central to the altered bone turnover characteristic of estrogen deficiency. PMID:12464669

Weitzmann, M. Neale; Roggia, Cristiana; Toraldo, Gianluca; Weitzmann, Louise; Pacifici, Roberto

2002-01-01

44

Leptin regulates bone formation via the sympathetic nervous system  

NASA Technical Reports Server (NTRS)

We previously showed that leptin inhibits bone formation by an undefined mechanism. Here, we show that hypothalamic leptin-dependent antiosteogenic and anorexigenic networks differ, and that the peripheral mediators of leptin antiosteogenic function appear to be neuronal. Neuropeptides mediating leptin anorexigenic function do not affect bone formation. Leptin deficiency results in low sympathetic tone, and genetic or pharmacological ablation of adrenergic signaling leads to a leptin-resistant high bone mass. beta-adrenergic receptors on osteoblasts regulate their proliferation, and a beta-adrenergic agonist decreases bone mass in leptin-deficient and wild-type mice while a beta-adrenergic antagonist increases bone mass in wild-type and ovariectomized mice. None of these manipulations affects body weight. This study demonstrates a leptin-dependent neuronal regulation of bone formation with potential therapeutic implications for osteoporosis.

Takeda, Shu; Elefteriou, Florent; Levasseur, Regis; Liu, Xiuyun; Zhao, Liping; Parker, Keith L.; Armstrong, Dawna; Ducy, Patricia; Karsenty, Gerard

2002-01-01

45

Bone sialoprotein plays a functional role in bone formation and osteoclastogenesis  

PubMed Central

Bone sialoprotein (BSP) and osteopontin (OPN) are both highly expressed in bone, but their functional specificities are unknown. OPN knockout (?/?) mice do not lose bone in a model of hindlimb disuse (tail suspension), showing the importance of OPN in bone remodeling. We report that BSP?/? mice are viable and breed normally, but their weight and size are lower than wild-type (WT) mice. Bone is undermineralized in fetuses and young adults, but not in older (?12 mo) BSP?/? mice. At 4 mo, BSP?/? mice display thinner cortical bones than WT, but greater trabecular bone volume with very low bone formation rate, which indicates reduced resorption, as confirmed by lower osteoclast surfaces. Although the frequency of total colonies and committed osteoblast colonies is the same, fewer mineralized colonies expressing decreased levels of osteoblast markers form in BSP?/? versus WT bone marrow stromal cultures. BSP?/? hematopoietic progenitors form fewer osteoclasts, but their resorptive activity on dentin is normal. Tail-suspended BSP?/? mice lose bone in hindlimbs, as expected. In conclusion, BSP deficiency impairs bone growth and mineralization, concomitant with dramatically reduced bone formation. It does not, however, prevent the bone loss resulting from loss of mechanical stimulation, a phenotype that is clearly different from OPN?/? mice. PMID:18458111

Malaval, Luc; Wade-Guéye, Ndéyé Marième; Boudiffa, Maya; Fei, Jia; Zirngibl, Ralph; Chen, Frieda; Laroche, Norbert; Roux, Jean-Paul; Burt-Pichat, Brigitte; Duboeuf, François; Boivin, Georges; Jurdic, Pierre; Lafage-Proust, Marie-Hélène; Amédée, Joëlle; Vico, Laurence; Rossant, Janet; Aubin, Jane E.

2008-01-01

46

Receptor tyrosine kinase inhibition causes simultaneous bone loss and excess bone formation within growing bone in rats  

SciTech Connect

During postnatal skeletal growth, adaptation to mechanical loading leads to cellular activities at the growth plate. It has recently become evident that bone forming and bone resorbing cells are affected by the receptor tyrosine kinase (RTK) inhibitor imatinib mesylate (STI571, Gleevec (registered)) . Imatinib targets PDGF, ABL-related gene, c-Abl, c-Kit and c-Fms receptors, many of which have multiple functions in the bone microenvironment. We therefore studied the effects of imatinib in growing bone. Young rats were exposed to imatinib (150 mg/kg on postnatal days 5-7, or 100 mg/kg on postnatal days 5-13), and the effects of RTK inhibition on bone physiology were studied after 8 and 70 days (3-day treatment), or after 14 days (9-day treatment). X-ray imaging, computer tomography, histomorphometry, RNA analysis and immunohistochemistry were used to evaluate bone modeling and remodeling in vivo. Imatinib treatment eliminated osteoclasts from the metaphyseal osteochondral junction at 8 and 14 days. This led to a resorption arrest at the growth plate, but also increased bone apposition by osteoblasts, thus resulting in local osteopetrosis at the osteochondral junction. The impaired bone remodelation observed on day 8 remained significant until adulthood. Within the same bone, increased osteoclast activity, leading to bone loss, was observed at distal bone trabeculae on days 8 and 14. Peripheral quantitative computer tomography (pQCT) and micro-CT analysis confirmed that, at the osteochondral junction, imatinib shifted the balance from bone resorption towards bone formation, thereby altering bone modeling. At distal trabecular bone, in turn, the balance was turned towards bone resorption, leading to bone loss. - Research Highlights: > 3-Day imatinib treatment. > Causes growth plate anomalies in young rats. > Causes biomechanical changes and significant bone loss at distal trabecular bone. > Results in loss of osteoclasts at osteochondral junction.

Nurmio, Mirja, E-mail: Mirja.Nurmio@utu.fi [Department of Physiology, University of Turku (Finland); Department of Pediatrics, University of Turku (Finland); Joki, Henna, E-mail: Henna.Joki@utu.fi [Department of Cell Biology and Anatomy, University of Turku (Finland); Kallio, Jenny, E-mail: Jenny.Kallio@utu.fi [Department of Physiology, University of Turku (Finland); Maeaettae, Jorma A., E-mail: jorma.maatta@utu.fi [Department of Cell Biology and Anatomy, University of Turku (Finland); Department of Turku Center for Disease Modeling, University of Turku (Finland); Vaeaenaenen, H. Kalervo, E-mail: kalervo.vaananen@utu.fi [Department of Cell Biology and Anatomy, University of Turku (Finland); Toppari, Jorma, E-mail: Jorma.Toppari@utu.fi [Department of Physiology, University of Turku (Finland); Department of Pediatrics, University of Turku (Finland); Jahnukainen, Kirsi, E-mail: Kirsi.Jahnukainen@utu.fi [Pediatric Endocrinology Unit, Department of Woman and Child Health, Karolinska Institutet and University Hospital, Stockholm (Sweden); Division of Hematology-Oncology and Stem Cell Transplantation, Hospital for Children and Adolescents, Helsinki (Finland); Laitala-Leinonen, Tiina, E-mail: tilale@utu.fi [Department of Cell Biology and Anatomy, University of Turku (Finland)

2011-08-01

47

Polymer-ceramic composite that mimics bone formation  

NASA Astrophysics Data System (ADS)

Research was done on a biomimetic building material with the unique properties of bone. Bone, as well as other natural materials such as shell, obtains its toughness and strength as a result of utilizing optimum materials, structural form and carefully controlling the process of bone formation. The organic fibers are made first and the matrix grown around them as opposed to conventional ceramics in which any fibers are added to the matrix. The research presented focuses on creating a polymer/cement composite which mimics bone by controlling the chemical makeup and sequencing of fabrication. The rules under which bone material naturally forms, albeit at a macroscale, are followed in order to match the intimate connection between material phases of bone. The research presented here uses cement and condensation polymers. The proposed design more carefully controls the formation process by utilizing the symbiotic relationship of the two material formation reactions. The inorganic phase formation is initiated and controlled by the organic phase formation as occurs in bone formation. Like bone this new material offers great opportunity for improved mechanical and chemical bonding.

Dry, Carolyn M.

1999-05-01

48

Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo  

PubMed Central

Amylin is a member of the calcitonin family of hormones cosecreted with insulin by pancreatic ? cells. Cell culture assays suggest that amylin could affect bone formation and bone resorption, this latter function after its binding to the calcitonin receptor (CALCR). Here we show that Amylin inactivation leads to a low bone mass due to an increase in bone resorption, whereas bone formation is unaffected. In vitro, amylin inhibits fusion of mononucleated osteoclast precursors into multinucleated osteoclasts in an ERK1/2-dependent manner. Although Amylin +/? mice like Amylin-deficient mice display a low bone mass phenotype and increased bone resorption, Calcr +/? mice display a high bone mass due to an increase in bone formation. Moreover, compound heterozygote mice for Calcr and Amylin inactivation displayed bone abnormalities observed in both Calcr +/? and Amylin +/? mice, thereby ruling out that amylin uses CALCR to inhibit osteoclastogenesis in vivo. Thus, amylin is a physiological regulator of bone resorption that acts through an unidentified receptor. PMID:14970190

Dacquin, Romain; Davey, Rachel A.; Laplace, Catherine; Levasseur, Regis; Morris, Howard A.; Goldring, Steven R.; Gebre-Medhin, Samuel; Galson, Deborah L.; Zajac, Jeffrey D.; Karsenty, Gerard

2004-01-01

49

Osteopenia and decreased bone formation in osteonectin-deficient mice  

PubMed Central

Bone continuously remodels in response to mechanical and physiological stresses, allowing vertebrates to renew bone as adults. Bone remodeling consists of the cycled synthesis and resorption of collagenous and noncollagenous extracellular matrix proteins, and an imbalance in this process can lead to disease states such as osteoporosis, or more rarely, osteopetrosis. There is evidence that the extracellular matrix glycoprotein osteonectin or secreted protein acidic and rich in cysteine (BM-40) may be important in bone remodeling. Osteonectin is abundant in bone and is expressed in areas of active remodeling outside the skeleton. In vitro studies indicate that osteonectin can bind collagen and regulate angiogenesis, metalloproteinase expression, cell proliferation, and cell-matrix interactions. In some osteopenic states, such as osteogenesis imperfecta and selected animal models for bone fragility, osteonectin expression is decreased. To determine the function of osteonectin in bone, we used contact x-ray, histomorphometry, and Northern blot analysis to characterize the skeletal phenotype of osteonectin-null mice. We found that osteonectin-null mice have decreased bone formation and decreased osteoblast and osteoclast surface and number, leading to decreased bone remodeling with a negative bone balance and causing profound osteopenia. These data indicate that osteonectin supports bone remodeling and the maintenance of bone mass in vertebrates. PMID:10749571

Delany, A.M.; Amling, M.; Priemel, M.; Howe, C.; Baron, R.; Canalis, E.

2000-01-01

50

Controlled Delivery of Zoledronate Improved Bone Formation Locally In Vivo  

PubMed Central

Bisphosphonates (BPs) have been widely used in clinical treatment of bone diseases with increased bone resorption because of their strong affinity for bone and their inhibition of bone resorption. Recently, there has been growing interest in their improvement of bone formation. However, the effect of local controlled delivery of BPs is unclear. We used polylactide acid-glycolic acid copolymer (PLGA) as a drug carrier to deliver various doses of the bisphosphonate zoledronate (Zol) into the distal femur of 8-week-old Sprague-Dawley rats. After 6 weeks, samples were harvested and analyzed by micro-CT and histology. The average bone mineral density and mineralized bone volume fraction were higher with medium- and high-dose PLGA-Zol (30 and 300 µg Zol, respectively) than control and low-dose Zol (3 µg PLGA-Zol; p<0.05). Local controlled delivery of Zol decreased the numbers of osteoclast and increased the numbers of osteoblast. Moreover, local controlled delivery of medium- and high-dose Zol accelerated the expression of bone-formation markers. PLGA used as a drug carrier for controlled delivery of Zol may promote local bone formation. PMID:24618585

Peng, Jiang; Lu, Qiang; Wang, Yu; Wang, Aiyuan; Guo, Quanyi; Gao, Xupeng; Xu, Wenjing; Lu, Shibi

2014-01-01

51

Bone Formation Rate in Experimental Disuse Osteoporosis in Monkeys  

NASA Technical Reports Server (NTRS)

Specific mechanisms underlying weightless and hypodynamic bone loss are obscure. A principal relationship which must be affected is the balance between bone formation and bone resorption rates. In order to better define the influence of those parameters on bone loss, and also to develop measurements in other species as a useful adjunct to human research, studies were undertaken with experimental monkeys. Tests were conducted with a total of 6 adult male monkeys, weighing 10-13 kg, and approximately 10-12 yrs. of age to evaluate specifically bone formation rate during the development of disuse osteoporosis and osteopenia. Three animals were restrained in a semi-recumbent position for six months; three animals served as normal caged controls. Food intake (Purina) was held relatively constant at 200g/day for each animal. Using a Norland Bone Mineral Analyzer, bone mineral losses of 3.5 to 6% were seen in the mid-shaft of the tibia and in the distal radius. Bone loss was confirmed radiographically, with observation of thinning of the proximal tibial cortex and trabeculae in the calcaneus. Bone formation rate was determined using standard Ca-47 kinetics under metabolic balance conditions. After six months of restraint, accretion was 7.2-13.2 mg Ca/kg/day, compared to 3.2-4.1 mg Ca/kg/day in caged controls and 3-8 mg Ca/kg/day in normal adult humans. Fecal and urine calcium was 25-40% higher in restrained animals than in controls. Dietary calcium absorption decreases during restraint, and calcium turnover increases, implying a rise in bone resorption rate concommitant with the observed rise in bone accretion rate. Further studies dealing specifically with bone resorption are underway to define this more fully.

Cann, Christopher; Young, Donald R.

1976-01-01

52

Deep Lamellar Keratoplasty  

Microsoft Academic Search

Purpose: To describe a new technique of lamellar surgery and to compare the results of 150 cases treated with this technique with those observed in as many cases of penetrating keratoplasty (PK). Patients and Methods: One hundred and fifty deep lamellar keratoplasty (DLKP) procedures were performed in patients affected by various diseases of the corneal stroma but having a preserved

Fernando Trimarchi; Elisa Poppi; Catherine Klersy; Cesare Piacentini

2001-01-01

53

Endochondral bone formation in embryonic mouse pre-metatarsals  

NASA Technical Reports Server (NTRS)

Long term exposure to a reduced gravitational environment has a deleterious effect on bone. The developmental events which occur prior to initial bone deposition will provide insight into the regulation of mature bone physiology. We have characterized a system in which the events preceding bone formation take place in an isolated in vitro organ culture environment. We show that cultured pre-metatarsal tissue parallels development of pre-metatarsal tissue in the embryo. Both undergo mesenchyme differentiation and morphogenesis to form a cartilage rod, which resembles the future bone, followed by terminal chondrocyte differentiation in a definite morphogenetic pattern. These sequential steps occur prior to osteoblast maturation and bone matrix deposition in the developing organism. Alkaline phosphatase (ALP) activity is a distinctive enzymatic marker for mineralizing tissues. We have measured this activity throughout pre-metatarsal development and show (a) where in the tissue it is predominantly found, and (b) that this is indeed the mineralizing isoform of the enzyme.

Klement, B. J.; Spooner, B. S.

1992-01-01

54

Overexpressing Sonic Hedgehog Peptide Restores Periosteal Bone Formation in a Murine Bone Allograft Transplantation Model  

PubMed Central

Although activation of hedgehog (Hh) signaling has been shown to induce osteogenic differentiation in vitro and bone formation in vivo, the underlying mechanisms and the potential use of Hh-activated mesenchymal progenitors in bone defect repair remain elusive. In this study, we demonstrated that implantation of periosteal-derived mesenchymal progenitor cells (PDMPCs) that overexpressed an N-terminal sonic hedgehog peptide (ShhN) via an adenoviral vector (Ad-ShhN) restored periosteal bone collar formation in a 4-mm segmental bone allograft model in immunodeficient mice. Ad-ShhN enhanced donor cell survival and microvessel formation in collagen scaffold at 2 weeks after surgery and induced donor cell–dependent bone formation at 6 weeks after surgery. Fluorescence-activated cell sorting analysis further showed that Ad-ShhN-PDMPC–seeded scaffold contained a twofold more CD45?Sca-1+CD34+VEGFR2+ endothelial progenitors than Ad-LacZ-PDMPC–seeded scaffold at day 7 after surgery. Ad-ShhN–transduced PDMPCs induced a 1.8-fold more CD31+ microvessel formation than Ad-LacZ–transduced PDMPCs in a coculture of endothelial progenitors and PDMPCs. Taken together, our data show that overexpression of ShhN in mesenchymal progenitors improves bone defect reconstruction by enhancing donor progenitor cell survival, differentiation, and scaffold revascularization at the site of compromised periosteum. Hh agonist–based therapy, therefore, merits further investigation in tissue engineering–based applications aimed at enhancing bone defect repair and reconstruction. PMID:24089140

Huang, Chunlan; Tang, Minghui; Yehling, Eric; Zhang, Xinping

2014-01-01

55

The influence of age on adaptive bone formation and bone resorption.  

PubMed

Bone is a tissue with enormous adaptive capacity, balancing resorption and formation processes. It is known that mechanical loading shifts this balance towards an increased formation, leading to enhanced bone mass and mechanical performance. What is not known is how this adaptive response to mechanical loading changes with age. Using dynamic micro-tomography, we show that structural adaptive changes of trabecular bone within the tibia of living mice subjected to two weeks of in vivo cyclic loading are altered by aging. Comparisons of 10, 26 and 78 weeks old animals reveal that the adaptive capacity diminishes. Strikingly, adaptation was asymmetric in that loading increases formation more than it reduces resorption. This asymmetry further shifts the (re)modeling balance towards a net bone loss with age. Loading results in a major increase in the surface area of mineralizing bone. Interestingly, the resorption thickness is independent of loading in trabecular bone in all age groups. This data suggests that during youth, mechanical stimulation induces the recruitment of bone modeling cells whereas in old age, only bone forming cells are affected. These findings provide mechanistic insights into the processes that guide skeletal aging in mice as well as in other mammals. PMID:25128376

Birkhold, Annette I; Razi, Hajar; Duda, Georg N; Weinkamer, Richard; Checa, Sara; Willie, Bettina M

2014-11-01

56

Some considerations on biomaterials and bone.  

PubMed

Osteoinduction is a property not traditionally attributed to Calcium Phosphate ceramics. Histologic, SEM and X-ray microanalyses of a biopsy of pulmonary alveolar microlithiasis allow to discredit this opinion. Bone, even lamellar type, was ectopically formed on microliths undergoing osteoclastic erosion. The SEM and X-ray microanalyses of coral granules implanted in humans indicate an osteoconductive property for both Calcium and Phosphorus. Analysis of in vitro allows to propose an enhancement of the osteocapability of coral. Lamellar bone formation in the near absence of loads undermines the opinion which sees a correlation between lamellar bone and mechanical loads. Analysis of the bone surrounding an uncemented titanium hip prosthesis highlights that both remodeled and newly formed bone have lamellae oriented parallel to prosthesis surfaces, i.e. orthogonal to loads, as opposed to that of lamellar bone of osteons which are oriented parallel to loads. Analysis of longitudinal sections of cortical bone under polarized light points out that lamellae are displaced parallel to the cement line surface both in the conic end of osteons and in Volkman's canals with thick wall, i.e. undergoing sloped load directions. In conclusion, there may be a relationship between lamellae formation and gravity. PMID:16169740

Zaffe, Davide

2005-01-01

57

Expression of bone morphogenic protein in sinonasal inverted papilloma with new bone formation  

PubMed Central

Inverted papilloma (IP) is a common benign tumor in the nose and sinus. Osteogenesis in sinonasal IP is extremely rare; to date, only five cases of IP with new bone formation appear in the literature. In addition, the mechanism of osteogenesis in IP remains unclear. Here, we describe three cases of IP with new bone formation and an investigation into a possible role for bone morphogenic protein (BMP) in osteogenesis. Of three patients with sinonasal IP with new bone formation, two were treated by endoscopic sinus surgery and one was followed up with watchful waiting. Tumor tissues were subjected to immunohistochemistry to detect BMP expression. The patients were successfully treated surgically and showed no evidence of recurrence postoperatively. Follow-up examination is ongoing. Immunohistochemically, the tumors expressed BMP-4 but not BMP-2 or BMP-7. ESS could be successfully used to achieve complete removal of the sinonasal IPs with new bone formation. BMP-4 might be associated with new bone formation in the tumor. PMID:22852110

Okamoto, Tomoyo; Nomi, Nozomi; Umemoto, Shingo; Suzuki, Masashi

2011-01-01

58

Local bone formation by injection of recombinant human bone morphogenetic protein-2 contained in polymer carriers.  

PubMed

The regenerating potential of human bone is limited. The repair of large bone defects often associated with bone tumor resections is not observed, and nonunion or delayed union of bone is a serious problem for fracture treatment. In these cases, autogeneic or allogeneic bone grafting has been routinely indicated, but these approaches require invasive surgical procedures. An alternative approach described in this paper involves the injection of bone morphogenetic proteins (BMPs) in a polymeric delivery system. We demonstrate that synthetic biodegradable polymers, poly-D,L-lactic acid-polyethylene glycol (PLA-PEG) block copolymers, which exhibit an exquisite temperature-dependent liquid-semisolid transition, work well as an injectable delivery system for recombinant human (rh) BMP-2. The thermosensitive property of the PLA-PEG/rhBMP-2 composite is permissive to percutaneous injection when heated. The fluidity of this composite decreases as it cools down to body temperature and the resultant semisolid form provides a scaffold for bone formation through the gradual local release of the rhBMP-2. This new type of injectable osteoinductive material will enable a less invasive approach to surgeries involving the restoration or repair of bone tissues. PMID:12689681

Saito, N; Okada, T; Horiuchi, H; Ota, H; Takahashi, J; Murakami, N; Nawata, M; Kojima, S; Nozaki, K; Takaoka, K

2003-04-01

59

Recapitulation of signals regulating embryonic bone formation during postnatal growth and in fracture repair  

E-print Network

that regulate embryonic endochondral ossification are also expressed during postnatal bone growth and fracture Ireland Ltd. Keywords: Ihh; Parathyroid hormone-related protein; Fracture repair; Bone; EndochondralRecapitulation of signals regulating embryonic bone formation during postnatal growth

Tabin, Cliff

60

Effects Of Stress On Bone-Formation Markers In Rats  

NASA Technical Reports Server (NTRS)

Report describes experiments involving simultaneous measurement of concentrations, in blood, of two substances indicative of formation of bone in rats. Measurements performed after flight in outer space plus 48 h of postflight environmental stress. Results emphasize critical influences of adrenal status and diet on functions of osteoblasts.

Arnaud, Sara B.; Fung, Paul; Vasques, Marilyn; Grindeland, Richard E.; Patterson-Buckendahl, Patricia; Durnova, Galina

1992-01-01

61

Chondrocyte-specific Knockout of Cbf? Reveals the Indispensable Function of Cbf? in Chondrocyte Maturation, Growth Plate Development and Trabecular Bone Formation in Mice  

PubMed Central

Despite years of research into bone formation, the mechanisms by which transcription factors specify growth plate development and trabecular bone formation remain unclear and the role of hypertrophic chondrocytes in trabeculae morphogenesis is controversial. To study the role of Core binding factor beta (Cbf?) in postnatal cartilage development and endochondral bone formation, we generated chondrocyte-specific Cbf?-deficient mice (Cbf?f/fCol2?1-Cre mice) using floxed alleles of Cbf? (Cbf?f/f) and Cre driven by the Collagen 2?1 promoter (Col2?1-Cre). Cbf?f/fCol2?1-Cre mice evaded developmental and newborn lethality to survive to adulthood and displayed severe skeletal malformation. Cbf?f/fCol2?1-Cre mice had dwarfism, hypoplastic skeletons, defective bone mineralization, shortened limbs, shortened sternum bodies, and un-calcified occipital bones and hyoid bones. In the long bone cartilage, the resting zone was elongated, and chondrocyte proliferation and hypertrophy were impaired in Cbf?f/fCol2?1-Cre mice, which led to deformation of the growth plates. Primary spongiosa formation was delayed, diaphysis was shortened and trabecular bone formation was almost absent in the mutant mice. In addition, lamellar bone formation in the secondary spongiosa was also impaired. However, osteoclast formation in the trabecular bone was not affected. Cbf? deficiency led to down-regulation of chondrocyte-regulating genes [i.e, patched (Ptc1), Cyclin D1 and Indian hedgehog (Ihh)] in the cartilage. Interestingly, the expression of Runx2 and Runx3 was not changed in the cartilage of the mutants. Collectively, the results revealed that Cbf? is crucial for postnatal skeletal development and endochondral bone formation through its function in growth plate development and chondrocyte proliferation and differentiation. This study also revealed that chondrocyte maturation, mediated by Cbf?, was critical to trabecular bone morphogenesis. Significantly, these findings provide insight into the role of Cbf? in postnatal skeletogenesis, which may assist in the development of new therapies for osteoporosis. PMID:25170300

Wu, Mengrui; Li, Yi-Ping; Zhu, Guochun; Lu, Yun; Wang, Yiping; Jules, Joel; McConnell, Matthew; Serra, Rosa; Shao, Jian-Zhong; Chen, Wei

2014-01-01

62

Chondrocyte-specific knockout of Cbf? reveals the indispensable function of Cbf? in chondrocyte maturation, growth plate development and trabecular bone formation in mice.  

PubMed

Despite years of research into bone formation, the mechanisms by which transcription factors specify growth plate development and trabecular bone formation remain unclear and the role of hypertrophic chondrocytes in trabeculae morphogenesis is controversial. To study the role of Core binding factor beta (Cbf?) in postnatal cartilage development and endochondral bone formation, we generated chondrocyte-specific Cbf?-deficient mice (Cbf?f/fCol2?1-Cre mice) using floxed alleles of Cbf? (Cbf?f/f) and Cre driven by the Collagen 2?1 promoter (Col2?1-Cre). Cbf?f/fCol2?1-Cre mice evaded developmental and newborn lethality to survive to adulthood and displayed severe skeletal malformation. Cbf?f/fCol2?1-Cre mice had dwarfism, hypoplastic skeletons, defective bone mineralization, shortened limbs, shortened sternum bodies, and un-calcified occipital bones and hyoid bones. In the long bone cartilage, the resting zone was elongated, and chondrocyte proliferation and hypertrophy were impaired in Cbf?f/fCol2?1-Cre mice, which led to deformation of the growth plates. Primary spongiosa formation was delayed, diaphysis was shortened and trabecular bone formation was almost absent in the mutant mice. In addition, lamellar bone formation in the secondary spongiosa was also impaired. However, osteoclast formation in the trabecular bone was not affected. Cbf? deficiency led to down-regulation of chondrocyte-regulating genes [i.e, patched (Ptc1), Cyclin D1 and Indian hedgehog (Ihh)] in the cartilage. Interestingly, the expression of Runx2 and Runx3 was not changed in the cartilage of the mutants. Collectively, the results revealed that Cbf? is crucial for postnatal skeletal development and endochondral bone formation through its function in growth plate development and chondrocyte proliferation and differentiation. This study also revealed that chondrocyte maturation, mediated by Cbf?, was critical to trabecular bone morphogenesis. Significantly, these findings provide insight into the role of Cbf? in postnatal skeletogenesis, which may assist in the development of new therapies for osteoporosis. PMID:25170300

Wu, Mengrui; Li, Yi-Ping; Zhu, Guochun; Lu, Yun; Wang, Yiping; Jules, Joel; McConnell, Matthew; Serra, Rosa; Shao, Jian-Zhong; Chen, Wei

2014-01-01

63

Decreased bone turnover with balanced resorption and formation prevent cortical bone loss during disuse (hibernation) in grizzly bears ( Ursus arctos horribilis)  

Microsoft Academic Search

Disuse uncouples bone formation from resorption, leading to increased porosity, decreased bone geometrical properties, and decreased bone mineral content which compromises bone mechanical properties and increases fracture risk. However, black bear bone properties are not adversely affected by aging despite annual periods of disuse (i.e., hibernation), which suggests that bears either prevent bone loss during disuse or lose bone and

Meghan E. McGee; Aaron J. Maki; Steven E. Johnson; O. Lynne Nelson; Charles T. Robbins; Seth W. Donahue

2008-01-01

64

Targeting the Wnt Signaling Pathway to Augment Bone Formation  

PubMed Central

Recent discoveries in humans and mice have revealed that the Wnt (Wingless and Int-1) signaling pathway is responsible for a complex array of functions in maintaining bone homeostasis. The Wnt proteins are key modulators of mesenchymal lineage specification and regulate most aspects of osteoblast physiology and post-natal bone acquisition by controlling the differentiation and activity of osteoblasts and osteoclasts. Initial reports have indicated that activators of Wnt signaling are potent promoters of osteogenesis; however, systemic hyperactivation of the canonical Wnt pathway could potentially accelerate neoplastic transformation and subsequent tumor growth. Alternatively, recent investigations of natural soluble antagonists of Wnt signaling in bone suggest the possibilities of bone-specific therapies targeting the negative regulators of Wnt pathway, especially sclerostin. With this new knowledge, novel pharmacologic interventions that alter Wnt signaling are being evaluated for the management of osteoporosis. In this article, we briefly describe the Wnt signaling elements, their characterized role in bone, and summarize the current knowledge on the potential to enhance bone formation through the manipulation of Wnt signaling antagonists. PMID:19032924

Shahnazari, Mohammad; Yao, Wei; Corr, Maripat; Lane, Nancy E.

2014-01-01

65

Surface microcracks signal osteoblasts to regulate alignment and bone formation.  

PubMed

Microcracks are present in bone and can result from fatigue damage due to repeated, cyclically applied stresses. From a mechanical point, microcracks can dissipate strain energy at the advancing tip of a crack to improve overall bone toughness. Physiologically, microcracks are thought to trigger bone remodeling. Here, we examine the effect of microcracks specifically on osteoblasts, which are bone-forming cells, by comparing cell responses on microcracked versus non-microcracked hydroxyapatite (HA) specimens. Osteoblast attachment was found to be greater on microcracked HA specimens (p<0.05). More importantly, we identified the preferential alignment of osteoblasts in the direction of the microcracks on HA. Cells also displayed a preferential attachment that was 75 to 90?m away from the microcrack indent. After 21days of culture, osteoblast maturation was notably enhanced on the HA with microcracks, as indicated by increased alkaline phosphatase activity and gene expression. Furthermore, examination of bone deposition by confocal laser scanning microscopy indicated preferential mineralization at microcrack indentation sites. Dissolution studies indicate that the microcracks increase calcium release, which could contribute to osteoblast responses. Our findings suggest that microcracks signal osteoblast attachment and bone formation/healing. PMID:25280696

Shu, Yutian; Baumann, Melissa J; Case, Eldon D; Irwin, Regina K; Meyer, Sarah E; Pearson, Craig S; McCabe, Laura R

2014-11-01

66

Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation  

E-print Network

Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone in disorders of reduced bone mass, we tested whether lithium could improve bone mass in mice. We gavage) and assessed the effect on bone metabolism after 4 weeks of therapy. Lrp5 / mice lack the Wnt coreceptor low

67

Interference with the Microenvironment Support Impairs the De Novo Formation of Bone Metastasis In Vivo  

Microsoft Academic Search

Interference with the microenvironmental growth support is an attractive therapeutic strategy for repressing metastatic tumor growth. Bone is a highly dynamic tissue that is continuously remodeled by bone resorption and subsequent bone formation. Growth factors supporting bone metastatic growth are released especially during bone resorption. Differently from most other tissues, drugs that can limit local turnover, such as bisphosphonates, are

Gabri van der Pluijm; Ivo Que; Bianca Sijmons; Jeroen T Buijs; Antoinette Wetterwald; George N Thalmann; Socrates E Papapoulos; Marco G Cecchini

68

Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation  

Microsoft Academic Search

Osteocytes are the most abundant cells in bone and are ideally located to influence bone turnover through their syncytial relationship with surface bone cells. Osteocyte-derived signals have remained largely enigmatic, but it was recently reported that human osteocytes secrete sclerostin, an inhibitor of bone formation. Absent sclerostin protein results in the high bone mass clinical disorder sclerosteosis. Here we report

Kenneth E. S. Poole; Rutger L. van Bezooijen; Nigel Loveridge; Herman Hamersma; Socrates E. Papapoulos; Clemens W. Löwik; Jonathan Reeve

2005-01-01

69

The clock genes Period 2 and Cryptochrome 2 differentially balance bone formation  

Microsoft Academic Search

Background: Clock genes and their protein products regulate circadian rhythms in mammals but have also been implicated in various physiological processes, including bone formation. Osteoblasts build new mineralized bone whereas osteoclasts degrade it thereby balancing bone formation. To evaluate the contribution of clock components in this process, we investigated mice mutant in clock genes for a bone volume phenotype. Methodology\\/Principal

Erik Maronde; Arndt F. Schilling; Sebastian Seitz; Thorsten Schinke; Isabelle Schmutz; Horst van der G. T. J; Michael Amling; Urs Albrecht

2010-01-01

70

MicroRNA control of bone formation and homeostasis  

Microsoft Academic Search

MicroRNAs (miRNAs) repress cellular protein levels to provide a sophisticated parameter of gene regulation that coordinates a broad spectrum of biological processes. Bone organogenesis is a complex process involving the differentiation and crosstalk of multiple cell types for formation and remodeling of the skeleton. Inhibition of mRNA translation by miRNAs has emerged as an important regulator of developmental osteogenic signaling

Gary S. Stein; Andre J. van Wijnen; Janet L. Stein; Mohammad Q. Hassan; Tripti Gaur; Ying Zhang; Jane B. Lian

2012-01-01

71

Decreased bone formation and increased osteoclastogenesis cause bone loss in mucolipidosis II  

PubMed Central

Mucolipidosis type II (MLII) is a severe multi-systemic genetic disorder caused by missorting of lysosomal proteins and the subsequent lysosomal storage of undegraded macromolecules. Although affected children develop disabling skeletal abnormalities, their pathogenesis is not understood. Here we report that MLII knock-in mice, recapitulating the human storage disease, are runted with accompanying growth plate widening, low trabecular bone mass and cortical porosity. Intralysosomal deficiency of numerous acid hydrolases results in accumulation of storage material in chondrocytes and osteoblasts, and impaired bone formation. In osteoclasts, no morphological or functional abnormalities are detected whereas osteoclastogenesis is dramatically increased in MLII mice. The high number of osteoclasts in MLII is associated with enhanced osteoblastic expression of the pro-osteoclastogenic cytokine interleukin-6, and pharmacological inhibition of bone resorption prevented the osteoporotic phenotype of MLII mice. Our findings show that progressive bone loss in MLII is due to the presence of dysfunctional osteoblasts combined with excessive osteoclastogenesis. They further underscore the importance of a deep skeletal phenotyping approach for other lysosomal diseases in which bone loss is a prominent feature. PMID:24127423

Kollmann, Katrin; Pestka, Jan Malte; Kuhn, Sonja Christin; Schone, Elisabeth; Schweizer, Michaela; Karkmann, Kathrin; Otomo, Takanobu; Catala-Lehnen, Philip; Failla, Antonio Virgilio; Marshall, Robert Percy; Krause, Matthias; Santer, Rene; Amling, Michael; Braulke, Thomas; Schinke, Thorsten

2013-01-01

72

Targeted deletion of Sost distal enhancer increases bone formation and bone mass  

PubMed Central

The Wnt antagonist Sost has emerged as a key regulator of bone homeostasis through the modulation of Lrp4/5/6 Wnt coreceptors. In humans, lack of Sclerostin causes sclerosteosis and van Buchem (VB) disease, two generalized skeletal hyperostosis disorders that result from hyperactive Wnt signaling. Unlike sclerosteosis, VB patients lack SOST coding mutations but carry a homozygous 52 kb noncoding deletion that is essential for the transcriptional activation of SOST in bone. We recently identified a putative bone enhancer, ECR5, in the VB deletion region, and showed that the transcriptional activity of ECR5 is controlled by Mef2C transcription factor in vitro. Here we report that mice lacking ECR5 or Mef2C through Col1-Cre osteoblast/osteocyte-specific ablation result in high bone mass (HBM) due to elevated bone formation rates. We conclude that the absence of the Sost-specific long-range regulatory element ECR5 causes VB disease in rodents, and that Mef2C is the main transcription factor responsible for ECR5-dependent Sost transcriptional activation in the adult skeleton. PMID:22886088

Collette, Nicole M.; Genetos, Damian C.; Economides, Aris N.; Xie, LiQin; Shahnazari, Mohammad; Yao, Wei; Lane, Nancy E.; Harland, Richard M.; Loots, Gabriela G.

2012-01-01

73

Abdominal Fat Is Associated With Lower Bone Formation and Inferior Bone Quality in Healthy Premenopausal Women: A Transiliac Bone Biopsy Study  

PubMed Central

Context: The conventional view that obesity is beneficial for bone strength has recently been challenged by studies that link obesity, particularly visceral obesity, to low bone mass and fractures. It is controversial whether effects of obesity on bone are mediated by increased bone resorption or decreased bone formation. Objective: The objective of the study was to evaluate bone microarchitecture and remodeling in healthy premenopausal women of varying weights. Design: We measured bone density and trunk fat by dual-energy x-ray absorptiometry in 40 women and by computed tomography in a subset. Bone microarchitecture, stiffness, remodeling, and marrow fat were assessed in labeled transiliac bone biopsies. Results: Body mass index (BMI) ranged from 20.1 to 39.2 kg/m2. Dual-energy x-ray absorptiometry-trunk fat was directly associated with BMI (r = 0.78, P < .001) and visceral fat by computed tomography (r = 0.79, P < .001). Compared with women in the lowest tertile of trunk fat, those in the highest tertile had inferior bone quality: lower trabecular bone volume (20.4 ± 5.8 vs 29.1 ± 6.1%; P = .001) and stiffness (433 ± 264 vs 782 ± 349 MPa; P = .01) and higher cortical porosity (8.8 ± 3.5 vs 6.3 ± 2.4%; P = .049). Bone formation rate (0.004 ± 0.002 vs 0.011 ± 0.008 mm2/mm · year; P = .006) was 64% lower in the highest tertile. Trunk fat was inversely associated with trabecular bone volume (r = ?0.50; P < .01) and bone formation rate (r = ?0.50; P < .001). The relationship between trunk fat and bone volume remained significant after controlling for age and BMI. Conclusions: At the tissue level, premenopausal women with more central adiposity had inferior bone quality and stiffness and markedly lower bone formation. Given the rising levels of obesity, these observations require further investigation. PMID:23515452

Dempster, David W.; Recker, Robert R.; Lappe, Joan M.; Zhou, Hua; Zwahlen, Alexander; Muller, Ralph; Zhao, Binsheng; Guo, Xiaotao; Lang, Thomas; Saeed, Isra; Liu, X. Sherry; Guo, X. Edward; Cremers, Serge; Rosen, Clifford J.; Stein, Emily M.; Nickolas, Thomas L.; McMahon, Donald J.; Young, Polly; Shane, Elizabeth

2013-01-01

74

Parathyroid hormone may maintain bone formation in hibernating black bears (Ursus americanus) to prevent disuse osteoporosis  

Microsoft Academic Search

Mechanical unloading of bone causes an imbalance in bone formation and resorption leading to bone loss and increased fracture risk. Black bears (Ursus americanus) are inactive for up to six months during hibernation, yet bone mineral content and strength do not decrease with disuse or aging. To test whether hibernating bears have biological mechanisms to prevent disuse osteoporosis, we measured

Seth W. Donahue; Sarah A. Galley; Michael R. Vaughan; Patricia Patterson-Buckendahl; Laurence M. Demers; Josef L. Vance; Meghan E. McGee

2006-01-01

75

SOST\\/sclerostin, an osteocyte-derived negative regulator of bone formation  

Microsoft Academic Search

Sclerosteosis and Van Buchem disease are two closely related bone disorders characterized by progressive bone thickening due to increased bone formation. Sclerosteosis is associated with mutations in the SOST gene and Van Buchem disease with a 52kb deletion downstream of the SOST gene that probably affects transcription of the gene. Expression of the gene product sclerostin in bone is restricted

Rutger L. van Bezooijen; Peter ten Dijke; Socrates E. Papapoulos; Clemens W. G. M. Löwik

2005-01-01

76

Cinacalcet Decreases Bone Formation Rate in Hypercalcemic Hyperparathyroidism after Kidney Transplantation  

Microsoft Academic Search

Background\\/Aims: Cinacalcet reduces serum calcium in kidney transplant recipients with hypercalcemic hyperparathyroidism. Its effect on bone, however, has not been investigated in this population. Methods: We prospectively examined bone turnover, histomorphometry and density as well as serum bone biomarkers in 10 transplant recipients before and after treatment with cinacalcet. Results: After 18–24 months of treatment with cinacalcet, bone formation decreased

Kyra A. Borchhardt; Danielle Diarra; Irene Sulzbacher; Thomas Benesch; Martin Haas; Gere Sunder-Plassmann

2010-01-01

77

Formation of liquid-crystalline structures in the bile salt-chitosan system and triggered release from lamellar phase bile salt-chitosan capsules.  

PubMed

Nanostructured capsules comprised of the anionic bile salt, sodium taurodeoxycholate (STDC), and the biocompatible cationic polymer, chitosan, were prepared to assess their potential as novel tailored release nanomaterials. For comparison, a previously studied system, sodium dodecyl sulfate (SDS), and polydiallyldimethylammonium chloride (polyDADMAC) was also investigated. Crossed-polarizing light microscopy (CPLM) and small-angle X-ray scattering (SAXS) identified the presence of lamellar and hexagonal phase at the surfactant-polymer interface of the respective systems. The hydrophobic and electrostatic interactions between the oppositely charged components were studied by varying temperature and salt concentration, respectively, and were found to influence the liquid-crystalline nanostructure formed. The hexagonal phase persisted at high temperatures, however the lamellar phase structure was lost above ca. 45 °C. Both mesophases were found to dissociate upon addition of 4% NaCl solution. The rate of release of the model hydrophilic drug, Rhodamine B (RhB), from the lamellar phase significantly increased in response to changes in the solution conditions studied, suggesting that modulating the drug release from these bile salt-chitosan capsules is readily achieved. In contrast, release from the hexagonal phase capsules had no appreciable response to the stimuli applied. These findings provide a platform for these oppositely charged surfactant and polymer systems to function as stimuli-responsive or sustained-release drug delivery systems. PMID:25050454

Tangso, Kristian J; Lindberg, Seth; Hartley, Patrick G; Knott, Robert; Spicer, Patrick; Boyd, Ben J

2014-08-13

78

Local treatment of a bone graft by soaking in zoledronic acid inhibits bone resorption and bone formation. A bone chamber study in rats  

PubMed Central

Background Bone grafts are frequently used in orthopaedic surgery. Graft remodelling is advantageous but can occur too quickly, and premature bone resorption might lead to decreased mechanical integrity of the graft. Bisphosphonates delay osteoclastic bone resorption but may also impair formation of new bone. We hypothesize that these effects are dose dependent. In the present study we evaluate different ways of applying bisphosphonates locally to the graft in a bone chamber model, and compare that with systemic treatment. Methods Cancellous bone grafts were placed in titanium chambers and implanted in the tibia of 50 male rats, randomly divided into five groups. The first group served as negative control and the grafts were rinsed in saline before implantation. In the second and third groups, the grafts were soaked in a zoledronic acid solution (0.5 mg/ml) for 5 seconds and 10 minutes respectively before being rinsed in saline. In the fourth group, 8 ?L of zoledronic acid solution (0.5 mg/ml) was pipetted onto the freeze-dried grafts without rinsing. The fifth group served as positive control and the rats were given zoledronic acid (0.1 mg/kg) systemically as a single injection two weeks after surgery. The grafts were harvested at 6 weeks and analysed with histomorphometry, evaluating the ingrowth distance of new bone into the graft as an equivalent to the anabolic osteoblast effect and the amount (bone volume/total volume; BV/TV) of remaining bone in the remodelled graft as equivalent to the catabolic osteoclast effect. Results In all chambers, almost the entire graft had been revascularized but only partly remodelled at harvest. The ingrowth distance of new bone into the graft was lower in grafts soaked in zoledronic acid for 10 minutes compared to control (p = 0.007). In all groups receiving zoledronic acid, the BV/TV was higher compared to control. Conclusions This study found a strong inhibitory effect on bone resorption by bisphosphonates but also a limited inhibition of the ingrowth of new bone. Local treatment at surgery resulted in stronger inhibition of both resorption and bone formation compared to systemic treatment. PMID:23217097

2012-01-01

79

Does locally delivered Zoledronate influence peri-implant bone formation? - Spatio-temporal monitoring of bone remodeling in vivo.  

PubMed

Bisphosphonates are known for their strong inhibitory effect on bone resorption. Their influence on bone formation however is less clear. In this study we investigated the spatio-temporal effect of locally delivered Zoledronate on peri-implant bone formation and resorption in an ovariectomized rat femoral model. A cross-linked hyaluronic acid hydrogel was loaded with the drug and applied bilaterally in predrilled holes before inserting polymer screws. Static and dynamic bone parameters were analyzed based on in vivo microCT scans performed first weekly and then biweekly. The results showed that the locally released Zoledronate boosted bone formation rate up to 100% during the first 17 days after implantation and reduced the bone resorption rate up to 1000% later on. This shift in bone remodeling resulted in an increase in bone volume fraction (BV/TV) by 300% close to the screw and 100% further away. The double effect on bone formation and resorption indicates a great potential of Zoledronate-loaded hydrogel for enhancement of peri-implant bone volume which is directly linked to improved implant fixation. PMID:25241159

Kettenberger, Ulrike; Ston, Julien; Thein, Eric; Procter, Philip; Pioletti, Dominique P

2014-12-01

80

Biglycan modulates angiogenesis and bone formation during fracture healing.  

PubMed

Matrix proteoglycans such as biglycan (Bgn) dominate skeletal tissue and yet its exact role in regulating bone function is still unclear. In this paper we describe the potential role of (Bgn) in the fracture healing process. We hypothesized that Bgn could regulate fracture healing because of previous work showing that it can affect normal bone formation. To test this hypothesis, we created fractures in femurs of 6-week-old male wild type (WT or Bgn+/0) and Bgn-deficient (Bgn-KO or Bgn-/0) mice using a custom-made standardized fracture device, and analyzed the process of healing over time. The formation of a callus around the fracture site was observed at both 7 and 14 days post-fracture in WT and Bgn-deficient mice and immunohistochemistry revealed that Bgn was highly expressed in the fracture callus of WT mice, localizing within woven bone and cartilage. Micro-computed tomography (?CT) analysis of the region surrounding the fracture line showed that the Bgn-deficient mice had a smaller callus than WT mice. Histology of the same region also showed the presence of less cartilage and woven bone in the Bgn-deficient mice compared to WT mice. Picrosirius red staining of the callus visualized under polarized light showed that there was less fibrillar collagen in the Bgn-deficient mice, a finding confirmed by immunohistochemistry using antibodies to type I collagen. Interestingly, real time RT-PCR of the callus at 7 days post-fracture showed a significant decrease in relative vascular endothelial growth factor A (VEGF) gene expression by Bgn-deficient mice as compared to WT. Moreover, VEGF was shown to bind directly to Bgn through a solid-phase binding assay. The inability of Bgn to directly enhance VEGF-induced signaling suggests that Bgn has a unique role in regulating vessel formation, potentially related to VEGF storage or stabilization in the matrix. Taken together, these results suggest that Bgn has a regulatory role in the process of bone formation during fracture healing, and further, that reduced angiogenesis could be the molecular basis. PMID:24373744

Berendsen, Agnes D; Pinnow, Emily L; Maeda, Azusa; Brown, Aaron C; McCartney-Francis, Nancy; Kram, Vardit; Owens, Rick T; Robey, Pamela G; Holmbeck, Kenn; de Castro, Luis F; Kilts, Tina M; Young, Marian F

2014-04-01

81

Dissociation of Bone Resorption and Bone Formation in Adult Mice with a Non-Functional V-ATPase in Osteoclasts Leads to Increased Bone Strength  

PubMed Central

Osteopetrosis caused by defective acid secretion by the osteoclast, is characterized by defective bone resorption, increased osteoclast numbers, while bone formation is normal or increased. In contrast the bones are of poor quality, despite this uncoupling of formation from resorption. To shed light on the effect of uncoupling in adult mice with respect to bone strength, we transplanted irradiated three-month old normal mice with hematopoietic stem cells from control or oc/oc mice, which have defective acid secretion, and followed them for 12 to 28 weeks. Engraftment levels were assessed by flow cytometry of peripheral blood. Serum samples were collected every six weeks for measurement of bone turnover markers. At termination bones were collected for µCT and mechanical testing. An engraftment level of 98% was obtained. From week 6 until termination bone resorption was significantly reduced, while the osteoclast number was increased when comparing oc/oc to controls. Bone formation was elevated at week 6, normalized at week 12, and reduced onwards. µCT and mechanical analyses of femurs and vertebrae showed increased bone volume and bone strength of cortical and trabecular bone. In conclusion, these data show that attenuation of acid secretion in adult mice leads to uncoupling and improves bone strength. PMID:22087326

Henriksen, Kim; Flores, Carmen; Thomsen, Jesper S.; Bruel, Anne-Marie; Thudium, Christian S.; Neutzsky-Wulff, Anita V.; Langenbach, Geerling E. J.; Sims, Natalie; Askmyr, Maria; Martin, Thomas J.; Everts, Vincent; Karsdal, Morten A.; Richter, Johan

2011-01-01

82

Ectopic bone formation associated with mesenchymal stem cells in a resorbable calcium deficient hydroxyapatite carrier  

Microsoft Academic Search

Bone substitute materials can induce bone formation in combination with mesenchymal stem cells (MSC). The aim of the current study was to examine ectopic in vivo bone formation with and without MSC on a new resorbable ceramic, called calcium deficient hydroxyapatite (CDHA). Ceramic blocks characterized by a large surface (48m2\\/g) were compared with ?-tricalcium phosphate (?-TCP), hydroxyapatite (HA) ceramics (both

Philip Kasten; Julia Vogel; Reto Luginbühl; Philip Niemeyer; Marcus Tonak; Helga Lorenz; Lars Helbig; Stefan Weiss; Jörg Fellenberg; Albrecht Leo; Hans-Georg Simank; Wiltrud Richter

2005-01-01

83

Histomorphometric evaluation of new bone formation in diabetic rats submitted to insertion of temporary implants  

Microsoft Academic Search

This study aimed to quantify new bone formation in the femurs of diabetic Wistar rats. Over an eight-week period, MTI-MP® implants were evaluated in control rats and in diabetic rats. At several points during this period, various markers for bone deposit were introduced. The material was observed under fluorescent light microscopy. New bone formation in periosteal and cortical regions linked

Cyro Eduardo de Carvalho; Renato Paulo Chopard

2004-01-01

84

Developing bones are differentially affected by compromised skeletal muscle formation  

PubMed Central

Mechanical forces are essential for normal adult bone function and repair, but the impact of prenatal muscle contractions on bone development remains to be explored in depth in mammalian model systems. In this study, we analyze skeletogenesis in two ‘muscleless’ mouse mutant models in which the formation of skeletal muscle development is disrupted; Myf5nlacZ/nlacZ:MyoD?/? and Pax3Sp/Sp (Splotch). Ossification centers were found to be differentially affected in the muscleless limbs, with significant decreases in bone formation in the scapula, humerus, ulna and femur, but not in the tibia. In the scapula and humerus, the morphologies of ossification centers were abnormal in muscleless limbs. Histology of the humerus revealed a decreased extent of the hypertrophic zone in mutant limbs but no change in the shape of this region. The elbow joint was also found to be clearly affected with a dramatic reduction in the joint line, while no abnormalities were evident in the knee. The humeral deltoid tuberosity was significantly reduced in size in the Myf5nlacZ/nlacZ:MyoD?/? mutants while a change in shape but not in size was found in the humeral tuberosities of the Pax3Sp/Sp mutants. We also examined skeletal development in a ‘reduced muscle’ model, the Myf5nlacZ/+:MyoD?/? mutant, in which skeletal muscle forms but with reduced muscle mass. The reduced muscle phenotype appeared to have an intermediate effect on skeletal development, with reduced bone formation in the scapula and humerus compared to controls, but not in other rudiments. In summary, we have demonstrated that skeletal development is differentially affected by the lack of skeletal muscle, with certain rudiments and joints being more severely affected than others. These findings indicate that the response of skeletal progenitor cells to biophysical stimuli may depend upon their location in the embryonic limb, implying a complex interaction between mechanical forces and location-specific regulatory factors affecting bone and joint development. PMID:19948261

Nowlan, Niamh C.; Bourdon, Celine; Dumas, Gerard; Tajbakhsh, Shahragim; Prendergast, Patrick J.; Murphy, Paula

2010-01-01

85

The Clock Genes Period 2 and Cryptochrome 2 Differentially Balance Bone Formation  

Microsoft Academic Search

BackgroundClock genes and their protein products regulate circadian rhythms in mammals but have also been implicated in various physiological processes, including bone formation. Osteoblasts build new mineralized bone whereas osteoclasts degrade it thereby balancing bone formation. To evaluate the contribution of clock components in this process, we investigated mice mutant in clock genes for a bone volume phenotype.Methodology\\/Principal FindingsWe found

Erik Maronde; Arndt F. Schilling; Sebastian Seitz; Thorsten Schinke; Isabelle Schmutz; Gijsbertus van der Horst; Michael Amling; Urs Albrecht; Dong-Yan Jin

2010-01-01

86

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

PubMed Central

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

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

2013-01-01

87

Constitutively Active PTH/PTHrP Receptor Specifically Expressed in Osteoblasts Enhances Bone Formation Induced by Bone Marrow Ablation  

PubMed Central

Bone is maintained by continuous bone formation by osteoblasts provided by proliferation and differentiation of osteoprogenitors. Parathyroid hormone (PTH) activates bone formation, but because of the complexity of cells in the osteoblast lineage, how these osteoprogenitors are regulated by PTH in vivo is incompletely understood. To elucidate how signals by PTH in differentiated osteoblasts regulate osteoprogenitors in vivo, we conducted bone marrow ablation using Col1a1-constitutively active PTH/PTHrP receptor (caPPR) transgenic mice. These mice express caPPR specifically in osteoblasts by using 2.3 kb Col1a1 promoter and showed higher trabecular bone volume under steady-state conditions. In contrast, after bone marrow ablation, stromal cells recruited from bone surface extensively proliferated in the marrow cavity in transgenic mice, compared to limited proliferation in wild-type mice. Whereas de novo bone formation was restricted to the ablated area in wild-type mice, the entire marrow cavity, including not only ablated area but also outside the ablated area, was filled with newly formed bone in transgenic mice. Bone mineral density was significantly increased after ablation in transgenic mice. Bone marrow cell culture in osteogenic medium revealed that alkaline phosphatase-positive area was markedly increased in the cells obtained from transgenic mice. Furthermore, mRNA expression of Wnt-signaling molecules such as LRP5, Wnt7b, and Wnt10b were upregulated after marrow ablation in bone marrow cells of transgenic mice. These results indicate that constitutive activation of PTH/PTHrP receptor in differentiated osteoblasts enhances bone marrow ablation-induced recruitment, proliferation, and differentiation of osteoprogenitors. PMID:21866553

ONO, NORIAKI; NAKASHIMA, KAZUHISA; SCHIPANI, ERNESTINA; HAYATA, TADAYOSHI; EZURA, YOICHI; SOMA, KUNIMICHI; KRONENBERG, HENRY M.; NODA, MASAKI

2013-01-01

88

Impaired Bone Formation in Pdia3 Deficient Mice  

PubMed Central

1?,25-dihydroxyvitamin D3 [1?,25(OH)2D3] is crucial for normal skeletal development and bone homeostasis. Protein disulfide isomerase family A, member 3 (PDIA3) mediates 1?,25(OH)2D3 initiated-rapid membrane signaling in several cell types. To understand its role in regulating skeletal development, we generated Pdia3-deficient mice and examined the physiologic consequence of Pdia3-disruption in embryos and Pdia3+/? heterozygotes at different ages. No mice homozygous for the Pdia3-deletion were found at birth nor were there embryos after E12.5, indicating that targeted disruption of the Pdia3 gene resulted in early embryonic lethality. Pdia3-deficiency also resulted in skeletal manifestations as revealed by µCT analysis of the tibias. In comparison to wild type mice, Pdia3 heterozygous mice displayed expanded growth plates associated with decreased tether formation. Histomorphometry also showed that the hypertrophic zone in Pdia3+/? mice was more cellular than seen in wild type growth plates. Metaphyseal trabecular bone in Pdia3+/? mice exhibited an age-dependent phenotype with lower BV/TV and trabecular numbers, which was most pronounced at 15 weeks of age. Bone marrow cells from Pdia3+/? mice exhibited impaired osteoblastic differentiation, based on reduced expression of osteoblast markers and mineral deposition compared to cells from wild type animals. Collectively, our findings provide in vivo evidence that PDIA3 is essential for normal skeletal development. The fact that the Pdia3+/? heterozygous mice share a similar growth plate and bone phenotype to nVdr knockout mice, suggests that PDIA3-mediated rapid membrane signaling might be an alternative mechanism responsible for 1?,25(OH)2D3’s actions in regulating skeletal development. PMID:25405762

Wang, Yun; Nizkorodov, Alexandr; Riemenschneider, Kelsie; Lee, Christopher S. D.; Olivares-Navarrete, Rene; Schwartz, Zvi; Boyan, Barbara D.

2014-01-01

89

Enhancement of bone morphogenetic protein-2 expression and bone formation by coumarin derivatives via p38 and ERK-dependent pathway in osteoblasts  

Microsoft Academic Search

Osteoporosis is a reduction in skeletal mass due to an imbalance between bone resorption and bone formation. Bone morphogenetic protein (BMP) plays important roles in osteoblastic differentiation and bone formation. Therefore, components involved in BMP activation are good targets for the development of anti-osteoporosis drugs. In this study, imperatorin and bergapten, two coumarin derivatives, were shown to enhance alkaline phosphatase

Chih-Hsin Tang; Rong-Sen Yang; Mei-Yin Chien; Chien-Chich Chen; Wen-Mei Fu

2008-01-01

90

Carbon nanotubes functionalized with fibroblast growth factor accelerate proliferation of bone marrow-derived stromal cells and bone formation  

NASA Astrophysics Data System (ADS)

Multi-walled carbon nanotubes (MWCNTs) were functionalized with fibroblast growth factor (FGF) and the advantages of their use as scaffolds for bone augmentation were evaluated in vitro and in vivo. The activity of FGF was assessed by measuring the effect on the proliferation of rat bone marrow stromal cells (RBMSCs). The presence of FGF enhanced the proliferation of RBMSCs and the FGF covalently conjugated to the nanotubes (FGF-CNT) showed the same effect as FGF alone. In addition, FGF-CNT coated sponges were implanted between the parietal bone and the periosteum of rats and the formation of new bone was investigated. At day 14 after implantation, a larger amount of newly formed bone was clearly observed in most pores of FGF-CNT coated sponges. These findings indicated that MWCNTs accelerated new bone formation in response to FGF, as well as the integration of particles into new bone during its formation. Scaffolds coated with FGF-CNT could be considered as promising novel substituting materials for bone regeneration in future tissue engineering applications.

Hirata, Eri; Ménard-Moyon, Cécilia; Venturelli, Enrica; Takita, Hiroko; Watari, Fumio; Bianco, Alberto; Yokoyama, Atsuro

2013-11-01

91

BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing  

E-print Network

BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture the ability to produce BMP2 in their limb bones have spontaneous fractures that do not resolve with time. In fact, in bones lacking BMP2, the earliest steps of fracture healing seem to be blocked. Although other

Tabin, Cliff

92

Connexin 43 Deficiency Attenuates Loss of Trabecular Bone and Prevents Suppression of Cortical Bone Formation During Unloading  

PubMed Central

Connexin 43 (Cx43) is the most abundant gap junction protein in bone and has been demonstrated as an integral component of skeletal homeostasis. In the present study, we sought to further refine the role of Cx43 in the response to mechanical unloading by subjecting skeletally mature mice with a bone-specific deletion of Cx43 (cKO) to three weeks of mechanical unloading via hindlimb suspension (HLS). The HLS model was selected to recapitulate the effects of skeletal unloading due to prolonged bed rest, reduced activity associated with aging, and spaceflight microgravity. At baseline, the cortical bone of cKO mice displayed an osteopenic phenotype, with expanded cortices, decreased cortical thickness, decreased bone mineral density, and increased porosity. There was no baseline trabecular phenotype. Following three weeks of HLS, wild-type (WT) mice experienced substantial declines in trabecular bone volume fraction, connectivity density, trabecular thickness, and trabecular tissue mineral density. These deleterious effects were attenuated in cKO mice. Conversely, there was a similar and significant amount of cortical bone loss in both WT and cKO. Interestingly, mechanical testing revealed a greater loss of strength and rigidity for cKO during HLS. Analysis of double-label quantitative histomorphometry data demonstrated a substantial decrease in bone formation rate, mineralizing surface, and mineral apposition rate at both the periosteal and endocortical surfaces of the femur following unloading of WT mice. This suppression of bone formation was not observed in cKO mice, where parameters were maintained at baseline levels. Taken together, the results of the present study indicate that Cx43 deficiency desensitizes bone to the effects of mechanical unloading, and that this may be due to an inability of mechanosensing osteocytes to effectively communicate the unloading state to osteoblasts to suppress bone formation. Cx43 may represent a novel therapeutic target for investigation as a countermeasure for age-related and unloading-induced bone loss. PMID:22714552

Lloyd, Shane A.; Lewis, Gregory S.; Zhang, Yue; Paul, Emmanuel M.; Donahue, Henry J.

2013-01-01

93

Type XII collagen regulates osteoblast polarity and communication during bone formation  

PubMed Central

Differentiated osteoblasts are polarized in regions of bone deposition, demonstrate extensive cell interaction and communication, and are responsible for bone formation and quality. Type XII collagen is a fibril-associated collagen with interrupted triple helices and has been implicated in the osteoblast response to mechanical forces. Type XII collagen is expressed by osteoblasts and localizes to areas of bone formation. A transgenic mouse null for type XII collagen exhibits skeletal abnormalities including shorter, more slender long bones with decreased mechanical strength as well as altered vertebrae structure compared with wild-type mice. Col12a?/? osteoblasts have decreased bone matrix deposition with delayed maturation indicated by decreased bone matrix protein expression. Compared with controls, Col12a?/? osteoblasts are disorganized and less polarized with disrupted cell–cell interactions, decreased connexin43 expression, and impaired gap junction function. The data demonstrate important regulatory roles for type XII collagen in osteoblast differentiation and bone matrix formation. PMID:21670218

Izu, Yayoi; Sun, Mei; Zwolanek, Daniela; Veit, Guido; Williams, Valerie; Cha, Byeong; Jepsen, Karl J.; Koch, Manuel

2011-01-01

94

Estrogen receptor-? in osteocytes is important for trabecular bone formation in male mice  

PubMed Central

The bone-sparing effect of estrogen in both males and females is primarily mediated via estrogen receptor-? (ER?), encoded by the Esr1 gene. ER? in osteoclasts is crucial for the trabecular bone-sparing effect of estrogen in females, but it is dispensable for trabecular bone in male mice and for cortical bone in both genders. We hypothesized that ER? in osteocytes is important for trabecular bone in male mice and for cortical bone in both males and females. Dmp1-Cre mice were crossed with ER?flox/flox mice to generate mice lacking ER? protein expression specifically in osteocytes (Dmp1-ER??/?). Male Dmp1-ER??/? mice displayed a substantial reduction in trabecular bone volume (?20%, P < 0.01) compared with controls. Dynamic histomorphometry revealed reduced bone formation rate (?45%, P < 0.01) but the number of osteoclasts per bone surface was unaffected in the male Dmp1-ER??/? mice. The male Dmp1-ER??/? mice had reduced expression of several osteoblast/osteocyte markers in bone, including Runx2, Sp7, and Dmp1 (P < 0.05). Gonadal intact Dmp1-ER??/? female mice had no significant reduction in trabecular bone volume but ovariectomized Dmp1-ER??/? female mice displayed an attenuated trabecular bone response to supraphysiological E2 treatment. Dmp1-ER??/? mice of both genders had unaffected cortical bone. In conclusion, ER? in osteocytes regulates trabecular bone formation and thereby trabecular bone volume in male mice but it is dispensable for the trabecular bone in female mice and the cortical bone in both genders. We propose that the physiological trabecular bone-sparing effect of estrogen is mediated via ER? in osteocytes in males, but via ER? in osteoclasts in females. PMID:23345419

Windahl, Sara H.; Borjesson, Anna E.; Farman, Helen H.; Engdahl, Cecilia; Moverare-Skrtic, Sofia; Sjogren, Klara; Lagerquist, Marie K.; Kindblom, Jenny M.; Koskela, Antti; Tuukkanen, Juha; Divieti Pajevic, Paola; Feng, Jian Q.; Dahlman-Wright, Karin; Antonson, Per; Gustafsson, Jan-Ake; Ohlsson, Claes

2013-01-01

95

Beta-catenin signaling pathway is crucial for bone morphogenetic protein 2 to induce new bone formation.  

PubMed

Endochondral ossification is recapitulated during bone morphogenetic protein (BMP)-induced ectopic bone formation. Although BMP and beta-catenin have been investigated in bone development and in mesenchymal cells, how they interact in this process is not clear. We implanted recombinant BMP-2 into the muscle of mice to investigate the effect of beta-catenin signaling on BMP-induced in vivo endochondral bone formation. BMP-2 induced expression of several Wnt ligands and their receptors and also activated beta-catenin-mediated T cell factor-dependent transcriptional activity. An adenovirus expressing Dickkopf-1 (Dkk-1, an inhibitor of canonical Wnt pathway) inhibited beta-catenin signaling and endochondral bone formation. Interestingly, Dkk-1 inhibited both chondrogenesis and osteogenesis. Likewise, mice expressing conditional beta-catenin null alleles also displayed an inhibition of BMP-induced chondrogenesis and osteogenesis. This is in contrast to studies of embryonic skeletogenesis, which demonstrate that beta-catenin is required for osteogenesis but is dispensable for chondrogenesis. These findings suggest that embryonic development pathways are not always recapitulated during post-natal regenerative processes, and the biochemical pathways utilized to regulate cell differentiation may be different. During in vivo ectopic bone formation, BMP-2 induces beta-catenin-mediated signaling through Wnt ligands, and beta-catenin is required for both chondrogenesis and osteogenesis. PMID:17085452

Chen, Yan; Whetstone, Heather C; Youn, Andrew; Nadesan, Puviindran; Chow, Edwin C Y; Lin, Alvin C; Alman, Benjamin A

2007-01-01

96

Osteocyte control of bone remodeling: is sclerostin a key molecular coordinator of the balanced bone resorption-formation cycles?  

PubMed

Osteocytes, entrapped within a newly mineralized bone matrix, possess a unique cellular identity due to a specialized morphology and a molecular signature. These features endow them to serve as a bone response mechanism for mechanical stress in their microenvironment. Sclerostin, a primarily osteocyte product, is widely considered as a mechanotranduction key molecule whose expression is suppressed by mechanical loading, or it is induced by unloading. This review presents a model suggesting that sclerostin is major mediator for integrating mechanical, local, and hormonal signals, sensed by the osteocytes, in controlling the remodeling apparatus. This central role is achieved through interplay between two opposing mechanisms: (1) unloading-induced high sclerostin levels, which antagonize Wnt-canonical-?-catenin signaling in osteocytes and osteoblasts, permitting simultaneously Wnt-noncanonical and/or other pathways in osteocytes and osteoclasts, directed at bone resorption; (2) mechanical loading results in low sclerostin levels, activation of Wnt-canonical signaling, and bone formation. Therefore, adaptive bone remodeling occurring at a distinct bone compartment is orchestrated by altered sclerostin levels, which regulate the expression of the other osteocyte-specific proteins, such as RANKL, OPG, and proteins encoded by "mineralization-related genes" (DMP1, PHEX, and probably FGF23). For example, under specific terms, sclerostin regulates differential RANKL and OPG production, and creates a dynamic RANKL/OPG ratio, leading either to bone formation or resorption. It also controls the expression of PHEX, DMP1, and most likely FGF23, leading to either bone matrix mineralization or its inhibition. Such opposing up- or down-regulation of remodeling phases allows osteocytes to function as an "external unit", ensuring transition from bone resorption to bone formation.Mini Abstract: The osteocyte network plays a central role in directing bone response either to mechanical loading, or to unloading, leading correspondingly to bone formation or resorption. This review shows a key role of the osteocyte-produced sclerostin as a major mediator of the molecular mechanisms involved in the process of adaptive bone remodeling. PMID:25030653

Sapir-Koren, R; Livshits, G

2014-12-01

97

Calcitonin stimulates bone formation when administered prior to initiation of osteogenesis.  

PubMed Central

The influence of calcitonin (CT) on various stages of bone formation was investigated. A demineralized collagenous bone matrix-induced bone forming system in rats was used to temporally segregate chondrogenesis and osteogenesis. Administration of CT (15 Medical Research Council Units [MRCU]) daily) at the initiation of matrix-induced bone formation (BF) resulted in a 76% stimulation of BF as measured by 45Ca incorporation and alkaline phosphatase activity. This increase was due, in part, to a stimulation of cartilage and bone precursor cell proliferation monitored by the rate of [3H]thymidine incorporation and ornithine decarboxylase activity. Chondrogenesis on day 7 as measured by 35SO4 incorporation was increased by 52% with CT treatment. To rule out the possibility of a secondary response due to parathyroid hormone, similar studies were done in parathyroidectomized animals and CT stimulation of BF was still observed. However, when CT injections were started after cartilage formation (day 8) there was no stimulation of BF but a significant decrease in 45Ca incorporation was observed. These results indicate CT has two actions: (a) when CT is administered during the initial phases of bone formation, it increases BF due to a stimulation of proliferation of cartilage and bone precursor cells; and (b) when CT is administered after bone formation has been initiated, subsequent bone formation is suppressed. PMID:7276173

Weiss, R E; Singer, F R; Gorn, A H; Hofer, D P; Nimni, M E

1981-01-01

98

Lamellar Keratoplasty: A Literature Review  

PubMed Central

The concept of lamellar keratoplasty (LK) is not new. However, newer forms of lamellar keratoplasty techniques have emerged in the last decade or so revolving around the concept of targeted replacement of diseased corneal layers. These include anterior lamellar keratoplasty (ALK) techniques that aim to selectively replace diseased corneal stroma and endothelial keratoplasty techniques aiming to replaced damaged endothelium in endothelial disorders. Recent improvements in surgical instruments and introduction of new techniques as well as inherent advantages such as preservation of globe integrity and decreased graft rejection have resulted in the reintroduction of LK as an acceptable alternative to conventional PK. In this review, indications, benefits, limitations, and outcomes of various anterior and posterior lamellar keratoplasty techniques are discussed. PMID:24223301

Espandar, Ladan; Carlson, Alan N.

2013-01-01

99

Genetics Home Reference: Lamellar ichthyosis  

MedlinePLUS

... Patients and Families Resources for Health Professionals What glossary definitions help with understanding lamellar ichthyosis? alopecia ; autosomal ; ... many other terms in the Genetics Home Reference Glossary . See also Understanding Medical Terminology . References (4 links) ...

100

Calcium ions and osteoclastogenesis initiate the induction of bone formation by coral-derived macroporous constructs.  

PubMed

Coral-derived calcium carbonate/hydroxyapatite macroporous constructs of the genus Goniopora with limited hydrothermal conversion to hydroxyapatite (7% HA/CC) initiate the induction of bone formation. Which are the molecular signals that initiate pattern formation and the induction of bone formation? To evaluate the role of released calcium ions and osteoclastogenesis, 7% HA/CC was pre-loaded with either 500 ?g of the calcium channel blocker, verapamil hydrochloride, or 240 ?g of the osteoclast inhibitor, biphosphonate zoledronate, and implanted in the rectus abdominis muscle of six adult Chacma baboons Papio ursinus. Generated tissues on days 15, 60 and 90 were analysed by histomorphometry and qRT-PCR. On day 15, up-regulation of type IV collagen characterized all the implanted constructs correlating with vascular invasion. Zoledronate-treated specimens showed an important delay in tissue patterning and morphogenesis with limited bone formation. Osteoclastic inhibition yielded minimal, if any, bone formation by induction. 7% HA/CC pre-loaded with the Ca(++) channel blocker verapamil hydrochloride strongly inhibited the induction of bone formation. Down-regulation of bone morphogenetic protein-2 (BMP-2) together with up-regulation of Noggin genes correlated with limited bone formation in 7% HA/CC pre-loaded with either verapamil or zoledronate, indicating that the induction of bone formation by coral-derived macroporous constructs is via the BMPs pathway. The spontaneous induction of bone formation is initiated by a local peak of Ca(++) activating stem cell differentiation and the induction of bone formation. PMID:24106923

Klar, Roland M; Duarte, Raquel; Dix-Peek, Therese; Dickens, Caroline; Ferretti, Carlo; Ripamonti, Ugo

2013-11-01

101

Estradiol17? and nutritional status affect calcium balance, scale and bone resorption, and bone formation in rainbow trout, Oncorhynchus mykiss  

Microsoft Academic Search

The effects of estradiol-17? (E2) on bone resorption and formation as well as its effects on scale resorption were investigated in rainbow trout in order\\u000a to elucidate the role of the hormone in calcium mobilization from calcified tissues, and to clarify the importance of scale\\u000a and bone as calcium reserves during sexual maturation. Furthermore, the effects of nutritional status on

Petra Persson; Sigurdur Hilmir Johannsson; Yasuaki Takagi; Björn Thrandur Björnsson

1997-01-01

102

Cadmium stimulates osteoclast-like multinucleated cell formation in mouse bone marrow cell cultures  

SciTech Connect

Most of cadmium (Cd)-treated animals have been reported to show osteoporosis-like changes in bones. This suggests that Cd may promote bone loss by a direct action on bone. It was found that Cd stimulated prostaglandin E{sub 2}(PGE{sub 2}) production in the osteoblast-like cell, MC3T3-E1. Therefore, Cd stimulates bone resorption by increasing PGE{sub 2} production. Recently, several bone marrow cell culture systems have been developed for examining the formation of osteoclast-like multinucleated cells in vitro. As osteoblasts produce PGE{sub 2} by Cd-induced cyclooxygenase and may play an important role in osteoclast formation, the present study was undertaken to clarify the possibility that Cd might stimulate osteoclast formation in a mouse bone marrow culture system.

Miyahara, Tatsuro; Takata, Masakazu; Miyata, Masaki; Nagai, Miyuki; Sugure, Akemi; Kozuka, Hiroshi; Kuze, Shougo (Toyama Medical and Pharmaceutical Univ. (Japan))

1991-08-01

103

Annulus fibrosus tissue engineering using lamellar silk scaffolds  

PubMed Central

Degeneration of the intervertebral disc (IVD) represents a significant muscular skeletal disease. Recently, scaffolds composed of synthetic, natural and hybrid biomaterials have been investigated as options to restore the IVD; however, they lack the hallmark lamellar morphological features of annulus fibrosus (AF) tissue. The goal of regenerating disc is to achieve anatomic morphology as well as restoration of mechanical and biological function. In this study, two types of scaffold morphologies formed from silk fibroin were investigated towards the goal of AF tissue restoration. The first design mimics the lamellar features of the IVD that is associated with the AF region. The second is a porous spongy scaffold that serves as a control. Toroidal scaffolds were formed from the lamellar and porous silk material systems to generate structures with an outer diameter of 8 mm, inner diameter of 3.5 mm and a height of 3 mm. The inter-lamellar spacing in the lamellar scaffold was 150~250 ?m and the average pore sizes in the porous scaffolds were 100~250 ?m. The scaffolds were seeded with porcine AF cells and, after growth over defined time frames in vitro, histology, biochemical assays, mechanical testing and gene expression indicated that the lamellar scaffold generated results that were more favorable in terms of ECM expression and tissue function than the porous scaffold for AF tissue. Further, the seeded porcine AF cells supported the native shape of AF tissue in the lamellar silk scaffolds. The lamellar silk scaffolds were effective in the formation of AF-like tissue in vitro. PMID:22311816

Park, Sang-Hyug; Gil, Eun Seok; Mandal, Biman B.; Cho, Hong Sik; Kluge, Jonathan A.; Min, Byoung-Hyun; Kaplan, David L.

2012-01-01

104

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

PubMed Central

Diseases that affect the regulation of bone turnover can lead to skeletal fragility and increased fracture risk. Members of the TGF-? superfamily have been shown to be involved in the regulation of bone mass. Activin A, a TGF-? signaling ligand, is present at high levels in bone and may play a role in the regulation of bone metabolism. Here we demonstrate that pharmacological blockade of ligand signaling through the high affinity receptor for activin, type II activin receptor (ActRIIA), by administration of the soluble extracellular domain of ActRIIA fused to a murine IgG2a-Fc, increases bone formation, bone mass, and bone strength in normal mice and in ovariectomized mice with established bone loss. These observations support the development of this pharmacological strategy for the treatment of diseases with skeletal fragility. PMID:18460605

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

2008-01-01

105

Regulation of bone formation and remodeling by G-protein-coupled receptor 48  

PubMed Central

Summary G-protein-coupled receptor (GPCR) 48 (Gpr48; Lgr4), a newly discovered member of the glycoprotein hormone receptor subfamily of GPCRs, is an orphan GPCR of unknown function. Using a knockout mouse model, we have characterized the essential roles of Gpr48 in bone formation and remodeling. Deletion of Gpr48 in mice results in a dramatic delay in osteoblast differentiation and mineralization, but not in chondrocyte proliferation and maturation, during embryonic bone formation. Postnatal bone remodeling is also significantly affected in Gpr48-/- mice, including the kinetic indices of bone formation rate, bone mineral density and osteoid formation, whereas the activity and number of osteoclasts are increased as assessed by tartrate-resistant acid phosphatase staining. Examination of the molecular mechanism of Gpr48 action in bone formation revealed that Gpr48 can activate the cAMP-PKA-CREB signaling pathway to regulate the expression level of Atf4 in osteoblasts. Furthermore, we show that Gpr48 significantly downregulates the expression levels of Atf4 target genes/proteins, such as osteocalcin (Ocn; Bglap2), bone sialoprotein (Bsp; Ibsp) and collagen. Together, our data demonstrate that Gpr48 regulates bone formation and remodeling through the cAMP-PKA-Atf4 signaling pathway. PMID:19605502

Luo, Jian; Zhou, Wei; Zhou, Xin; Li, Dali; Weng, Jinsheng; Yi, Zhengfang; Cho, Sung Gook; Li, Chenghai; Yi, Tingfang; Wu, Xiushan; Li, Xiao-Ying; de Crombrugghe, Benoit; Hook, Magnus; Liu, Mingyao

2009-01-01

106

Regulation of bone formation and remodeling by G-protein-coupled receptor 48.  

PubMed

G-protein-coupled receptor (GPCR) 48 (Gpr48; Lgr4), a newly discovered member of the glycoprotein hormone receptor subfamily of GPCRs, is an orphan GPCR of unknown function. Using a knockout mouse model, we have characterized the essential roles of Gpr48 in bone formation and remodeling. Deletion of Gpr48 in mice results in a dramatic delay in osteoblast differentiation and mineralization, but not in chondrocyte proliferation and maturation, during embryonic bone formation. Postnatal bone remodeling is also significantly affected in Gpr48(-/-) mice, including the kinetic indices of bone formation rate, bone mineral density and osteoid formation, whereas the activity and number of osteoclasts are increased as assessed by tartrate-resistant acid phosphatase staining. Examination of the molecular mechanism of Gpr48 action in bone formation revealed that Gpr48 can activate the cAMP-PKA-CREB signaling pathway to regulate the expression level of Atf4 in osteoblasts. Furthermore, we show that Gpr48 significantly downregulates the expression levels of Atf4 target genes/proteins, such as osteocalcin (Ocn; Bglap2), bone sialoprotein (Bsp; Ibsp) and collagen. Together, our data demonstrate that Gpr48 regulates bone formation and remodeling through the cAMP-PKA-Atf4 signaling pathway. PMID:19605502

Luo, Jian; Zhou, Wei; Zhou, Xin; Li, Dali; Weng, Jinsheng; Yi, Zhengfang; Cho, Sung Gook; Li, Chenghai; Yi, Tingfang; Wu, Xiushan; Li, Xiao-Ying; de Crombrugghe, Benoit; Höök, Magnus; Liu, Mingyao

2009-08-01

107

Bone formation in psoriatic arthritis: a report from the GRAPPA 2013 Annual Meeting.  

PubMed

The simultaneous presence of bone erosions and bony spurs (osteophytes, enthesophytes) in the joints of patients with psoriatic arthritis (PsA) suggests that the disease leads to enhanced bone resorption as well as increased bone formation, the latter of which has not been observed in patients with rheumatoid arthritis. At the 2013 Annual Meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), members heard an update on the current research into the cytokine signature in PsA and its effects on new bone formation. PMID:24882855

Schett, Georg

2014-06-01

108

Reduced bone formation and increased bone resorption: rational targets for the treatment of osteoporosis  

Microsoft Academic Search

The net amount of bone lost during aging is determined by the difference between the amount of bone removed from the endocortical, trabecular and intracortical components of its endosteal (inner) envelope and formed beneath its periosteal (outer) envelope. Endosteal bone loss is determined by the remodeling rate (number of basic multicellular units, BMUs) and the negative balance (the difference between

Ego Seeman

2003-01-01

109

Negative Regulation of Bone Formation by the Transmembrane Wnt Antagonist Kremen-2  

PubMed Central

Wnt signalling is a key pathway controlling bone formation in mice and humans. One of the regulators of this pathway is Dkk1, which antagonizes Wnt signalling through the formation of a ternary complex with the transmembrane receptors Krm1/2 and Lrp5/6, thereby blocking the induction of Wnt signalling by the latter ones. Here we show that Kremen-2 (Krm2) is predominantly expressed in bone, and that its osteoblast-specific over-expression in transgenic mice (Col1a1-Krm2) results in severe osteoporosis. Histomorphometric analysis revealed that osteoblast maturation and bone formation are disturbed in Col1a1-Krm2 mice, whereas bone resorption is increased. In line with these findings, primary osteoblasts derived from Col1a1-Krm2 mice display a cell-autonomous differentiation defect, impaired canonical Wnt signalling and decreased production of the osteoclast inhibitory factor Opg. To determine whether the observed effects of Krm2 on bone remodeling are physiologically relevant, we analyzed the skeletal phenotype of 24 weeks old Krm2-deficient mice and observed high bone mass caused by a more than three-fold increase in bone formation. Taken together, these data identify Krm2 as a regulator of bone remodeling and raise the possibility that antagonizing KRM2 might prove beneficial in patients with bone loss disorders. PMID:20436912

Schneebauer, Michael; Marshall, Robert P.; Baranowsky, Anke; Busse, Bjoern; Schilling, Arndt F.; Friedrich, Felix W.; Albers, Joachim; Spiro, Alexander S.; Zustin, Jozef; Streichert, Thomas; Ellwanger, Kristina; Niehrs, Christof; Amling, Michael; Baron, Roland; Schinke, Thorsten

2010-01-01

110

Chondrocyte ?-Catenin Signaling Regulates Postnatal Bone Remodeling Through Modulation of Osteoclast Formation in a Murine Model  

PubMed Central

Objective To investigate whether ?-catenin signaling in chondrocytes regulates osteoclastogenesis, thereby contributing to postnatal bone growth and bone remodeling. Methods Mice with conditional knockout (cKO) or conditional activation (cAct) of chondrocyte-specific ?-catenin were generated. Changes in bone mass, osteoclast numbers, and osteoblast activity were examined. The mechanisms by which ?-catenin signaling in chondrocytes regulates osteoclast formation were determined. Results The ?-catenin cKO mice developed localized bone loss, whereas cAct mice developed a high bone mass phenotype. Histologic findings suggested that these phenotypes were caused primarily by impaired osteoclast formation, rather than impaired bone formation. Further molecular signaling analyses revealed that ?-catenin signaling controlled this process by regulating the expression of the RANKL and osteoprotegerin (OPG) genes in chondrocytes. Activation of ?-catenin signaling in chondrocytes suppressed Rankl gene transcription through a glucocorticoid receptor–dependent mechanism. The severe bone loss phenotype observed in ?-catenin cKO mice was largely restored by treatment with human recombinant OPG or transgenic overexpression of Opg in chondrocytes. Conclusion ?-catenin signaling in chondrocytes plays a key role in postnatal bone growth and bone remodeling through its regulation of osteoclast formation. PMID:24431282

Wang, Baoli; Jin, Hongting; Zhu, Mei; Li, Jia; Zhao, Lan; Zhang, Yejia; Tang, Dezhi; Xiao, Guozhi; Xing, Lianping; Boyce, Brendan F.; Chen, Di

2014-01-01

111

Short-term aluminum administration in the rat: reductions in bone formation without osteomalacia  

SciTech Connect

Aluminum may be a pathogenic factor in dialysis-associated osteomalacia. To study the early effects of Al on bone, cortical bone growth was measured in pair-fed rats given Al and control rats over two consecutive intervals of 28 (period I) and 16 (period II) days, respectively, using tetracycline labeling of bone. Al (2 mg elemental Al per rat) was administered intraperitoneally for 5 days each week, except for the first week of study, when an incremental dose of Al was given. Control rats received saline vehicle only. For the entire 44-day study, bone and matrix formation were reduced from control values in rats given Al. Although bone and matrix formation remained at control levels during period I in rats given Al, both measurements decreased from control values during period II. During Al exposure, bone and matrix apposition at the periosteum were reduced from control levels in period II, but not in period I. Neither osteoid width nor mineralization front width increased from control values in rats given Al. These findings indicate that Al reduces bone and matrix formation early in the course of Al exposure and prior to the development of histologic osteomalacia. Rather than acting as an inhibitor of mineralization, the early effect of Al on bone is the suppression of matrix synthesis. Our results suggest that the state of low bone formation seen in dialysis-associated osteomalacia may be the consequence of a direct toxic effect of Al on the cellular activity of osteoblasts. 29 references, 3 tables.

Goodman, W.G.

1984-05-01

112

Parathyroid hormone may maintain bone formation in hibernating black bears (Ursus americanus) to prevent disuse osteoporosis.  

PubMed

Mechanical unloading of bone causes an imbalance in bone formation and resorption leading to bone loss and increased fracture risk. Black bears (Ursus americanus) are inactive for up to six months during hibernation, yet bone mineral content and strength do not decrease with disuse or aging. To test whether hibernating bears have biological mechanisms to prevent disuse osteoporosis, we measured the serum concentrations of hormones and growth factors involved in bone metabolism and correlated them with the serum concentration of a bone formation marker (osteocalcin). Serum was obtained from black bears over a 7-month duration that included periods of activity and inactivity. Both resorption and formation markers increased during hibernation, suggesting high bone turnover occurred during inactivity. However, bone formation appeared to be balanced with bone resorption. The serum concentration of parathyroid hormone (PTH) was higher in the hibernation (P=0.35) and post-hibernation (P=0.006) seasons relative to pre-hibernation levels. Serum leptin was lower (P<0.004) post-hibernation relative to pre-hibernation and hibernation periods. Insulin-like growth factor I (IGF-I) decreased (P<0.0001) during hibernation relative to pre-hibernation and reached its highest value during remobilization. There was no difference (P=0.64) in 25-OH vitamin D between the three seasons. Serum osteocalcin (bone formation marker) was significantly correlated with PTH, but not with leptin, IGF-I or 25-OH vitamin D. Osteocalcin and PTH were positively correlated when samples from all seasons were pooled and when only hibernation samples were considered, raising the possibility that the anabolic actions of PTH help maintain bone formation to prevent disuse osteoporosis. Prostaglandin E(2) (PGE(2)) release from MC3T3 osteoblastic cells was significantly affected by treatment with bear serum from different seasons (i.e. hibernation versus active periods). The seasonal changes in PGE(2) release showed trends similar to the seasonal changes in serum IGF-I. Since both PGE(2) and IGF-I are associated with collagenous bone formation, it is possible that seasonal changes in a circulating factor influence IGF-I levels in vivo in bears and PGE(2) release in osteoblastic cells in vitro. The significant decrease in serum leptin following arousal from hibernation may promote bone formation during remobilization, assuming there is a similar decrease in intracerebroventricular leptin. These findings support the idea that seasonal changes in the concentration of circulating molecules help regulate bone formation activity and may be important for preventing disuse osteoporosis in bears. PMID:16621944

Donahue, Seth W; Galley, Sarah A; Vaughan, Michael R; Patterson-Buckendahl, Patricia; Demers, Laurence M; Vance, Josef L; McGee, Meghan E

2006-05-01

113

Morphologic and radiological observations on the earliest bone marrow formation in human embryos and fetuses.  

PubMed

Morphologic and radiologic studies were undertaken on 26 human embryos and fetuses to determine the stage and site of the earliest bone marrow formation. Up to the 10th week of gestation, primary bone marrow is not present anywhere although the intramembranous ossification occurs in the maxilla and mandible and also in the middle portion of the clavicle. At the 11th week of gestation, X-ray examination showed in two fetuses the bone formation in the clavicle, scapula, maxilla, mandible, and the diaphysis of the long bones. Serial sections of these fetuses revealed that the primary bone marrow occurs first in the middle portion of the clavicle. From a series of our embryological studies, the concept of the mononuclear phagocyte system which involves the bone-marrow-derived monocytic origin of tissue macrophages, is not accepted, at least, on the origin of Kupffer cells in human fetal livers. PMID:6624441

Enzan, H; Hara, H; Izumi, T; Ohkita, T

1983-05-01

114

The Effect of Skeletal Unloading on Bone Formation: Role of IGF-I  

NASA Technical Reports Server (NTRS)

The best documented change in bone during space flight is the near cessation of bone formation. Space flight leads to a decrease in osteoblast number and activity, likely the result of altered differentiation of osteoblast precursors. The net result of these space flight induced changes is weaker bone. To understand the mechanism for these changes poses a challenge. Space flight studies must overcome enormous technical problems, and are necessarily limited in size and frequency. Therefore, ground based models have been developed to evaluate the effects of skeletal unloading. The hindlimb elevation (tail suspension) model simulates space flight better than other models because it reproduces the fluid shifts seen in space travel, is reversible, and is well tolerated by the animals with minimal evidence of stress as indicated by continued weight gain and normal levels and circadian rhythms of corticosterone. This is the model we have used for our experiments. Skeletal unloading by the hindlimb elevation method simulates a number of features of space flight in that bone formation, mineralization, and maturation are inhibited, osteoblast number is decreased, serum and skeletal osteocalcin levels fall, the ash content of bone decreases, and bone strength diminishes. We and others have shown that when osteoblasts or osteoprogenitor cells from the bones of the unloaded limbs are cultured in vitro they proliferate and differentiate more slowly, suggesting that skeletal unloading causes a persistent change in cell function which can be assessed in vitro. In contrast to the unweighted bones of the hindlimbs, no significant change in bone mass or bone formation is observed in the humeri, mandible, and cervical vertebrae during hindlimb elevation. The lack of effect of hindlimb elevation on bones like the humeri, mandible, and cervical vertebrae which are not unloaded by this procedure suggests that local factors rather than systemic effects dominate the response of bone to skeletal unloading. We have focussed on the role of IGF- 1 as the local factor mediating the effects of skeletal unloading on bone formation. IGF-I is produced by bone cells and chondrocytes; these cells have receptors for IGF-I, and respond to IGF-I with an increase in proliferation and function (e.g. collagen, and glycosaminoglycan production, respectively). IGF-I production by bone is under hormonal control, principally by GH and PTH, and IGF-I is thought to mediate some if not all of the effects of GH and PTH on bone growth. Thus, systemic changes in hormones such as GH and PTH may still have effects which vary from bone to bone depending on the loading history.

Bikle, D. D.; Kostenuik, P.; Holton, E. M.; Halloran, B. P.

1999-01-01

115

FLUORIDE EFFECTS ON BONE FORMATION AND MINERALIZATION ARE INFLUENCED BY GENETICS  

PubMed Central

Introduction A variation in bone response to fluoride (F?) exposure has been attributed to genetic factors. Increasing fluoride doses (0ppm, 25ppm, 50ppm, 100ppm) for three inbred mouse strains with different susceptibilities to developing dental enamel fluorosis (A/J, a “susceptible” strain; SWR/J, an “intermediate” strain; 129P3/J, a “resistant” strain) had different effects on their cortical and trabecular bone mechanical properties. In this paper, the structural and material properties of the bone were evaluated to explain the previously observed changes in mechanical properties. Materials and Methods This study assessed the effect of increasing fluoride doses on the bone formation, microarchitecture, mineralization and microhardness of the A/J, SWR/J and 129P3/J mouse strains. Bone microarchitecture was quantified with microcomputed tomography and strut analysis. Bone formation was evaluated by static histomorphometry. Bone mineralization was quantified with backscattered electron (BSE) imaging and powder x-ray diffraction. Microhardness measurements were taken from the vertebral bodies (cortical and trabecular bone) and the cortex of the distal femur. Results Fluoride treatment had no significant effect on bone microarchitecture for any of the strains. All three strains demonstrated a significant increase in osteoid formation at the largest fluoride dose. Vertebral body trabecular bone BSE imaging revealed significantly decreased mineralization heterogeneity in the SWR/J strain at 50ppm and 100ppm F?. The trabecular and cortical bone mineralization profiles showed a non-significant shift towards higher mineralization with increasing F? dose in the three strains. Powder x-ray diffraction showed significantly smaller crystals for the 129P3/J strain, and increased crystal width with increasing F? dose for all strains. There was no effect of F? on trabecular and cortical bone microhardness. Conclusion Fluoride treatment had no significant effect on bone microarchitecture in these three strains. The increased osteoid formation and decreased mineralization heterogeneity support the theory that F? delays mineralization of new bone. The increasing crystal width with increasing F? dose confirms earlier results and correlates with most of the decreased mechanical properties. An increase in bone F? may affect the mineral-organic interfacial bonding and/or bone matrix proteins, interfering with bone crystal growth inhibition on the crystallite faces as well as bonding between the mineral and organic interface. The smaller bone crystallites of the 129P3/J (resistant) strain may indicate a stronger organic/inorganic interface, reducing crystallite growth rate and increasing interfacial mechanical strength. PMID:18755305

Mousny, M.; Omelon, S.; Wise, L.; Everett, E. T.; Dumitriu, M.; Holmyard, D. P.; Banse, X.; Devogelaer, J. P.; Grynpas, M. D

2008-01-01

116

Mechanical loading, damping, and load-driven bone formation in mouse tibiae  

PubMed Central

Mechanical loads play a pivotal role in the growth and maintenance of bone and joints. Although loading can activate anabolic genes and induce bone remodeling, damping is essential for preventing traumatic bone injury and fracture. In this study we investigated the damping capacity of bone, joint tissue, muscle, and skin using a mouse hindlimb model of enhanced loading in conjunction with finite element modeling to model bone curvature. Our hypothesis was that loads were primarily absorbed by the joints and muscle tissue, but that bone also contributed to damping through its compression and natural bending. To test this hypothesis, fresh mouse distal lower limb segments were cyclically loaded in axial compression in sequential bouts, with each subsequent bout having less surrounding tissue. A finite element model was generated to model effects of bone curvature in silico. Two damping-related parameters (phase shift angle and energy loss) were determined from the output of the loading experiments. Interestingly, the experimental results revealed that the knee joint contributed to the largest portion of the damping capacity of the limb, and bone itself accounted for approximately 38% of the total phase shift angle. Computational results showed that normal bone curvature enhanced the damping capacity of the bone by approximately 40%, and the damping effect grew at an accelerated pace as curvature was increased. Although structural curvature reduces critical loads for buckling in beam theory, evolution apparently favors maintaining curvature in the tibia. Histomorphometric analysis of the tibia revealed that in response to axial loading, bone formation was significantly enhanced in the regions that were predicted to receive a curvature-induced bending moment. These results suggest that in addition to bone’s compressive damping capacity, surrounding tissues, as well as naturally-occurring bone curvature, also contribute to mechanical damping, which may ultimately affect bone remodeling and bone quality. PMID:22878153

Dodge, Todd; Wanis, Mina; Ayoub, Ramez; Zhao, Liming; Watts, Nelson B.; Bhattacharya, Amit; Akkus, Ozan; Robling, Alexander; Yokota, Hiroki

2012-01-01

117

Load Regulates Bone Formation and Sclerostin Expression through a TGF?-Dependent Mechanism  

PubMed Central

Bone continually adapts to meet changing physical and biological demands. Osteoblasts, osteoclasts, and osteocytes cooperate to integrate these physical and biochemical cues to maintain bone homeostasis. Although TGF? acts on all three of these cell types to maintain bone homeostasis, the extent to which it participates in the adaptation of bone to mechanical load is unknown. Here, we investigated the role of the TGF? pathway in load-induced bone formation and the regulation of Sclerostin, a mechanosensitive antagonist of bone anabolism. We found that mechanical load rapidly represses the net activity of the TGF? pathway in osteocytes, resulting in reduced phosphorylation and activity of key downstream effectors, Smad2 and Smad3. Loss of TGF? sensitivity compromises the anabolic response of bone to mechanical load, demonstrating that the mechanosensitive regulation of TGF? signaling is essential for load-induced bone formation. Furthermore, sensitivity to TGF? is required for the mechanosensitive regulation of Sclerostin, which is induced by TGF? in a Smad3-dependent manner. Together, our results show that physical cues maintain bone homeostasis through the TGF? pathway to regulate Sclerostin expression and the deposition of new bone. PMID:23308287

Nguyen, Daniel; Alliston, Tamara

2013-01-01

118

Decreased bone turnover with balanced resorption and formation prevent cortical bone loss during disuse (hibernation) in grizzly bears (Ursus arctos horribilis).  

PubMed

Disuse uncouples bone formation from resorption, leading to increased porosity, decreased bone geometrical properties, and decreased bone mineral content which compromises bone mechanical properties and increases fracture risk. However, black bear bone properties are not adversely affected by aging despite annual periods of disuse (i.e., hibernation), which suggests that bears either prevent bone loss during disuse or lose bone and subsequently recover it at a faster rate than other animals. Here we show decreased cortical bone turnover during hibernation with balanced formation and resorption in grizzly bear femurs. Hibernating grizzly bear femurs were less porous and more mineralized, and did not demonstrate any changes in cortical bone geometry or whole bone mechanical properties compared to active grizzly bear femurs. The activation frequency of intracortical remodeling was 75% lower during hibernation than during periods of physical activity, but the normalized mineral apposition rate was unchanged. These data indicate that bone turnover decreases during hibernation, but osteons continue to refill at normal rates. There were no changes in regional variation of porosity, geometry, or remodeling indices in femurs from hibernating bears, indicating that hibernation did not preferentially affect one region of the cortex. Thus, grizzly bears prevent bone loss during disuse by decreasing bone turnover and maintaining balanced formation and resorption, which preserves bone structure and strength. These results support the idea that bears possess a biological mechanism to prevent disuse osteoporosis. PMID:18037367

McGee, Meghan E; Maki, Aaron J; Johnson, Steven E; Nelson, O Lynne; Robbins, Charles T; Donahue, Seth W

2008-02-01

119

A Seven Day Continuous Infusion of PTH or PTHrP Suppresses Bone Formation and Uncouples Bone Turnover  

PubMed Central

Human in vivo models of primary hyperparathyroidism (HPT), humoral hypercalcemia of malignancy (HHM) or lactational bone mobilization for more than 48 hours have not been described previously. We therefore developed seven-day continuous infusion models using hPTH(1–34) and hPTHrP(1–36) in healthy human adult volunteers. Study subjects developed sustained mild increases in serum calcium (10.0 mg/dl), with marked suppression of endogenous PTH(1–84). The maximal tolerated infused doses over a seven-day period (2 and 4 pmol/kg/hr, for PTH and PTHrP, respectively) were far lower than in prior, briefer human studies (8–28 pmol/kg/hr). In contrast to prior reports using higher PTH and PTHrP doses, both 1,25(OH)2D and TmP/GFR remained unaltered with these low doses, despite achievement of hypercalcemia and hypercalciuria. As expected, bone resorption increased rapidly, and reversed promptly with cessation of the infusion. However, in contrast to events in primary HPT, bone formation was suppressed by 30–40% for the seven days of the infusions. With cessation of PTH and PTHrP infusion, bone formation markers abruptly rebounded upward, confirming that bone formation is suppressed by continuous PTH or PTHrP infusion. These studies demonstrate that continuous exposure of the human skeleton to PTH or PTHrP in vivo recruits and activates the bone resorption program, but causes sustained arrest in the osteoblast maturation program. These events would most closely mimic and model events in HHM. Although not a perfect model for lactation, the increase in resorption and the rebound increase in formation with cessation of the infusions is reminiscent of the maternal skeletal calcium mobilization and reversal that occur following lactation. The findings also highlight similarities and differences between the model and HPT. PMID:21544866

Horwitz, Mara J.; Tedesco, Mary Beth; Sereika, Susan M.; Prebehala, Linda; Gundberg, Caren M.; Hollis, Bruce W.; Bisello, Alessandro; Garcia-Ocana, Adolfo; Carneiro, Raquel M.; Stewart, Andrew F.

2011-01-01

120

Platelet concentration and its effect on bone formation in calvarial defects: An experimental study in rabbits  

Microsoft Academic Search

Statement of problem. The use of the platelet concentration technique is widespread in dental implant surgery. However, its effect or mechanism is not clearly understood. Purpose. This study introduced an animal model for the platelet concentration technique and evaluated its effect on bone formation with natural cancellous bovine bone mineral. Material and methods. Adult New Zealand white rabbits were used

Eun-Seok Kim; Eun-Jin Park; Pill-Hoon Choung

2001-01-01

121

Induction of bone formation by activated monocytes / macrophages depends on Oncostatin M signaling  

E-print Network

) activation by lipopolysaccharide or endogenous ligands, OSM was produced in classically activated induced by monocytes/macrophages and TLRs activation: IL-6 and Leukemia inhibitory factor. We propose and TLR ligands stimulates bone formation that is largely uncoupled from bone resorption and is thus

Boyer, Edmond

122

MESENCHYMAL STEM CELLS AND THEIR PROGENY: DEVELOPMENTAL PARADIGMS GOVERNING OSTEOBLAST DIFFERENTIATION & BONE FORMATION  

Microsoft Academic Search

1 . We will provide insights into the developmental paradigms governing osteoblast differentiation and bone formation from cellular and molecular analyses of developing bone colonies in vitro. METHODS: Cells were isolated from 21 day Wistar rat calvariae, plated at different densities and cultured for up to 3-4 weeks in differentiation medium (?MEM, with antibiotics, 10% FBS, 50 ?g\\/ml ascorbic acid,

Jane E. Aubin; Shulin Zhang; Soshi Uchida

123

Pulsed electromagnetic fields partially preserve bone mass, microarchitecture, and strength by promoting bone formation in hindlimb-suspended rats.  

PubMed

A large body of evidence indicates that pulsed electromagnetic fields (PEMF), as a safe and noninvasive method, could promote in vivo and in vitro osteogenesis. Thus far, the effects and underlying mechanisms of PEMF on disuse osteopenia and/or osteoporosis remain poorly understood. Herein, the efficiency of PEMF on osteoporotic bone microarchitecture, bone strength, and bone metabolism, together with its associated signaling pathway mechanism, was systematically investigated in hindlimb-unloaded (HU) rats. Thirty young mature (3-month-old), male Sprague-Dawley rats were equally assigned to control, HU, and HU?+?PEMF groups. The HU?+?PEMF group was subjected to daily 2-hour PEMF exposure at 15?Hz, 2.4 mT. After 4 weeks, micro-computed tomography (µCT) results showed that PEMF ameliorated the deterioration of trabecular and cortical bone microarchitecture. Three-point bending test showed that PEMF mitigated HU-induced reduction in femoral mechanical properties, including maximum load, stiffness, and elastic modulus. Moreover, PEMF increased serum bone formation markers, including osteocalcin (OC) and N-terminal propeptide of type 1 procollagen (P1NP); nevertheless, PEMF exerted minor inhibitory effects on bone resorption markers, including C-terminal crosslinked telopeptides of type I collagen (CTX-I) and tartrate-resistant acid phosphatase 5b (TRAcP5b). Bone histomorphometric analysis demonstrated that PEMF increased mineral apposition rate, bone formation rate, and osteoblast numbers in cancellous bone, but PEMF caused no obvious changes on osteoclast numbers. Real-time PCR showed that PEMF promoted tibial gene expressions of Wnt1, LRP5, ?-catenin, OPG, and OC, but did not alter RANKL, RANK, or Sost mRNA levels. Moreover, the inhibitory effects of PEMF on disuse-induced osteopenia were further confirmed in 8-month-old mature adult HU rats. Together, these results demonstrate that PEMF alleviated disuse-induced bone loss by promoting skeletal anabolic activities, and imply that PEMF might become a potential biophysical treatment modality for disuse osteoporosis. © 2014 American Society for Bone and Mineral Research. PMID:24753111

Jing, Da; Cai, Jing; Wu, Yan; Shen, Guanghao; Li, Feijiang; Xu, Qiaoling; Xie, Kangning; Tang, Chi; Liu, Juan; Guo, Wei; Wu, Xiaoming; Jiang, Maogang; Luo, Erping

2014-10-01

124

Skeletal Repair by in Situ Formation of the Mineral Phase of Bone  

Microsoft Academic Search

A process has been developed for the in situ formation of the mineral phase of bone. Inorganic calcium and phosphate sources are combined to form a paste that is surgically implanted by injection. Under physiological conditions, the material hardens in minutes concurrent with the formation of dahllite. After 12 hours, dahllite formation was nearly complete, and an ultimate compressive strength

Brent R. Constantz; Ira C. Ison; Mark T. Fulmer; Robert D. Poser; Susanne T. Smith; Michelle Vanwagoner; John Ross; Steven A. Goldstein; Jesse B. Jupiter; Daniel I. Rosenthal

1995-01-01

125

Ultrastructure of lamellar bodies in congenital surfactant deficiency.  

PubMed

Congenital surfactant deficiency (CSD) is a newly identified neonatal lung disorder associated with a variety of molecular defects affecting surfactant synthesis and secretion in alveolar type II cells. The authors present ultrastructural findings of abnormal lamellar bodies in lung biopsies from 4 infants with CSD. All were term infants presenting shortly after birth with severe respiratory failure that was unresponsive to conventional therapy and all died within the first month of life. Lung biopsies were performed between 8 and 25 days of age. Biochemical and molecular studies in 2 unrelated male infants identified SP-B deficiency, one case with 121 ins 2 mutation and the second with a 209 + 4 A > G mutation. Light microscopy in both cases showed features of alveolar proteinosis. Ultrastructurally, alveolar type II cells lacked mature lamellar bodies, and their cytoplasm contained numerous pleomorphic inclusions with membranous and vesicular structures not seen in normal type II cells. The other 2 infants were a pair of siblings in whom molecular studies identified mutations in ABCA3 transporter gene. Light microscopy showed features of acinar dysplasia and desquamative interstitial pneumonitis. TEM studies revealed absence of mature lamellar bodies in type II cells and instead showed a mixture of cytoplasmic electron-dense inclusions with concentric membranes and distinctive electron dense aggregates. The ultrastructural changes in alveolar type II cells correlated well with specific gene defect. In SP-B deficiency, the absence of mature lamellar bodies is consistent with the postulated role for this protein in the formation of lamellar bodies. The lack of mature lamellar bodies in the ABCA3 gene mutations is due to the dysfunction of this endogenous lipid transporter that targets surfactant lipid moieties to the lamellar bodies. The findings demonstrate the importance of TEM studies of lung biopsies from infants with CSD as it is a critical adjunct in the diagnosis of neonatal lung disease and in defining the underlying cellular defects. PMID:16316951

Edwards, V; Cutz, E; Viero, S; Moore, A M; Nogee, L

2005-01-01

126

Suppression of Inflammation and Effects on New Bone Formation in Ankylosing Spondylitis  

MedlinePLUS

... been shown to prevent new bone formation." Meaning, TNF-a Inhibitor / biologic class medications have not been ... and they are not in an advanced stage, TNF-a inhibitors may be much more effective in ...

127

Bmp2 in osteoblasts of periosteum and trabecular bone links bone formation to vascularization and mesenchymal stem cells  

PubMed Central

Summary We generated a new Bmp2 conditional-knockout allele without a neo cassette that removes the Bmp2 gene from osteoblasts (Bmp2-cKOob) using the 3.6Col1a1-Cre transgenic model. Bones of Bmp2-cKOob mice are thinner, with increased brittleness. Osteoblast activity is reduced as reflected in a reduced bone formation rate and failure to differentiate to a mature mineralizing stage. Bmp2 in osteoblasts also indirectly controls angiogenesis in the periosteum and bone marrow. VegfA production is reduced in Bmp2-cKOob osteoblasts. Deletion of Bmp2 in osteoblasts also leads to defective mesenchymal stem cells (MSCs), which correlates with the reduced microvascular bed in the periosteum and trabecular bones. Expression of several MSC marker genes (?-SMA, CD146 and Angiopoietin-1) in vivo, in vitro CFU assays and deletion of Bmp2 in vitro in ?-SMA+ MSCs support our conclusions. Critical roles of Bmp2 in osteoblasts and MSCs are a vital link between bone formation, vascularization and mesenchymal stem cells. PMID:23843612

Yang, Wuchen; Guo, Dayong; Harris, Marie A.; Cui, Yong; Gluhak-Heinrich, Jelica; Wu, Junjie; Chen, Xiao-Dong; Skinner, Charles; Nyman, Jeffry S.; Edwards, James R.; Mundy, Gregory R.; Lichtler, Alex; Kream, Barbara E.; Rowe, David W.; Kalajzic, Ivo; David, Val; Quarles, Darryl L.; Villareal, Demetri; Scott, Greg; Ray, Manas; Liu, S.; Martin, James F.; Mishina, Yuji; Harris, Stephen E.

2013-01-01

128

Local treatment of cancellous bone grafts with BMP-7 and zoledronate increases both the bone formation rate and bone density  

PubMed Central

Background and purpose The remodeling of morselized bone grafts in revision surgery can be enhanced by an anabolic substance such as a bone morphogenetic protein (BMP). On the other hand, BMPs boost catabolism and might cause a premature resorption, both of the graft and of the new-formed bone. Bisphosphonates inactivate osteoclasts and can be used to control the resorption. We studied a combination of both drugs as a local admix to a cancellous allograft. Methods Cancellous bone allografts were harvested and freeze-dried. Either saline, BMP-7, the bisphosphonate zoledronate, or a combination of BMP-7 and zoledronate were added in solution. The grafts were placed in bone conduction chambers and implanted in the proximal tibia of 34 rats. The grafts were harvested after 6 weeks and evaluated by histomorphometry. Results Bone volume/total volume (BV/TV) was 50% in the grafts treated with the combination of BMP-7 and zoledronate and 16% in the saline controls (p < 0.001). In the zoledronate group BV/TV was 56%, and in the BMP group it was 14%. The ingrowth distance of new bone into the graft was 3.5 mm for the combination of BMP-7 and zoledronate and 2.6 mm in the saline control (p = 0.002). The net amount of retained remodeled bone was more than 4 times higher when BMP-7 and zoledronate were combined than in the controls. Interpretation An anabolic drug like BMP-7 can be combined with an anti-catabolic bisphosphonate as local bone graft adjunct, and the combination increases the amount of remaining bone after remodeling is complete. PMID:21434769

2011-01-01

129

Silicon: A requirement in bone formation independent of vitamin D 1  

Microsoft Academic Search

Summary  Silicon has been reported to be involved in an early stage of bone formation as a result of earlier in vitro and in vivo studies\\u000a in this laboratory. It is now possible to demonstrate that silicon exerts an effect on bone formation independent of the action\\u000a of vitamin D. Day-old cockerels were fed Sideficient and Si-supplemented diets with adequate and

Edith M. Carlisle

1981-01-01

130

Tamoxifen Attenuates Glucocorticoid Actions on Bone Formation in Vitro  

Microsoft Academic Search

Tamoxifen is a synthetic estrogen analog which may regulate os- teogenesis in vivo by virtue of its antiglucocorticoid properties. We have examined tamoxifen regulation of glucocorticoid-induced osteo- genesis in two different in vitro bone systems: the chicken periosteal osteogenesis model (CPO) and rat bone marrow stromal cells (RBMC). Hormone uptake studies were conducted with the osteosarcoma cell line, ROS 17\\/2.8.

B. Sukhu; B. ROTENBERG; C. BINKERT; H. KOHNO; R. ZOHAR; C. A. G. MCCULLOCH; H. C. TENENBAUM

1997-01-01

131

Insulin and new bone formation in diffuse idiopathic skeletal hyperostosis  

Microsoft Academic Search

Summary  \\u000aThe tendency of patients with DISH towards obesity or an adult onset of diabetes has been reflected in marked hyperinsulinaemia following glucose challenge. It is hypothesized that insulin at prolonged and high physiologic levels promotes new bone growth, particularly in the entheseal regions. These areas are also subject to various mechanical forces. The resulting new bone produces the radiological

G. O. Littlejohn

1985-01-01

132

Effects of sodium acetate on rat bone-nodule formation and mineralization in vitro.  

PubMed

Sodium acetate reportedly promotes bone atrophy by inducing resorption and inhibiting osteoprogenitor-cell proliferation, but little is known about its effects on bone-matrix deposition and mineralization by a population containing osteoprogenitor cells. The objective here was to assess the effects of 1-20 mM sodium acetate on the proliferation and differentiation of these cells and their resultant bone-nodule formation and mineralization in an in vitro assay. Exposure to 10 mM sodium acetate had no effect on cellular proliferation but significantly increased the production and mineralization of bone nodules (p < 0.01), suggesting that it affected osteoprogenitor differentiation and subsequent metabolism. However, 10 mM acetate did not increase net bone mass. Dilutions of 1-5 and 20 mM inhibited cellular proliferation and resultant bone-nodule formation and mineralization, significantly reducing the percentage bone area as compared to controls (p < 0.001). These data suggest that 1-5 and 20 mM sodium acetate significantly inhibit bone deposition, whereas 10 mM has no effects, which could contribute to iatrogenic metabolic bone disease in patients receiving either renal dialysis or total parenteral nutrition. PMID:9783827

Visconti, L A; Yen, E H; Johnson, R B

1998-09-01

133

Profilin1 regulates sternum development and endochondral bone formation.  

PubMed

Bone development is a dynamic process that requires cell motility and morphological adaptation under the control of actin cytoskeleton. This actin cytoskeleton system is regulated by critical modulators including actin-binding proteins. Among them, profilin1 (Pfn1) is a key player to control actin fiber structure, and it is involved in a number of cellular activities such as migration. During the early phase of body development, skeletal stem cells and osteoblastic progenitor cells migrate to form initial rudiments for future skeletons. During this migration, these cells extend their process based on actin cytoskeletal rearrangement to locate themselves in an appropriate location within microenvironment. However, the role of Pfn1 in regulation of mesenchymal progenitor cells (MPCs) during skeletal development is incompletely understood. Here we examined the role of Pfn1 in skeletal development using a genetic ablation of Pfn1 in MPCs by using Prx1-Cre recombinase. We found that Pfn1 deficiency in MPCs caused complete cleft sternum. Notably, Pfn1-deficient mice exhibited an absence of trabecular bone in the marrow space of appendicular long bone. This phenotype is location-specific, as Pfn1 deficiency did not largely affect osteoblasts in cortical bone. Pfn1 deficiency also suppressed longitudinal growth of long bone. In vitro, Pfn1 deficiency induced retardation of osteoblastic cell migration. These observations revealed that Pfn1 is a critical molecule for the skeletal development, and this could be at least in part associated with the retardation of cell migration. PMID:22773831

Miyajima, Daisuke; Hayata, Tadayoshi; Suzuki, Takafumi; Hemmi, Hiroaki; Nakamoto, Tetsuya; Notomi, Takuya; Amagasa, Teruo; Böttcher, Ralph T; Costell, Mercedes; Fässler, Reinhard; Ezura, Yoichi; Noda, Masaki

2012-09-28

134

Non-invasive monitoring of BMP2 retention and bone formation in composites for bone tissue engineering using SPECT\\/CT and scintillation probes  

Microsoft Academic Search

Non-invasive imaging can provide essential information for the optimization of new drug delivery-based bone regeneration strategies to repair damaged or impaired bone tissue. This study investigates the applicability of nuclear medicine and radiological techniques to monitor growth factor retention profiles and subsequent effects on bone formation. Recombinant human bone morphogenetic protein-2 (BMP-2, 6.5 ?g\\/scaffold) was incorporated into a sustained release vehicle

Diederik H. R. Kempen; Michael J. Yaszemski; Andras Heijink; Theresa E. Hefferan; Laura B. Creemers; Jason Britson; Avudaiappan Maran; Kelly L. Classic; Wouter J. A. Dhert; Lichun Lu

2009-01-01

135

Bone formation in rabbit's leg muscle after autologous transplantation of bone marrow-derived mesenchymal stem cells expressing human bone morphogenic protein-2  

PubMed Central

Background: To test whether autologous transplantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) expressing human bone morphogenic protein-2 (hBMP-2) can produce bone in rabbit leg muscles. Materials and Methods: MSCs were isolated from BM of the iliac crest of rabbits and then infected with lentiviral vectors (LVs) bearing hBMP-2 and green fluorescent protein under the control of the cytomegalovirus (immediate early promoter). Differentiation of transduced MSCs to osteoblasts in vitro was evaluated with an alkaline phosphatase activity assay and immuohistochemistry against osteoblast specific markers. MSCs expressing hBMP-2 were placed in an absorbable gelatin sponge, which was then transplanted into the gastrocnemius of rabbits from which MSCs were isolated. Bone formation was examined by X-ray and histological analysis. Results: LVs efficiently mediated hBMP-2 gene expression in rabbit BM-MSCs. Ectopic expression of hBMP in these MSCs induced osteoblastic differentiation in vitro. Bone was formed after the MSCs expressing hBMP-2 were transplanted into rabbit muscles. Conclusion: Ectopic expression of hBMP-2 in rabbit MSCs induces them to differentiate into osteoblasts in vitro and to form a bone in vivo. PMID:25143636

Wei, Licheng; Lei, Guang-Hua; Yi, Han-Wen; Sheng, Pu-yi

2014-01-01

136

Effect of coating Straumann Bone Ceramic with Emdogain on mesenchymal stromal cell hard tissue formation.  

PubMed

Periodontal tissue engineering requires a suitable biocompatible scaffold, cells with regenerative capacity, and instructional molecules. In this study, we investigated the capacity of Straumann Bone Ceramic coated with Straumann Emdogain, a clinical preparation of enamel matrix protein (EMP), to aid in hard tissue formation by post-natal mesenchymal stromal cells (MSCs) including bone marrow stromal cells (BMSCs) and periodontal ligament fibroblasts (PDLFs). MSCs were isolated and ex vivo-expanded from human bone marrow and periodontal ligament and, in culture, allowed to attach to Bone Ceramic in the presence or absence of Emdogain. Gene expression of bone-related proteins was investigated by real time RT-PCR for 72 h, and ectopic bone formation was assessed histologically in subcutaneous implants of Bone Ceramic containing MSCs with or without Emdogain in NOD/SCID mice. Alkaline phosphatase activity was also assessed in vitro, in the presence or absence of Emdogain. Collagen-I mRNA was up-regulated in both MSC populations over the 72-h time course with Emdogain. Expression of BMP-2 and the osteogenic transcription factor Cbfa-1 showed early stimulation in both MSC types after 24 h. In contrast, expression of BMP-4 was consistently down-regulated in both MSC types with Emdogain. Up-regulation of osteopontin and periostin mRNA was restricted to BMSCs, while higher levels of bone sialoprotein-II were observed in PDLFs with Emdogain. Furthermore, alkaline phosphatase activity levels were reduced in both BMSCs and PDLFs in the presence of Emdogain. Very little evidence was found for ectopic bone formation following subcutaneous implantation of MSCs with Emdogain-coated or -uncoated Bone Ceramic in NOD/SCID mice. The early up-regulation of several important bone-related genes suggests that Emdogain may have a significant stimulatory effect in the commitment of mesenchymal cells to osteogenic differentiation in vitro. While Emdogain inhibited AP activity and appeared not to induce ectopic bone formation, longer-term studies are required to determine whether it promotes the final stages of osteoblast formation and mineralization at gene and protein levels. While used in clinical applications, whether Emdogain and other commercial preparations of EMPs truly possess the capacity to induce the regeneration of bone or other components of the periodontium remains to be established. PMID:21584694

Mrozik, Krzysztof Marek; Gronthos, Stan; Menicanin, Danijela; Marino, Victor; Bartold, P Mark

2012-06-01

137

Palm Tocotrienol Supplementation Enhanced Bone Formation in Oestrogen-Deficient Rats  

PubMed Central

Postmenopausal osteoporosis is the commonest cause of osteoporosis. It is associated with increased free radical activity induced by the oestrogen-deficient state. Therefore, supplementation with palm-oil-derived tocotrienols, a potent antioxidant, should be able to prevent this bone loss. Our earlier studies have shown that tocotrienol was able to prevent and even reverse osteoporosis due to various factors, including oestrogen deficiency. In this study we compared the effects of supplementation with palm tocotrienol mixture or calcium on bone biomarkers and bone formation rate in ovariectomised (oestrogen-deficient) female rats. Our results showed that palm tocotrienols significantly increased bone formation in oestrogen-deficient rats, seen by increased double-labeled surface (dLS/Bs), reduced single-labeled surface (sLS/BS), increased mineralizing surface (MS/BS), increased mineral apposition rate (MAR), and an overall increase in bone formation rate (BFR/BS). These effects were not seen in the group supplemented with calcium. However, no significant changes were seen in the serum levels of the bone biomarkers, osteocalcin, and cross-linked C-telopeptide of type I collagen, CTX. In conclusion, palm tocotrienol is more effective than calcium in preventing oestrogen-deficient bone loss. Further studies are needed to determine the potential of tocotrienol as an antiosteoporotic agent. PMID:23150728

Soelaiman, Ima Nirwana; Ming, Wang; Abu Bakar, Roshayati; Hashnan, Nursyahrina Atiqah; Mohd Ali, Hanif; Mohamed, Norazlina; Muhammad, Norliza; Shuid, Ahmad Nazrun

2012-01-01

138

Mechanical Load Increases in Bone Formation via a Sclerostin-Independent Pathway.  

PubMed

Sclerostin, encoded by the Sost gene, is an important negative regulator of bone formation that has been proposed to have a key role in regulating the response to mechanical loading. To investigate the effect of long-term Sclerostin deficiency on mechanotransduction in bone, we performed experiments on unloaded or loaded tibiae of 10 week old female Sost-/- and wild type mice. Unloading was induced via 0.5U botulinum toxin (BTX) injections into the right quadriceps and calf muscles, causing muscle paralysis and limb disuse. On a separate group of mice, increased loading was performed on the left tibiae through unilateral cyclic axial compression of equivalent strains (+1200?µe) at 1200 cycles/day, 5 days/week. Another cohort of mice receiving equivalent loads (-9.0?N) also were assessed. Contralateral tibiae served as normal load controls. Loaded/unloaded and normal load tibiae were assessed at day 14 for bone volume (BV) and formation changes. Loss of BV was seen in the unloaded tibiae of wild type mice, but BV was not different between normal load and unloaded Sost-/- tibiae. An increase in BV was seen in the loaded tibiae of wild type and Sost-/- mice over their normal load controls. The increased BV was associated with significantly increased mid-shaft periosteal mineralizing surface/bone surface (MS/BS), mineral apposition rate (MAR), and bone formation rate/bone surface (BFR/BS), and endosteal MAR and BFR/BS. Notably, loading induced a greater increase in periosteal MAR and BFR/BS in Sost-/- mice than in wild type controls. Thus, long-term Sclerostin deficiency inhibits the bone loss normally induced with decreased mechanical load, but it can augment the increase in bone formation with increased load. © 2014 American Society for Bone and Mineral Research. PMID:24821585

Morse, A; McDonald, Mm; Kelly, Nh; Melville, Km; Schindeler, A; Kramer, I; Kneissel, M; van der Meulen, McH; Little, Dg

2014-11-01

139

Identification of Mechanosensitive Genes during Embryonic Bone Formation  

Microsoft Academic Search

Although it is known that mechanical forces are needed for normal bone development, the current understanding of how biophysical stimuli are interpreted by and integrated with genetic regulatory mechanisms is limited. Mechanical forces are thought to be mediated in cells by ''mechanosensitive'' genes, but it is a challenge to demonstrate that the genetic regulation of the biological system is dependant

Niamh C. Nowlan; Patrick J. Prendergast; Paula Murphy

2008-01-01

140

Ectopic Osteoid and Bone Formation by Three Calcium-Phosphate Ceramics in Rats, Rabbits and Dogs  

PubMed Central

Calcium phosphate ceramics with specific physicochemical properties have been shown to induce de novo bone formation upon ectopic implantation in a number of animal models. In this study we explored the influence of physicochemical properties as well as the animal species on material-induced ectopic bone formation. Three bioceramics were used for the study: phase-pure hydroxyapatite (HA) sintered at 1200°C and two biphasic calcium phosphate (BCP) ceramics, consisting of 60 wt.% HA and 40 wt.% TCP (?-Tricalcium phosphate), sintered at either 1100°C or 1200°C. 108 samples of each ceramic were intramuscularly implanted in dogs, rabbits, and rats for 6, 12, and 24 weeks respectively. Histological and histomorphometrical analyses illustrated that ectopic bone and/or osteoid tissue formation was most pronounced in BCP sintered at 1100°C and most limited in HA, independent of the animal model. Concerning the effect of animal species, ectopic bone formation reproducibly occurred in dogs, while in rabbits and rats, new tissue formation was mainly limited to osteoid. The results of this study confirmed that the incidence and the extent of material-induced bone formation are related to both the physicochemical properties of calcium phosphate ceramics and the animal model. PMID:25229501

Wang, Liao; Zhang, Bi; Bao, Chongyun; Habibovic, Pamela; Hu, Jing; Zhang, Xingdong

2014-01-01

141

Bare Bones Pattern Formation: A Core Regulatory Network in Varying Geometries Reproduces Major  

E-print Network

Bare Bones Pattern Formation: A Core Regulatory Network in Varying Geometries Reproduces Major-D) and anteroposterior (A-P) axes are determined and how the shape of a growing limb affects skeletal element formation. Hypothetical developmental scenarios reproduce skeletal morphologies with features of fossil limbs. Conclusions

Zhang, Yong-Tao

142

Enhanced Control of In Vivo Bone Formation with Surface Functionalized Alginate Microbeads Incorporating Heparin and Human Bone Morphogenetic Protein-2  

PubMed Central

In this study, we tested the hypothesis that a surface functionalization delivery platform incorporating heparin onto strontium alginate microbeads surfaces would convert this “naive carriers” into “mini-reservoirs” for localized in vivo delivery of recombinant human bone morphogenetic protein-2 (rhBMP-2) that will induce functional bone regeneration. In vitro evaluation confirmed that (1) heparin incorporation could immobilize and prolong rhBMP-2 release for approximately 3 weeks; (2) a significant decrease (p<0.01) in rhBMP-2 burst release is attainable depending on initial protein load; and (3) rhBMP-2 released from surface functionalized microbeads retained bioactivity and stimulated higher alkaline phosphatase activity in cultured C2C12 cells when compared with daily administration of fresh bolus rhBMP-2. Subsequently, surface functionalized microbeads were used for in vivo delivery of rhBMP-2 at local sites of posterolateral spinal fusion surgery in rats. The microbeads were loaded into the pores of medical-grade polyepsilone caprolactone-tricalcium phosphate scaffolds before implantation. Results revealed robust bone formation and a biomechanically solid fusion after 6 weeks. When compared with a control group consisting of an equivalent amount of rhBMP-2 that was directly adsorbed onto bare-surfaced microbeads with no heparin, a 5.3-fold increase in bone volume fraction and a 2.6-fold increase in bending stiffness (flexion/extension) were observed. When compared with collagen sponge carriers of rhBMP-2, a 1.5-fold and a 1.3-fold increase in bone volume fraction and bending stiffness were observed, respectively. More importantly, 3D micro-computed tomography images enabled the visualization of a well-contained newly formed bone at ipsilateral implant sites with surface functionalized rhBMP-2 delivery. This was absent with collagen sponge carriers where newly formed bone tissue was poorly contained and crossed over the posterior midline to contralateral implants. These findings are important because of complications with current rhBMP-2 delivery method, including excessive, uncontrolled bone formation. PMID:22894570

Abbah, Sunny Akogwu; Liu, Jing; Goh, James Cho Hong

2013-01-01

143

Id1 Represses Osteoclast-Dependent Transcription and Affects Bone Formation and Hematopoiesis  

PubMed Central

Background The bone-bone marrow interface is an area of the bone marrow microenvironment in which both bone remodeling cells, osteoblasts and osteoclasts, and hematopoietic cells are anatomically juxtaposed. The close proximity of these cells naturally suggests that they interact with one another, but these interactions are just beginning to be characterized. Methodology/Principal Findings An Id1?/? mouse model was used to assess the role of Id1 in the bone marrow microenvironment. Micro-computed tomography and fracture tests showed that Id1?/? mice have reduced bone mass and increased bone fragility, consistent with an osteoporotic phenotype. Osteoclastogenesis and pit formation assays revealed that loss of Id1 increased osteoclast differentiation and resorption activity, both in vivo and in vitro, suggesting a cell autonomous role for Id1 as a negative regulator of osteoclast differentiation. Examination by flow cytometry of the hematopoietic compartment of Id1?/? mice showed an increase in myeloid differentiation. Additionally, we found increased expression of osteoclast genes, TRAP, Oscar, and CTSK in the Id1?/? bone marrow microenvironment. Lastly, transplantation of wild-type bone marrow into Id1?/? mice repressed TRAP, Oscar, and CTSK expression and activity and rescued the hematopoietic and bone phenotype in these mice. Conclusions/Significance In conclusion, we demonstrate an osteoporotic phenotype in Id1?/? mice and a mechanism for Id1 transcriptional control of osteoclast-associated genes. Our results identify Id1 as a principal player responsible for the dynamic cross-talk between bone and bone marrow hematopoietic cells. PMID:19956687

Doty, Stephen; Lederman, Hannah K.; Kaplan, Rosandra N.; Rafii, Shahin; Rivella, Stefano; Lyden, David

2009-01-01

144

Long-term anabolic effects of prostaglandin-E2 on tibial diaphyseal bone in male rats  

NASA Technical Reports Server (NTRS)

The effects of long-term prostaglandin E2 (PGE2) on tibial diaphyseal bone were studied in 7-month-old male Sprague-Dawley rats given daily subcutaneous injections of 0, 1, 3 and 6 mg PGE2/kg/day for 60, 120 and 180 days. The tibial shaft was measured by single photon absorptiometry and dynamic histomorphometric analyses were performed on double-fluorescent labeled undecalcified tibial diaphyseal bone samples. Exogenous PGE2 administration produced the following transient changes in a dose-response manner between zero and 60 days: (1) increased bone width and mineral density; (2) increased total tissue and total bone areas; (3) decreased marrow area; (4) increased periosteal and corticoendosteal lamellar bone formation; (5) activated corticoendosteal lamellar and woven trabecular bone formation; and (6) activated intracortical bone remodeling. A new steady-state of increased tibial diaphyseal bone mass and elevated bone activities were observed from day 60 onward. The elevated bone mass level attained after 60 days of PGE2 treatment was maintained at 120 and 180 days. These observations indicate that the powerful anabolic effects of PGE2 will increase both periosteal and corticoendosteal bone mass and sustain the transient increase in bone mass with continuous daily administration of PGE2.

Jee, Webster S. S.; Ke, Hua Zhu; Li, Xiao Jian

1991-01-01

145

Hydroxyapatite coating for titanium fibre mesh scaffold enhances osteoblast activity and bone tissue formation.  

PubMed

This study investigated the bone regeneration properties of titanium fibre mesh as a tissue engineering material. A thin hydroxyapatite (HA) coating on the titanium fibre web was created using the developed molecular precursor method without losing the complex interior structure. HA-coated titanium fibre mesh showed apatite crystal formation in vitro in a human osteoblast culture. Titanium fibre mesh discs with or without a thin HA coating were implanted into rat cranial bone defects, and the animals were killed at 2 and 4 weeks. The in vivo experience revealed that the amount of newly formed bone was significantly higher in the HA-coated titanium fibre mesh than in the non-coated titanium fibre mesh 2 weeks after implantation. These results suggest that thin HA coating enhances osteoblast activity and bone regeneration in the titanium fibre mesh scaffold. Thin HA-coating improved the ability of titanium fibre mesh to act as a bone regeneration scaffold. PMID:22513355

Hirota, Makoto; Hayakawa, Tohru; Yoshinari, Masao; Ametani, Akihiro; Shima, Takaki; Monden, Yuka; Ozawa, Tomomichi; Sato, Mitsunobu; Koyama, Chika; Tamai, Naoto; Iwai, Toshinori; Tohnai, Iwai

2012-10-01

146

Geochemical and mineralogical studies of dinosaur bone from the Morrison Formation at Dinosaur Ridge  

USGS Publications Warehouse

The dinosaur bones first discovered in 1877 in the Upper Jurassic Morrison Formation at Morrison, Colorado were the first major find of dinosaur skeletons in the western U.S. and led to the recognition of four new dinosaur genera (Apatosaurus, Allosaurus, Diplodocus, and Stegosaurus). Eight articles dealing with these bones which appeared as research reports in the annual reports of the Friends of Dinosaur Ridge from 1990-1999 are condensed and summarized with some additional comments. Two of the articles are about the mineralogy and preservation of the bones; two are about the physical description of the bone occurrence; two are about the history of the site, and two are about use of novel instrumental methods (ground-penetrating radar and a directional scintillometer) to search for new bones.

Modreski, P.J.

2001-01-01

147

Premature loss of bone remodeling compartment canopies is associated with deficient bone formation: a study of healthy individuals and patients with Cushing's syndrome.  

PubMed

A remarkable property of bone remodeling is that osteoblasts form bone matrix exactly where and when osteoclasts have removed it. The bone remodeling compartment (BRC) canopies that cover bone surfaces undergoing remodeling were proposed to be critical players in this mechanism. Here, we provide support to this hypothesis by analyzing the changes in prevalence of BRC canopies during the progress of the remodeling cycle in a cohort of healthy individuals and in patients with endogenous Cushing's syndrome (CS), and by relating these changes in prevalence with the extent of bone forming surfaces. Both cohorts showed almost 100% canopy coverage above resorbing osteoclasts, and only about 76% above bone forming surfaces. This indicates that BRC canopies are invariably associated with the early stage of the remodeling cycle, but may disappear later. Interestingly, in control and two-thirds of the CS patients, a significant decline in canopy coverage occurred only once bone formation was initiated, but in the remaining third of the CS patients the prevalence of canopies already decreased before bone formation. This canopy loss before initiation of bone formation coincided with significantly less bone-forming surface compared with canopy loss at a later stage. These observations support a model where bone restitution is compromised in the absence of BRC canopies, and apparently does not start when the BRC canopy is lost before initiation of the bone formation step. This model is discussed in the context of possible biological roles of BRC canopies. It suggests that BRC canopies could be privileged targets for treating patients suffering from a negative bone formation-resorption balance. PMID:22162180

Jensen, Pia Rosgaard; Andersen, Thomas Levin; Søe, Kent; Hauge, Ellen Margrethe; Bollerslev, Jens; Amling, Michael; Barvencik, Florian; Delaissé, Jean-Marie

2012-04-01

148

Creep of fully lamellar near {gamma}-TiAl intermetallics  

SciTech Connect

The influence of the fully lamellar morphology and third phase {beta} on the creep properties of near {gamma}-TiAl intermetallics is presented. Specifically, the effect of improved microstructural control obtainable by a stepped cool, involving furnace cooling and air cooling from the {alpha} single phase, on creep resistance is demonstrated for three near {gamma}-TiAl intermetallics: binary Ti-48Al, ternary Ti-48Al-2W and Ti-47Al-2Nb-1Mn-0.5W-0.5Mo-0.2Si. The results indicate that appropriate stepped cooling can be used to reduce the lamellar interface spacing without the formation of Widmanstaetten, feathery {gamma} or {gamma}{sub M} structures, leading to longer creep life and reduced creep strain rates. A second benefit of stepped cooling is prevention of {beta} formation during cooling from the {alpha} phase, allowing controlled {beta} precipitation during aging at 950 C. Creep tests on variously aged Ti-48Al-2W indicate that {beta} precipitation along lamellar grain boundaries improves creep resistance. Development of a uniform fully lamellar structure in Ti-47Al-2Nb-1Mn-0.5W-0.5Mo-0.2Si significantly improves creep resistance. Applying the stepped cool to this alloy allows the precipitation of {beta} and silicides to be controlled during lower temperature aging.

Beddoes, J.; Zhao, L.; Chen, W.R.; Du, X.

1999-07-01

149

Formation of a calcium phosphate-rich layer on absorbable calcium carbonate bone graft substitutes  

Microsoft Academic Search

The use of natural coral as a bone graft substitute is common in Europe. However, the bone-coral bonding mechanism remains elusive. A rat subcutaneous model was used to demonstrate changes at the surface of resorbable calcium carbonate in the form of natural coral. Histological results indicated in vivo formation of a calcium phosphate (CaP)-rich layer on the surface of the

C. J. Damien; J. L. Ricci; P. Christel; H. Alexander; J.-L. Patat

1994-01-01

150

Engineering anatomically shaped human bone grafts  

PubMed Central

The ability to engineer anatomically correct pieces of viable and functional human bone would have tremendous potential for bone reconstructions after congenital defects, cancer resections, and trauma. We report that clinically sized, anatomically shaped, viable human bone grafts can be engineered by using human mesenchymal stem cells (hMSCs) and a “biomimetic” scaffold-bioreactor system. We selected the temporomandibular joint (TMJ) condylar bone as our tissue model, because of its clinical importance and the challenges associated with its complex shape. Anatomically shaped scaffolds were generated from fully decellularized trabecular bone by using digitized clinical images, seeded with hMSCs, and cultured with interstitial flow of culture medium. A bioreactor with a chamber in the exact shape of a human TMJ was designed for controllable perfusion throughout the engineered construct. By 5 weeks of cultivation, tissue growth was evidenced by the formation of confluent layers of lamellar bone (by scanning electron microscopy), markedly increased volume of mineralized matrix (by quantitative microcomputer tomography), and the formation of osteoids (histologically). Within bone grafts of this size and complexity cells were fully viable at a physiologic density, likely an important factor of graft function. Moreover, the density and architecture of bone matrix correlated with the intensity and pattern of the interstitial flow, as determined in experimental and modeling studies. This approach has potential to overcome a critical hurdle—in vitro cultivation of viable bone grafts of complex geometries—to provide patient-specific bone grafts for craniofacial and orthopedic reconstructions. PMID:19820164

Grayson, Warren L.; Frohlich, Mirjam; Yeager, Keith; Bhumiratana, Sarindr; Chan, M. Ete; Cannizzaro, Christopher; Wan, Leo Q.; Liu, X. Sherry; Guo, X. Edward; Vunjak-Novakovic, Gordana

2009-01-01

151

Formation of engineered bone with adipose stromal cells from buccal fat pad.  

PubMed

A robust method for inducing bone formation from adipose-derived stromal cells (ADSCs) has not been established. Moreover, the efficacy of strong osteogenic inducers including BMP-2 for ADSC-mediated bone engineering remains controversial. Meanwhile, the buccal fat pad (BFP), which is found in the oral cavity as an adipose-encapsulated mass, has been shown to have potential as a new accessible source of ADSCs for oral surgeons. However, to date, there have been no reports that define the practical usefulness of ADSCs from BFP (B-ADSCs) for bone engineering. Here, we report an efficient method of generating bone from B-ADSCs using rhBMP-2. The analyses show that B-ADSCs can differentiate in vitro toward the osteoblastic lineage by the addition of rhBMP-2 to culture medium, regardless of the presence of osteoinductive reagents (OSR), as demonstrated by measurements of ALP activity, in vitro calcification, and osteogenic gene expression. Interestingly, adipogenic genes were clearly detectable only in cultures with rhBMP-2 and OSR. However, in vivo bone formation was most substantial when B-ADSCs cultured in this condition were transplanted. Thus, B-ADSCs reliably formed engineered bone when pre-treated with rhBMP-2 for inducing mature osteoblastic differentiation. This study supports the potential translation for B-ADSC use in the clinical treatment of bone defects. PMID:22538411

Shiraishi, T; Sumita, Y; Wakamastu, Y; Nagai, K; Asahina, I

2012-06-01

152

Exercise-Induced Bone Formation Is Poorly Linked to Local Strain Magnitude in the Sheep Tibia  

PubMed Central

Functional interpretations of limb bone structure frequently assume that diaphyses adjust their shape by adding bone primarily across the plane in which they are habitually loaded in order to minimize loading-induced strains. Here, to test this hypothesis, we characterize the in vivo strain environment of the sheep tibial midshaft during treadmill exercise and examine whether this activity promotes bone formation disproportionately in the direction of loading in diaphyseal regions that experience the highest strains. It is shown that during treadmill exercise, sheep tibiae were bent in an anteroposterior direction, generating maximal tensile and compressive strains on the anterior and posterior shaft surfaces, respectively. Exercise led to significantly increased periosteal bone formation; however, rather than being biased toward areas of maximal strains across the anteroposterior axis, exercise-related osteogenesis occurred primarily around the medial half of the shaft circumference, in both high and low strain regions. Overall, the results of this study demonstrate that loading-induced bone growth is not closely linked to local strain magnitude in every instance. Therefore, caution is necessary when bone shaft shape is used to infer functional loading history in the absence of in vivo data on how bones are loaded and how they actually respond to loading. PMID:24897411

Wallace, Ian J.; Demes, Brigitte; Mongle, Carrie; Pearson, Osbjorn M.; Polk, John D.; Lieberman, Daniel E.

2014-01-01

153

Effects of preparation methods on the bone formation potential of apatite-coated chitosan microspheres.  

PubMed

To investigate the effects of preparation methods on the bone formation potential of apatite-coated chitosan microspheres, coacervate precipitation method and emulsion cross-linking method were chosen to prepare chitosan microspheres, and then apatite coatings were deposited using simulated body fluid. Rat bone marrow-derived mesenchymal stem cells (BMSCs) were seeded on these microspheres. Cell adhesion, proliferation, and differentiation potential were monitored. For in vivo analysis, some cell/microsphere constructs were implanted in the subcutaneous pockets of male Wistar rats. After 3, 6, 12 weeks, the samples were retrieved and stained with hematoxylin and eosin (HE). Some cell/microsphere constructs were implanted in the calvarial defects of rats. Micro-CT and HE analysis were performed to analyze the new bone formation. It was found that BMSCs on apatite-coated emulsion cross-linked microspheres (EM1) exhibited better proliferation and differentiation than cells on apatite-coated coacervate-precipitated microspheres. The in vivo results showed that no bone was observed in ectopic areas. While in calvarial defects, both histological slices and Micro-CT images demonstrated that a substantial amount of new bone was formed in the EM1/BMSCs construct. These data suggest that preparation methods do exert great influence on the in vitro cell behaviors and in vivo orthotopic bone regeneration of apatite-coated chitosan microspheres. Appropriate method should be considered when preparing chitosan microspheres for bone tissue engineering scaffold. PMID:25324120

Xu, Fei; Ding, Huifen; Song, Fangfang; Wang, Jiawei

2014-12-01

154

FAD104, a Regulatory Factor of Adipogenesis, Acts as a Novel Regulator of Calvarial Bone Formation*  

PubMed Central

Osteogenesis is a complex process that is orchestrated by several growth factors, extracellular cues, signaling molecules, and transcriptional factors. Understanding the mechanisms of bone formation is pivotal for clarifying the pathogenesis of bone diseases. Previously, we reported that fad104 (factor for adipocyte differentiation 104), a novel positive regulator of adipocyte differentiation, negatively regulated the differentiation of mouse embryonic fibroblasts into osteocytes. However, the physiological role of fad104 in bone formation has not been elucidated. Here, we clarified the role of fad104 in bone formation in vivo and in vitro. fad104 disruption caused craniosynostosis-like premature ossification of the calvarial bone. Furthermore, analyses using primary calvarial cells revealed that fad104 negatively regulated differentiation and BMP/Smad signaling pathway. FAD104 interacted with Smad1/5/8. The N-terminal region of FAD104, which contains a proline-rich motif, was capable of binding to Smad1/5/8. We demonstrated that down-regulation of Smad1/5/8 phosphorylation by FAD104 is dependent on the N-terminal region of FAD104 and that fad104 functions as a novel negative regulator of BMP/Smad signaling and is required for proper development for calvarial bone. These findings will aid a comprehensive description of the mechanism that controls normal and premature calvarial ossification. PMID:24052261

Kishimoto, Keishi; Nishizuka, Makoto; Katoh, Daiki; Kato, Ayumi; Osada, Shigehiro; Imagawa, Masayoshi

2013-01-01

155

WNT7B Promotes Bone Formation in part through mTORC1  

PubMed Central

WNT signaling has been implicated in both embryonic and postnatal bone formation. However, the pertinent WNT ligands and their downstream signaling mechanisms are not well understood. To investigate the osteogenic capacity of WNT7B and WNT5A, both normally expressed in the developing bone, we engineered mouse strains to express either protein in a Cre-dependent manner. Targeted induction of WNT7B, but not WNT5A, in the osteoblast lineage dramatically enhanced bone mass due to increased osteoblast number and activity; this phenotype began in the late-stage embryo and intensified postnatally. Similarly, postnatal induction of WNT7B in Runx2-lineage cells greatly stimulated bone formation. WNT7B activated mTORC1 through PI3K-AKT signaling. Genetic disruption of mTORC1 signaling by deleting Raptor in the osteoblast lineage alleviated the WNT7B-induced high-bone-mass phenotype. Thus, WNT7B promotes bone formation in part through mTORC1 activation. PMID:24497849

Chen, Jianquan; Tu, Xiaolin; Esen, Emel; Joeng, Kyu Sang; Lin, Congxin; Arbeit, Jeffrey M.; Ruegg, Markus A.; Hall, Michael N.; Ma, Liang; Long, Fanxin

2014-01-01

156

Fibrillin-1 and -2 differentially modulate endogenous TGF-? and BMP bioavailability during bone formation.  

PubMed

Extracellular regulation of signaling by transforming growth factor (TGF)-? family members is emerging as a key aspect of organ formation and tissue remodeling. In this study, we demonstrate that fibrillin-1 and -2, the structural components of extracellular microfibrils, differentially regulate TGF-? and bone morphogenetic protein (BMP) bioavailability in bone. Fibrillin-2-null (Fbn2(-/-)) mice display a low bone mass phenotype that is associated with reduced bone formation in vivo and impaired osteoblast maturation in vitro. This Fbn2(-/-) phenotype is accounted for by improper activation of latent TGF-? that selectively blunts expression of osterix, the transcriptional regulator of osteoblast maturation, and collagen I, the structural template for bone mineralization. Cultured osteoblasts from Fbn1(-/-) mice exhibit improper latent TGF-? activation as well, but mature faster because of increased availability of otherwise matrix-bound BMPs. Additional in vitro evidence excludes a direct role of microfibrils in supporting mineral deposition. Together, these findings identify the extracellular microfibrils as critical regulators of bone formation through the modulation of endogenous TGF-? and BMP signaling. PMID:20855508

Nistala, Harikiran; Lee-Arteaga, Sui; Smaldone, Silvia; Siciliano, Gabriella; Carta, Luca; Ono, Robert N; Sengle, Gerhard; Arteaga-Solis, Emilio; Levasseur, Regis; Ducy, Patricia; Sakai, Lynn Y; Karsenty, Gerard; Ramirez, Francesco

2010-09-20

157

Vascularized Bone Tissue Formation Induced by Fiber-Reinforced Scaffolds Cultured with Osteoblasts and Endothelial Cells  

PubMed Central

The repair of the damaged bone tissue caused by damage or bone disease was still a problem. Current strategies including the use of autografts and allografts have the disadvantages, namely, diseases transmission, tissue availability and donor morbidity. Bone tissue engineering has been developed and regarded as a new way of regenerating bone tissues to repair or substitute damaged or diseased ones. The main limitation in engineering in vitro tissues is the lack of a sufficient blood vessel system, the vascularization. In this paper, a new-typed hydroxyapatite/collagen composite scaffold which was reinforced by chitosan fibers and cultured with osteoblasts and endothelial cells was fabricated. General observation, histological observation, detection of the degree of vascularization, and X-ray examination had been done to learn the effect of vascularized bone repair materials on the regeneration of bone. The results show that new vessel and bone formed using implant cultured with osteoblasts and endothelial cells. Nanofiber-reinforced scaffold cultured with osteoblasts and endothelial cells can induce vascularized bone tissue formation. PMID:24369019

Liu, Xinhui; Zhang, Guoping; Hou, Chuanyong; Wang, Hua; Yang, Yelin; Guan, Guoping; Dong, Wei; Gao, Hongyang

2013-01-01

158

Is Lipid Profile Associated with Bone Mineral Density and Bone Formation in Subjects with Spinal Cord Injury?  

PubMed Central

Purpose. The association between serum lipids and bone mineral density (BMD) has been investigated previously but, up to now, these relationships have not yet been described in spinal cord injury (SCI). We tried to assess the correlation between serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) and BMD in male subjects with SCI. Methods. Dual-energy X-ray absorptiometry (DXA) was used to assess BMD in femoral neck, trochanter, intertrochanteric zone, and lumbar vertebras. Blood samples were taken to measure serums lipids and bone biomarkers including osteocalcin, cross-linked type I collagen (CTX), and bone alkaline phosphatase (BALP). Partial correlation analysis was used to evaluate the relationships between mentioned measurements after adjustment for weight and age. Results. We found a positive correlation between HDL and femoral neck BMD (P: 0.004, r = 0.33). HDL was negatively correlated with osteocalcin (P: 0.017, r = ?0.31) which was not in consistency with its relationship with BMD. TC and LDL were not related to CTX, BALP and BMD. Conclusion. This study does not support a strong association between serum lipids and BMD in subjects with SCI. Moreover it seems that positive association between HDL and BMD is not mediated through increased bone formation.

Sabour, Hadis; Norouzi Javidan, Abbas; Latifi, Sahar; Hadian, Mohammad Reza; Emami Razavi, Seyed-Hassan; Shidfar, Farzad; Vafa, Mohammad Reza; Aghaei Meybodi, Hamidreza

2014-01-01

159

Soluble and insoluble signals and the induction of bone formation: molecular therapeutics recapitulating development  

PubMed Central

The osteogenic molecular signals of the transforming growth factor-? (TGF-?) superfamily, the bone morphogenetic/osteogenic proteins (BMPs/OPs) and uniquely in primates the TGF-? isoforms per se, pleiotropic members of the TGF-? supergene family, induce de novo endochondral bone formation as a recapitulation of embryonic development. Naturally derived BMPs/OPs and gamma-irradiated human recombinant osteogenic protein-1 (hOP-1) delivered by allogeneic and xenogeneic insoluble collagenous matrices initiate de novo bone induction in heterotopic and orthotopic sites of the primate Papio ursinus, culminating in complete calvarial regeneration by day 90 and maintaining the regenerated structures by day 365. The induction of bone by hOP-1 in P. ursinus develops as a mosaic structure with distinct spatial and temporal patterns of gene expression of members of the TGF-? superfamily that singly, synergistically and synchronously initiate and maintain tissue induction and morphogenesis. The temporal and spatial expressions of TGF-?1 mRNA indicate a specific temporal transcriptional window during which expression of TGF-?1 is mandatory for successful and optimal osteogenesis. Highly purified naturally derived bovine BMPs/OPs and hOP-1 delivered by human collagenous bone matrices and porous hydroxyapatite, respectively, induce bone formation in mandibular defects of human patients. By using healthy body sites as bioreactors it is possible to recapitulate embryonic developments by inducing selected biomaterials combined with recombinant proteins to transform into custom-made prefabricated bone grafts for human reconstruction. The osteogenic proteins of the TGF-? superfamily, BMPs/OPs and TGF-?s, the last endowed with the striking prerogative of inducing endochondral bone formation in primates only, are helping to engineer skeletal reconstruction in molecular terms. PMID:17005018

Ripamonti, Ugo; Ferretti, C; Heliotis, M

2006-01-01

160

Titanium nanotubes activate genes related to bone formation in vitro  

PubMed Central

Background: Titanium is used worldwide to make osseointegrable devices, thanks to its favorable characteristics as mechanical proprieties and biocompatibility, demonstrated by in vivo studies with animal models and clinical trials over a forty-year period. However, the exact genetic effect of the titanium layer on cells is still not well characterized. Materials and Methods: To investigate how titanium nanotubes stimulate osteoblasts differentiation and proliferation, some osteoblast genes (SP7, RUNX2, COL3A1, COL1A1, ALPL, SPP1 and FOSL1) were analyzed by quantitative Real Time RT- PCR. Results: After 15 days, osteoblasts cultivated on titanium naotube showed the up-regulation of bone related genes SP7, ENG, FOSL1 and SPP1 and the down-regulation of RUNX2, COL3A1, COL1A1, and ALPL. After 30 days of treatment, the bone related genes SP7, ENG, FOSL1 and RUNX2 were up-regulated while COL3A1, COL1A1, ALPL and SPP1 were down-regulated. Conclusions: Our results, demonstrates that titanium nanotubes can lead to osteoblast differentiation and extracellular matrix deposition and mineralization in dental pulp stem cells by the activation of osteoblast related genes SPP1, FOSL1 and RUNX2. PMID:23814577

Pozio, Alfonso; Palmieri, Annalisa; Girardi, Ambra; Cura, Francesca; Carinci, Francesco

2012-01-01

161

The Novel Zinc Finger-Containing Transcription Factor Osterix Is Required for Osteoblast Differentiation and Bone Formation  

Microsoft Academic Search

We have identified a novel zinc finger-containing transcription factor, called Osterix (Osx), that is specifically expressed in all developing bones. In Osx null mice, no bone formation occurs. In endochondral skeletal elements of Osx null mice, mesenchymal cells, together with osteoclasts and blood vessels, invade the mineralized cartilage matrix. However, the mesenchymal cells do not deposit bone matrix. Similarly, cells

Kazuhisa Nakashima; Xin Zhou; Gary Kunkel; Zhaoping Zhang; Jian Min Deng; Richard R. Behringer; Benoit de Crombrugghe

2002-01-01

162

Advanced Molecular Profiling in Vivo Detects Novel Function of Dickkopf-3 in the Regulation of Bone Formation  

E-print Network

development(1) and fracture healing.(2) Endochondral bone formation is a multistep process that involves to verify and understand the complexity of endochondral bone forma- tion. In a rat fracture model, severalAdvanced Molecular Profiling in Vivo Detects Novel Function of Dickkopf-3 in the Regulation of Bone

Domany, Eytan

163

Partial Loss of Anabolic Effect of Prostaglandin E2 on Bone After Its Withdrawal in Rats  

NASA Technical Reports Server (NTRS)

The object of this study was to determine the fate of PGE(sub 2)-induced new bone mass after withdrawal of PGE(sub 2) administration. Seven-month-old male Sprague-Dawley rats were given subcutaneous injections of 1, 3, and 6 mg PGE(sub 2)/kg/d for 60 days and then withdrawn for 60 and 120 days. Histomorphometric analyses were performed on double fluorescent labeled undecalcified proximal tibial bone specimens. After 60 days of PGE(sub 2) treatment, a new steady state of increased trabecular bone area (+67% and +81% with 3 and 6 mg PGE(sub 2)/kg/d) from woven bone and stimulated lamellar bone formation, elevated bone turnover, and shortened remodeling periods were achieved compared to age-matched controls. In contrast, after 60 and 120 days withdrawal of PGE(sub 2), a new steady state characterized by less trabecular bone area (+40% to +60% of controls with 3 and 6 mg/kg/d doses), normal lamellar bone formation, no woven bone formation from controls, and eroded surface greater than those seen in controls and previously in 60-day PGE(sub 2) treated rats. The decrease in new bone mass after withdrawal of PGE(sub 2) was due to a further elevation of bone resorption above that induced by the PGE(sub 2) treatment and a reduction in PGE(sub 2) stimulated bone formation activities. Although there is more trabecular bone than in controls after 120 days' withdrawal of PGE(sub 2), we postulate that the skeletal adaptation to mechanical usage will eventually reduce the bone mass to control levels. Thus, it is conservative to conclude that the anabolic effect of PGE(sub 2) was dependent upon continuous daily administration of PGE(sub 2) in these older rats.

Ke, H. Z.; Li, X. J.; Jee, Webster S. S.

1991-01-01

164

Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation  

PubMed Central

Cathepsin K (CTSK) is secreted by osteoclasts to degrade collagen and other matrix proteins during bone resorption. Global deletion of Ctsk in mice decreases bone resorption, leading to osteopetrosis, but also increases the bone formation rate (BFR). To understand how Ctsk deletion increases the BFR, we generated osteoclast- and osteoblast-targeted Ctsk knockout mice using floxed Ctsk alleles. Targeted ablation of Ctsk in hematopoietic cells, or specifically in osteoclasts and cells of the monocyte-osteoclast lineage, resulted in increased bone volume and BFR as well as osteoclast and osteoblast numbers. In contrast, targeted deletion of Ctsk in osteoblasts had no effect on bone resorption or BFR, demonstrating that the increased BFR is osteoclast dependent. Deletion of Ctsk in osteoclasts increased their sphingosine kinase 1 (Sphk1) expression. Conditioned media from Ctsk-deficient osteoclasts, which contained elevated levels of sphingosine-1-phosphate (S1P), increased alkaline phosphatase and mineralized nodules in osteoblast cultures. An S1P1,3 receptor antagonist inhibited these responses. Osteoblasts derived from mice with Ctsk-deficient osteoclasts had an increased RANKL/OPG ratio, providing a positive feedback loop that increased the number of osteoclasts. Our data provide genetic evidence that deletion of CTSK in osteoclasts enhances bone formation in vivo by increasing the generation of osteoclast-derived S1P. PMID:23321671

Lotinun, Sutada; Kiviranta, Riku; Matsubara, Takuma; Alzate, Jorge A.; Neff, Lynn; Lüth, Anja; Koskivirta, Ilpo; Kleuser, Burkhard; Vacher, Jean; Vuorio, Eero; Horne, William C.; Baron, Roland

2013-01-01

165

Coordination of bone morphogenetic protein 2 (BMP2) and aberrant canonical Wnt/?-catenin signaling for heterotopic bone formation in adrenal myelolipoma: A case report  

PubMed Central

The precise mechanism of heterotopic ossification caused by several types of tumours is largely unknown. However, recent studies have indicated that bone morphogenetic protein 2 (BMP2) is closely linked to the Wnt/?-catenin signaling pathway in this rare phenomenon of bone formation. We report a rare case of adrenal myelolipoma (ML) in a 27-year-old woman with heterotopic bone formation. Immunohistochemical findings showed BMP2 expression in the cytoplasm of tumour cells, as well as the matrix adjacent to newly developed bone tissue. In addition, ?-catenin was prominent in the cytoplasm and nuclei of BMP2-positive tumour cells. To the best of our knowledge, this is the first report of adrenal ML showing heterotopic ossification with accelerated expression of both BMP2 and ?-catenin. Our case findings indicate that BMP2 overexpression via aberrant canonical Wnt/?-catenin signaling may contribute to heterotopic bone formation occurring in adrenal ML. PMID:24554972

Mitsui, Yozo; Yasumoto, Hiroaki; Hiraki, Miho; Arichi, Naoko; Ishikawa, Noriyoshi; Harada, Yuji; Maruyama, Riruke; Shiina, Hiroaki

2014-01-01

166

Coordination of bone morphogenetic protein 2 (BMP2) and aberrant canonical Wnt/?-catenin signaling for heterotopic bone formation in adrenal myelolipoma: A case report.  

PubMed

The precise mechanism of heterotopic ossification caused by several types of tumours is largely unknown. However, recent studies have indicated that bone morphogenetic protein 2 (BMP2) is closely linked to the Wnt/?-catenin signaling pathway in this rare phenomenon of bone formation. We report a rare case of adrenal myelolipoma (ML) in a 27-year-old woman with heterotopic bone formation. Immunohistochemical findings showed BMP2 expression in the cytoplasm of tumour cells, as well as the matrix adjacent to newly developed bone tissue. In addition, ?-catenin was prominent in the cytoplasm and nuclei of BMP2-positive tumour cells. To the best of our knowledge, this is the first report of adrenal ML showing heterotopic ossification with accelerated expression of both BMP2 and ?-catenin. Our case findings indicate that BMP2 overexpression via aberrant canonical Wnt/?-catenin signaling may contribute to heterotopic bone formation occurring in adrenal ML. PMID:24554972

Mitsui, Yozo; Yasumoto, Hiroaki; Hiraki, Miho; Arichi, Naoko; Ishikawa, Noriyoshi; Harada, Yuji; Maruyama, Riruke; Shiina, Hiroaki

2014-01-01

167

Triple red blood cell alloantibody formation after bone-allograft transplantation.  

PubMed

In this case report, we provide evidence for the possibility of red blood cell alloimmunization after bone-allograft transplantation. Here, we present a 13-year-old boy who received a bone allograft due to impending hip-luxation. Five months later he was shown to have developed three different alloantibodies: anti-D, anti-C and anti-E, which were induced by the bone allograft. Red blood cell alloimmunization is a possible adverse event when a patient is exposed to allogenic red blood cells. These antibodies may cause transfusion reactions when incompatible blood is administered. More importantly, these antibodies may cause severe, or even fatal, hemolytic disease of the fetus or newborn, stretching the importance of preventing antibody formation, especially in young women. This case demonstrates the importance of selecting rhesus phenotype compatible bone allografts. PMID:23094701

Prinzen, L; Staal, H M; Rouwette, S J M; Beckers, E A M; ten Broeke, R H M; van Rhijn, L W; Henskens, Y M C

2013-01-01

168

Unique Roles of Phosphorus in Endochondral Bone Formation and Osteocyte Maturation  

PubMed Central

The mechanisms by which inorganic phosphate (Pi) homeostasis controls bone biology are poorly understood. Here we used Dmp1 null mice, a hypophosphatemic rickets/osteomalacia model, combined with a metatarsal organ culture and an application of neutralizing fibroblast growth factor 23 (FGF-23) antibodies to gain insight into the roles of Pi in bone biology. We showed (1) that abnormal bone remodeling in Dmp1 null mice is due to reduced osteoclast number, which is secondary to a reduced ratio of RANKL/OPG expressed by osteoclast supporting cells and (2) that osteoblast extracellular matrix mineralization, growth plate maturation, secondary ossification center formation, and osteoblast differentiation are phosphate-dependent. Finally, a working hypothesis is proposed to explain how phosphate and DMP1 control osteocyte maturation. © 2011 American Society for Bone and Mineral Research. PMID:21542006

Zhang, Rong; Lu, Yongbo; Ye, Ling; Yuan, Baozhi; Yu, Shibin; Qin, Chunlin; Xie, Yixia; Gao, Tian; Drezner, Marc K; Bonewald, Lynda F; Feng, Jian Q

2011-01-01

169

Factors and Mechanisms Involved in the Coupling from Bone Resorption to Formation: How Osteoclasts Talk to Osteoblasts  

PubMed Central

Bone remodeling is the fundamental means by which the quality as well as quantity of the skeleton is maintained throughout adult life. When bone remodeling goes awry, a metabolic bone disease such as osteoporosis ensues. Among multiple phases of the complex remodeling process, we focus in this review on factors and mechanisms that are involved in the coupling of bone formation to preceding resorption. PMID:25247154

Takeshita, Sunao

2014-01-01

170

The induction of bone formation by the recombinant human transforming growth factor-?3.  

PubMed

Implantation of recombinant human transforming growth factor-?3 (hTGF-?3) with coral-derived calcium carbonate-based macroporous bioreactors with limited conversion to hydroxyapatite (7% HA/CC) in the rectus abdominis muscle of the non-human primate Chacma baboon Papio ursinus induces endochondral bone formation. The exact mechanisms by which hTGF-?3 signalling induces bone in heterotopic sites of P. ursinus are not known. Coral-derived 7% HA/CC bioreactors with and without 125 ?g hTGF-?3 were implanted in triplicate in the rectus abdominis muscle of 6 adult baboons. 7% HA/CC bioreactors either with or without hTGF-?3 were loaded with 125 ?g of recombinant human Noggin (hNoggin), a bone morphogenetic proteins (BMPs) antagonist. Tissues on day 15, 60 and 90 were analysed by histomorphometry and quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). Down-regulation of BMP-2 characterized 7% HA/CC constructs preloaded with 125 ?g hNoggin with Noggin down-regulated on day 60 and 90 together with lack of TGF-?3 expression. Down-regulation of BMP-2 correlated with minimal bone formation by induction. hTGF-?3/hNoggin pre-treated bioreactors up-regulated BMP-2 but only on day 90 together with a significant down-regulation of Noggin on day 60 and 90, correlating with the induction of bone formation, albeit limited, on day 90 at the periphery of the macroporous bioreactors only. hTGF-?3 treated bioreactors significantly down-regulated BMP-2 on day 15 whilst up-regulating BMP-2 on day 60 and 90, together with down-regulation of Noggin on day 60 and 90 correlating with the prominent induction of bone formation. hTGF-?3 significantly up-regulated RUNX-2 and Osteocalcin expression on day 15 controlling the differentiation of progenitor stem cells into the osteoblastic lineage. The induction of bone as initiated by hTGF-?3 in the rectus abdominis muscle of P. ursinus is via the BMPs pathway with hTGF-?3 controlling the induction of bone formation by regulating the expression of BMPs via Noggin expression. These results unequivocally demonstrate that hTGF-?3 elicits bone induction by up-regulation of endogenous BMP-2 and is blocked by hNoggin. PMID:24438909

Klar, Roland M; Duarte, Raquel; Dix-Peek, Therese; Ripamonti, Ugo

2014-03-01

171

The effects of prostaglandin E2 in growing rats - Increased metaphyseal hard tissue and cortico-endosteal bone formation  

NASA Technical Reports Server (NTRS)

The role of in vivo prostaglandin E2 (PGE2) in bone formation is investigated. Twenty-five male Sprague-Dawley rats weighing between 223-267 g were injected subcutaneously with 0.3, 1.0, 3.0, and 6.0 mg of PGE2-kg daily for 21 days. The processing of the tibiae for observation is described. Radiographs and histomorphometric analyses are also utilized to study bone formation. Body weight, weights of soft tissues and bones morphometry are evaluated. It is observed that PGE2 depressed longitudinal bone growth, increased growth cartilage thickness, decreased degenerative cartilage cell size and cartilage cell production, and significantly increased proximal tibial metaphyseal hard tissue mass. The data reveal that periosteal bone formation is slowed down at higher doses of PGE2 and endosteal bone formation is slightly depressed less than 10 days post injection; however, here is a late increase (10 days after post injection) in endosteal bone formation and in the formation of trabecular bone in the marrow cavity of the tibial shaft. It is noted that the effects of PGE2 on bone formation are similar to the responses of weaning rats to PGE2.

Jee, W. S. S.; Ueno, K.; Deng, Y. P.; Woodbury, D. M.

1985-01-01

172

Feasibility of Using a Bone-Targeted, Macromolecular Delivery System Coupled with Prostaglandin E1 to Promote Bone Formation in Aged, Estrogen-Deficient Rats  

PubMed Central

Purpose Macromolecular delivery systems have therapeutic uses because of their ability to deliver and release drugs to specific tissues. The uptake and localization of HPMA copolymers using Asp8 as the bone-targeting moiety was determined in aged, ovariectomized (ovx) rats. PGE1 was attached via a cathepsin K-sensitive linkage to HPMA copolymer–Asp8 conjugate and was tested to determine if it could promote bone formation. Materials and Methods The uptake of FITC-labeled HPMA copolymer–Asp8 conjugate (P-Asp8-FITC) on bone surfaces was compared with the mineralization marker, tetracycline. Then a targeted PGE1-HPMA copolymer conjugate (P-Asp8-FITC-PGE1) was given as a single injection and its effects on bone formation were measured 4 weeks later. Results P-Asp8-FITC preferentially deposited on resorption surfaces, unlike tetracycline. A single injection of P-Asp8-FITC-PGE1 resulted in greater indices of bone formation in aged, ovx rats. Conclusions HPMA copolymers can be targeted to bone surfaces using Asp8, with preferential uptake on resorption surfaces. Additionally, PGE1 attached to the Asp8-targeted HPMA copolymers and given by a single injection resulted in greater bone formation measured 4 weeks later. This initial in vivo study suggests that macromolecular delivery systems targeted to bone may offer some therapeutic opportunities and advantages for the treatment of skeletal diseases. PMID:18758923

Miller, S. C.; Pan, H.; Wang, D.; Bowman, B. M.; Kopeckova, P.; Kopecek, J.

2009-01-01

173

Disruption of Kif3a in osteoblasts results in defective bone formation and osteopenia  

PubMed Central

We investigated whether Kif3a in osteoblasts has a direct role in regulating postnatal bone formation. We conditionally deleted Kif3a in osteoblasts by crossing osteocalcin (Oc; also known as Bglap)–Cre with Kif3aflox/null mice. Conditional Kif3a-null mice (Kif3aOc-cKO) had a 75% reduction in Kif3a transcripts in bone and osteoblasts. Conditional deletion of Kif3a resulted in the reduction of primary cilia number by 51% and length by 27% in osteoblasts. Kif3aOc-cKO mice developed osteopenia by 6 weeks of age unlike Kif3aflox/+ control mice, as evidenced by reductions in femoral bone mineral density (22%), trabecular bone volume (42%) and cortical thickness (17%). By contrast, Oc-Cre;Kif3aflox/+ and Kif3aflox/null heterozygous mice exhibited no skeletal abnormalities. Loss of bone mass in Kif3aOc-cKO mice was associated with impaired osteoblast function in vivo, as reflected by a 54% reduction in mineral apposition rate and decreased expression of Runx2, osterix (also known as Sp7 transcription factor 7; Sp7), osteocalcin and Dmp1 compared with controls. Immortalized osteoblasts from Kif3aOc-cKO mice exhibited increased cell proliferation, impaired osteoblastic differentiation, and enhanced adipogenesis in vitro. Osteoblasts derived from Kif3aOc-cKO mice also had lower basal cytosolic calcium levels and impaired intracellular calcium responses to fluid flow shear stress. Sonic hedgehog-mediated Gli2 expression and Wnt3a-mediated ?-catenin and Axin2 expression were also attenuated in Kif3aOc-cKO bone and osteoblast cultures. These data indicate that selective deletion of Kif3a in osteoblasts disrupts primary cilia formation and/or function and impairs osteoblast-mediated bone formation through multiple pathways including intracellular calcium, hedgehog and Wnt signaling. PMID:22357948

Qiu, Ni; Xiao, Zhousheng; Cao, Li; Buechel, Meagan M.; David, Valentin; Roan, Esra; Quarles, L. Darryl

2012-01-01

174

The Wnt Serpentine Receptor Frizzled-9 Regulates New Bone Formation in Fracture Healing  

PubMed Central

Wnt signaling is a key regulator of bone metabolism and fracture healing. The canonical Wnt/?-catenin pathway is regarded as the dominant mechanism, and targeting this pathway has emerged as a promising strategy for the treatment of osteoporosis and poorly healing fractures. In contrast, little is known about the role of non-canonical Wnt signaling in bone. Recently, it was demonstrated that the serpentine receptor Fzd9, a Wnt receptor of the Frizzled family, is essential for osteoblast function and positively regulates bone remodeling via the non-canonical Wnt pathway without involving ?-catenin-dependent signaling. Here we investigated whether the Fzd9 receptor is essential for fracture healing using a femur osteotomy model in Fzd9?/? mice. After 10, 24 and 32 days the fracture calli were analyzed using biomechanical testing, histomorphometry, immunohistochemistry, and micro-computed tomography. Our results demonstrated significantly reduced amounts of newly formed bone at all investigated healing time points in the absence of Fzd9 and, accordingly, a decreased mechanical competence of the callus tissue in the late phase of fracture healing. In contrast, cartilage formation and numbers of osteoclasts degrading mineralized matrix were unaltered. ?-Catenin immunolocalization showed that canonical Wnt-signaling was not affected in the absence of Fzd9 in osteoblasts as well as in proliferating and mature chondrocytes within the fracture callus. The expression of established differentiation markers was not altered in the absence of Fzd9, whereas chemokines Ccl2 and Cxcl5 seemed to be reduced. Collectively, our results suggest that non-canonical signaling via the Fzd9 receptor positively regulates intramembranous and endochondral bone formation during fracture healing, whereas it does not participate in the formation of cartilage or in the osteoclastic degradation of mineralized matrix. The finding that Fzd9, in addition to its role in physiological bone remodeling, regulates bone repair may have implications for the development of treatments for poorly or non-healing fractures. PMID:24391920

Heilmann, Aline; Schinke, Thorsten; Bindl, Ronny; Wehner, Tim; Rapp, Anna; Haffner-Luntzer, Melanie; Nemitz, Claudia; Liedert, Astrid; Amling, Michael; Ignatius, Anita

2013-01-01

175

Diffuse idiopathic skeletal hyperostosis and new bone formation in male gouty subjects  

Microsoft Academic Search

Ninety-nine males with gout were identified and their radiographs examined for features of vertebral hyperostosis and entheseal changes (diffuse idiopathic skeletal hyperostosis, DISH). Of patients over the age of 45 years 43% fulfilled criteria for diagnosis of DISH. New bone formation in other regions of the skeleton was also common. The overhanging margin sign, seen in well developed tophi, was

G. O. Littlejohn; S. Hall

1982-01-01

176

Transgenic overexpression of ephrin b1 in bone cells promotes bone formation and an anabolic response to mechanical loading in mice.  

PubMed

To test if ephrin B1 overexpression enhances bone mass, we generated transgenic mice overexpressing ephrin B1 under the control of a 3.6 kb rat collagen 1A1 promoter (Col3.6-Tg (efnb1) ). Col3.6-Tg (efnb1) mice express 6-, 12- and 14-fold greater levels of full-length ephrin B1 protein in bone marrow stromal cells, calvarial osteoblasts, and osteoclasts, respectively. The long bones of both genders of Col3.6-Tg (efnb1) mice have increased trabecular bone volume, trabecular number, and trabecular thickness and decreased trabecular separation. Enhanced bone formation and decreased bone resorption contributed to this increase in trabecular bone mass in Col3.6-Tg (efnb1) mice. Consistent with these findings, our in vitro studies showed that overexpression of ephrin B1 increased osteoblast differentiation and mineralization, osterix and collagen 1A1 expression in bone marrow stromal cells. Interaction of ephrin B1 with soluble clustered EphB2-Fc decreased osteoclast precursor differentiation into multinucleated cells. Furthermore, we demonstrated that the mechanical loading-induced increase in EphB2 expression and newly formed bone were significantly greater in the Col3.6-Tg (efnb1) mice than in WT littermate controls. Our findings that overexpression of ephrin B1 in bone cells enhances bone mass and promotes a skeletal anabolic response to mechanical loading suggest that manipulation of ephrin B1 actions in bone may provide a means to sensitize the skeleton to mechanical strain to stimulate new bone formation. PMID:23874863

Cheng, Shaohong; Kesavan, Chandrasekhar; Mohan, Subburaman; Qin, Xuezhong; Alarcon, Catrina M; Wergedal, Jon; Xing, Weirong

2013-01-01

177

Fabrication of multilayer ZrO?-biphasic calcium phosphate-poly-caprolactone unidirectional channeled scaffold for bone tissue formation.  

PubMed

We developed a continuously porous scaffold with laminated matrix and bone-like microstructure by a multi-pass extrusion process. In this scaffold, tetragonal ZrO?, biphasic calcium phosphate and poly-caprolactone layers were arranged in a co-axially laminated unit cell with a channel in the center. The entire matrix phase had a laminated microstructure of alternate lamina of tetragonal ZrO?, biphasic calcium phosphate and poly-caprolactone--biphasic calcium phosphate with optimized designed thickness and channeled porosity. Each of the continuous pores was coaxially encircled by the poly-caprolactone--biphasic calcium phosphate layer, biphasic calcium phosphate layer and finally tetragonal ZrO? layer, one after the other. Before extrusion, 5?vol% graphite powder was mixed with tetragonal ZrO? to ensure pores in the outer layer and connectivity among the lamellas. The design strategy is aimed to incorporate a lamellar microstructure like the natural bone in the macro-scaled ceramic body to investigate the strengthening phenomenon and pave the way for fabricating complex microstructure of natural bone could be applied for whole bone replacement. The final fabricated scaffold had a compressive strength of 12.7?MPa and porosity of 78?vol% with excellent cell viability, cell attachment and osteocalcin and collagen expression from cultured MG63 cells on scaffold. PMID:23064831

Mondal, Dibakar; So-Ra, Son; Sarkar, Swapan Kumar; Min, Young Ki; Yang, Hun Mo; Lee, Byong Taek

2013-09-01

178

p27(kip1) deficiency accelerates dentin and alveolar bone formation.  

PubMed

To assess the role of p27(kip1) in regulating dental formation and alveolar bone development, we compared the teeth and mandible phenotypes of homozygous p27(kip1) -deficient (p27(-/-) ) mice with their wild-type littermates at 2 weeks of age. At 2 weeks of age, dental mineral density, dental volume and dentin sialoprotein-immunopositive areas were increased significantly, whereas the predentin area : total dentin area and biglycan-immunopositive area : dentin area ratios were decreased significantly in p27(-/-) mice compared with their wild-type (WT) littermates. Mandible mineral density, cortical thickness, alveolar bone volume, type I collagen and osterix-immunopositive areas, osteoblast number and activity and mRNA expression of Runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), osteocalcin and bone morphogenetic protein (bmp2) were all significantly increased in the mandibles, as was the number and surface of tartrate-resistant acid phosphatase-positive osteoclasts in the alveolar bone of p27(-/-) mice compared with their WT littermates. Furthermore, the percentage of proliferating cell nuclear antigen-positive cells in Hertwig's epithelial root sheath and protein expression of cyclin E and cyclin-dependent kinase 2 were increased significantly in p27(-/-) mice relative to their WT littermates. The results from this study indicate that p27 plays a negative regulatory role in dentin formation and alveolar bone development. PMID:24916068

Yin, Ying; Wang, Qun; Sun, Wen; Wang, Yuli; Chen, Ning; Miao, Dengshun

2014-10-01

179

Osteopotentia regulates osteoblast maturation, bone formation, and skeletal integrity in mice  

PubMed Central

During skeletal development and regeneration, bone-forming osteoblasts respond to high metabolic demand by active expansion of their rough endoplasmic reticulum (rER) and increased synthesis of type I collagen, the predominant bone matrix protein. However, the molecular mechanisms that orchestrate this response are not well understood. We show that insertional mutagenesis of the previously uncharacterized osteopotentia (Opt) gene disrupts osteoblast function and causes catastrophic defects in postnatal skeletal development. Opt encodes a widely expressed rER-localized integral membrane protein containing a conserved SUN (Sad1/Unc-84 homology) domain. Mice lacking Opt develop acute onset skeletal defects that include impaired bone formation and spontaneous fractures. These defects result in part from a cell-autonomous failure of osteoblast maturation and a posttranscriptional decline in type I collagen synthesis, which is concordant with minimal rER expansion. By identifying Opt as a crucial regulator of bone formation in the mouse, our results uncover a novel rER-mediated control point in osteoblast function and implicate human Opt as a candidate gene for brittle bone disorders. PMID:20440000

Jiang, Yebin; Zhao, Jenny J.; Mohr, Andreas; Roemer, Frank

2010-01-01

180

Improving osteoblast functions and bone formation upon BMP-2 immobilization on titanium modified with heparin.  

PubMed

The aim of this study was to develop bone morphogenetic protein-2 (BMP-2) immobilization on titanium (Ti) modified by heparin for improving osteoblast function in vitro and bone formation in vivo. The Ti surface was first modified with heparin and then immobilized with BMP-2 (BMP-2/Hep-Ti). The Ti and modified Ti were characterized by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and contact angle. In vitro studies demonstrated that osteoblasts cultured on BMP-2/Hep-Ti substrate increased ALP activity, calcium deposition, osteocalcin (OCN) and osteopontin (OPN) levels as compared to those cultured on Ti or BMP-2/Ti. In addition, intra-thread bone density and bone to implant contact ratio of BMP-2/Hep-Ti were significantly greater than those of Ti in the in vivo study. In conclusion, BMP-2 immobilized Ti modified heparin implants seemed to be a suitable delivery system for BMP-2 to improve osteoblast functions and new bone formation at the defect area around an implant. PMID:25263872

Kim, Sung Eun; Kim, Chang-Seop; Yun, Young-Pil; Yang, Dae Hyeok; Park, Kyeongsoon; Kim, Se Eun; Jeong, Chang-Mo; Huh, Jung-Bo

2014-12-19

181

Deep Lamellar Keratoplasty Combined With Cataract Surgery  

Microsoft Academic Search

e used a surgical technique that combines deep lamellar keratoplasty, phaco- emulsification, and intraocular lens implantation for treating patients with cata- ract and corneal stromal disease. Deep lamellar dissection of the cornea was first performed with viscoelastic substances (hyaluronate sodium) until the highly transparent Descemet membrane solely remained. We then created a short corneal tunnel to per- form phacoemulsification with

Marc C. Muraine; Amelie Collet; Gerard Brasseur; Arch Ophthalmol

182

Therapeutic lamellar keratoplasty with an automated microkeratome  

Microsoft Academic Search

Penetrating keratoplasty (PKP) is the predominant form of corneal transplantation because both manual and automated lamellar keratoplasty are technically difficult and lead to complications such as irregularities and scarring. A microkeratome for laser in situ keratomileusis can be used to overcome these disadvantages. We describe a technique of lamellar keratoplasty performed with an automated microkeratome to treat corneal opacities in

Ignacio Jiménez-Alfaro; Juan J Pérez-Santonja; Germán Gómez Teller??a; José L Bueno Palac??n; Pilar Puy

2001-01-01

183

Tenascin-W inhibits proliferation and differentiation of preosteoblasts during endochondral bone formation  

SciTech Connect

We identified a cDNA encoding mouse Tenascin-W (TN-W) upregulated by bone morphogenetic protein (Bmp)2 in ATDC5 osteo-chondroprogenitors. In adult mice, TN-W was markedly expressed in bone. In mouse embryos, during endochondral bone formation TN-W was localized in perichondrium/periosteum, but not in trabecular and cortical bones. During bone fracture repair, cells in the newly formed perichondrium/periosteum surrounding the cartilaginous callus expressed TN-W. Furthermore, TN-W was detectable in perichondrium/periosteum of Runx2-null and Osterix-null embryos, indicating that TN-W is expressed in preosteoblasts. In CFU-F and -O cells, TN-W had no effect on initiation of osteogenesis of bone marrow cells, and in MC3T3-E1 osteoblastic cells TN-W inhibited cell proliferation and Col1a1 expression. In addition, TN-W suppressed canonical Wnt signaling which stimulates osteoblastic differentiation. Our results indicate that TN-W is a novel marker of preosteoblasts in early stage of osteogenesis, and that TN-W inhibits cell proliferation and differentiation of preosteoblasts mediated by canonical Wnt signaling.

Kimura, Hiroaki [Department of Orthopaedics, Kyoto University, Kyoto 606-8507 (Japan); Akiyama, Haruhiko [Department of Orthopaedics, Kyoto University, Kyoto 606-8507 (Japan)]. E-mail: hakiyama@kuhp.kyoto-u.ac.jp; Nakamura, Takashi [Department of Orthopaedics, Kyoto University, Kyoto 606-8507 (Japan); Crombrugghe, Benoit de [Department of Molecular Genetics, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030 (United States)

2007-05-18

184

The Effect of Heparan Sulfate Application on Bone Formation during Distraction Osteogenesis  

PubMed Central

Bone morphogenetic proteins (BMPs) are recognized for their ability to induce bone formation in vivo and in vitro. Their osteogenic and osteoinductive properties are tightly regulated by the secretion of specific BMP antagonists, which have been shown to physically bind and sometimes be blocked by the extracellular proteoglycan heparan sulphate side chains (from hereon referred to as HS). The purpose of this study was to investigate if local application of 5 µg of HS proteoglycan to a bone regenerate site in a mouse model of distraction osteogenesis (DO) can accelerate bone healing and affect the expression of key members of the BMP signaling pathway. DO was performed on the right tibia of 115 adult male wild-type mice. At mid-distraction (day 11), half the group was injected locally with 5 µg of HS, while the other half was injected with saline. The mice were sacrificed at 2 time-points: mid-consolidation (34 days) and full consolidation (51 days). The distracted tibial zone was then collected for analysis by ?CT, radiology, biomechanical testing, immunohistochemistry, and histology. While ?CT data showed no statistically significant difference in bone formation, the results of biomechanical testing in stiffness and ultimate force were significantly lower in the HS-injected bones at 51 days, compared to controls. Immunohistochemistry results also suggested a decrease in expression of several key members of the BMP signaling pathway at 34 days. Furthermore, wound dehiscence and infection rates were significantly elevated in the HS group compared to the controls, which resulted in a higher rate of euthanasia in the treatment group. Our findings demonstrate that exogenous application of 5 µg of HS in the distracted gap of a murine model had a negative impact on bone and wound healing. PMID:23457615

Gdalevitch, Marie; Kasaai, Bahar; Alam, Norine; Dohin, Bruno; Lauzier, Dominique; Hamdy, Reggie C.

2013-01-01

185

Pyk2 Regulates Megakaryocyte-Induced Increases in Osteoblast Number and Bone Formation  

PubMed Central

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

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

2013-01-01

186

Mechanical regulation of localized and appositional bone formation around bone-interfacing implants  

E-print Network

dif- ferentiation; finite element analysis; porous-surfaced im- plant; plasma-sprayed implant. However, ef- forts to quantify the relationship between mechanical stimuli and tissue formation have in the healing tissue is difficult, and consequently mechanical stimuli are described by the applied loading

Simmons, Craig A.

187

Local delivery of FTY720 accelerates cranial allograft incorporation and bone formation  

PubMed Central

Endogenous stem cell recruitment to the site of skeletal injury is key to enhanced osseous remodeling and neovascularization. To this end, this study utilized a novel bone allograft coating of poly(lactic-co-glycolic acid) (PLAGA) to sustain the release of FTY720, a selective agonist for sphingosine 1-phosphate (S1P) receptors, from calvarial allografts. Uncoated allografts, vehicle-coated, low dose FTY720 in PLAGA (1:200 w:w) and high dose FTY720 in PLAGA (1:40) were implanted into critical size calvarial bone defects. The ability of local FTY720 delivery to promote angiogenesis, maximize osteoinductivity and improve allograft incorporation by recruitment of bone progenitor cells from surrounding soft tissues and microcirculation was evaluated. FTY720 bioactivity after encapsulation and release was confirmed with sphingosine kinase 2 assays. HPLC-MS quantified about 50% loaded FTY720 release of the total encapsulated drug (4.5 µg) after 5 days. Following 2 weeks of defect healing, FTY720 delivery led to statistically significant increases in bone volumes compared to controls, with total bone volume increases for uncoated, coated, low FTY720 and high FTY720 of 5.98, 3.38, 7.2 and 8.9 mm3, respectively. The rate and extent of enhanced bone growth persisted through week 4 but, by week 8, increases in bone formation in FTY720 groups were no longer statistically significant. However, micro-computed tomography (microCT) of contrast enhanced vascular ingrowth (MICROFIL®) and histological analysis showed enhanced integration as well as directed bone growth in both high and low dose FTY720 groups compared to controls. PMID:21863314

Huang, Cynthia; Das, Anusuya; Barker, Daniel; Tholpady, Sunil; Wang, Tiffany; Cui, Quanjun; Ogle, Roy

2012-01-01

188

Heterotopic Bone Formation Around Vessels: Pilot Study of a New Animal Model  

PubMed Central

Abstract To achieve an easily established, safe, and reproducible animal model for the study of heterotopic bone formation around vessels, a small animal series using New Zealand White rabbits was performed. Three different dosages of recombinant human bone morphogenic protein (rhBMP-2) carried by fibrin matrix were tested. A guided tissue regeneration (GTR) membrane sheet was formed into a tube and allowed to harden; it served both to maintain the space around the vessel bundle and to separate the fibrin matrix with rhBMP-2 from skeletal muscle. Wrapped around the femoral vessel bundle and fixed in place, the tube was filled with the fibrin matrix containing rhBMP-2. The surgical site was closed in layers, and the postoperative healing was uneventful. All animals resumed their full preoperative daily activities 3–4 days after the operation. No adverse events such as wound dehiscence or infection occurred, and all animals could be sacrified at the scheduled date. Micro–computed tomography and histological investigations showed heterotopic bone formation around the vessel bundle in the medium- and high-dosage rhBMP-2 groups. An easy, safe, and reproducible animal model that allows the study of heterotopic bone formation around vessels was successfully established. PMID:23914333

Cai, Wei-Xin; Zheng, Li-Wu; Weber, Franz E.; Li, Chun-Lei; Ma, Li; Ehrbar, Martin

2013-01-01

189

Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts.  

PubMed

The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signalling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the nonselective S1P receptor agonist FTY720 causes increased bone formation in wild-type, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts. PMID:25333900

Keller, Johannes; Catala-Lehnen, Philip; Huebner, Antje K; Jeschke, Anke; Heckt, Timo; Lueth, Anja; Krause, Matthias; Koehne, Till; Albers, Joachim; Schulze, Jochen; Schilling, Sarah; Haberland, Michael; Denninger, Hannah; Neven, Mona; Hermans-Borgmeyer, Irm; Streichert, Thomas; Breer, Stefan; Barvencik, Florian; Levkau, Bodo; Rathkolb, Birgit; Wolf, Eckhard; Calzada-Wack, Julia; Neff, Frauke; Gailus-Durner, Valerie; Fuchs, Helmut; de Angelis, Martin Hrab?; Klutmann, Susanne; Tsourdi, Elena; Hofbauer, Lorenz C; Kleuser, Burkhard; Chun, Jerold; Schinke, Thorsten; Amling, Michael

2014-01-01

190

Assessment of bone formation and bone resorption in osteoporosis: a comparison between tetracycline-based iliac histomorphometry and whole body /sup 85/Sr kinetics  

SciTech Connect

Bone formation and resorption have been measured in patients with idiopathic osteoporosis by histomorphometry of 7.5-mm trephine biopsies and in the whole body by 85Sr radiotracer methodology and calcium balances. The studies were synchronized and most were preceded by double in vivo tetracycline labeling. Correlations between histological and kinetic bone formation indices were better when better when based on the extent of double tetracycline labels than on measurements of osteoid by visible light microscopy. Correction of the kinetic data for long-term exchange, using 5 months' serial whole body counting of retained 85Sr, improved the fit of the kinetic to the histological data. A statistical analysis of the measurement uncertainties showed that the residual scatter in the best correlations (between exchange-corrected bone formation rates and double-labeled osteoid surface indices) could be attributed to measurement imprecision alone. The exchange-corrected resorption rate correlated fairly well with iliac trabecular resorption surfaces, and using a volume referent rather than a surface referent for the histological index improved the statistical fit when patients with therapeutically accelerated bone turnover were included. A much better correlation was obtained by including osteoid volume acting as an independent predictor of bone resorption in a bivariate regression with a resorption surface index. The residual errors could then be accounted for by known measurement uncertainties. Whereas osteoid taking a double label closely predicted the kinetic rate of bone formation, further analysis suggested that osteoid that took no label or a single label was more closely related to bone resorption, presumably as a secondary result of the coupling of bone formation to bone resorption.

Reeve, J.; Arlot, M.E.; Chavassieux, P.M.; Edouard, C.; Green, J.R.; Hesp, R.; Tellez, M.; Meunier, P.J.

1987-12-01

191

Partial Loss of Anabolic Effect of Prostaglandin E(sub 2) on Bone After Its Withdrawal in Rats  

NASA Technical Reports Server (NTRS)

The object of this study was to determine the fate of PGE(sub 2)-induced new bone mass after withdrawal of PGE(sub 2) administration. Seven-month-old male Sprague-Dawley rats were given subcutaneous injections of 1, 3, and 6 mg PGE(sub 2),/kg/d for 60 days and then withdrawn for 60 and 120 days. Histomorphometric analyses were performed on double fluorescent labeled undecalcified proximal tibial bone specimens. After 60 days of PGE(sub 2) treatment, a new steady state of increased trabecular bone area (+67% and +81% with 3 and 6 mg PGE(sub 2)/kg/d) from woven bone and stimulated lamellar bone formation, elevated bone turnover, and shortened remodeling periods were achieved compared to age-matched controls. In contrast, after 60 and 120 days withdrawal of PGE(sub 2), a new steady state characterized by less trabecular bone area (+40% to +60% of controls with 3 and 6 mg/kg/d doses), normal lamellar bone formation, no woven bone formation from controls, and eroded surface greater than those seen in controls and previously in 60-day PGE(sub 2) treated rats. The decrease in new bone mass after withdrawal of PGE(sub 2), was due to a further elevation of bone resorption above that induced by the PGE(sub 2) treatment and a reduction in PGE(sub 2), stimulated bone formation activities. Although there is more trabecular bone than in controls after 120 days withdrawal of PGE(sub 2), we postulate that the skeletal adaptation to mechanical usage will eventually reduce the bone mass to control levels. Thus, it is conservative to conclude that the anabolic effect of PGE(sub 2) was dependent upon continuous daily administration of PGE(sub 2) in these older rats.

Ke, H. Z.; Li, X. J.; Jee, W. S. S.

1991-01-01

192

Posterior Lamellar Keratoplasty in Perspective  

Microsoft Academic Search

\\u000a \\u000a \\u000a \\u000a \\u000a \\u000a • \\u000a \\u000a \\u000a Posterior lamellar keratoplasty (PLK) offers many substantial benefits compared to penetrating keratoplasty (PK) including:\\u000a closed eye surgery elimination of both regular and irregular postoperative astigmatism leading to full visual rehabilitation\\u000a with spectacles within 3–6 months, elimination of postoperative corneal anaesthesia, and a reduced risk of postoperative globe\\u000a rupture.\\u000a \\u000a \\u000a \\u000a \\u000a • \\u000a \\u000a \\u000a Disadvantages of PLK compared to PK include: corneal stromal scarring

F Arnalich-Montiel; JKG Dart

193

NAA10 controls osteoblast differentiation and bone formation as a feedback regulator of Runx2.  

PubMed

Runt-related transcription factor 2 (Runx2) transactivates many genes required for osteoblast differentiation. The role of N-?-acetyltransferase 10 (NAA10, arrest-defective-1), originally identified in yeast, remains poorly understood in mammals. Here we report a new NAA10 function in Runx2-mediated osteogenesis. Runx2 stabilizes NAA10 in osteoblasts during BMP-2-induced differentiation, and NAA10 in turn controls this differentiation by inhibiting Runx2. NAA10 delays bone healing in a rat calvarial defect model and bone development in neonatal mice. Mechanistically, NAA10 acetylates Runx2 at Lys225, and this acetylation inhibits Runx2-driven transcription by interfering with CBF? binding to Runx2. Our study suggests that NAA10 acts as a guard ensuring balanced osteogenesis by fine-tuning Runx2 signalling in a feedback manner. NAA10 inhibition could be considered a potential strategy for facilitating bone formation. PMID:25376646

Yoon, Haejin; Kim, Hye-Lim; Chun, Yang-Sook; Shin, Dong Hoon; Lee, Kyoung-Hwa; Shin, Chan Soo; Lee, Dong Yeon; Kim, Hong-Hee; Lee, Zang Hee; Ryoo, Hyun-Mo; Lee, Mi-Ni; Oh, Goo Taeg; Park, Jong-Wan

2014-01-01

194

TWIST1 expression in breast cancer cells facilitates bone metastasis formation.  

PubMed

The transcription factor TWIST1 induces epithelial-mesenchymal transition and/or escape to the oncogenic-induced failsafe program, facilitating the intravasation of breast cancer cells in the systemic circulation and their dissemination to the lungs. Its involvement in breast cancer bone metastasis is unknown. To address this question, human osteotropic MDA-MB-231/B02 breast cancer cells were stably transfected with a Tet-inducible vector encoding for TWIST1, whose expression was specifically repressed in the presence of doxycycline (dox). The intra-arterial inoculation of transfectants expressing TWIST1 in immunodeficient mice substantially increased the extent of osteolytic lesions in these animals, being 50% larger than that of animals bearing mock-transfected tumors, as determined by radiography. This difference was accompanied by a sharp reduction of the bone volume (indicating a higher bone destruction) and a twofold increase in the tumor volume compared with mice bearing mock-transfected tumors, as determined by histomorphometry. Importantly, the suppression of TWIST1 expression in MDA-MB-231/B02 cells in the presence of dox abolished the stimulatory effect of TWIST1 on bone metastasis formation in vivo. Additionally, examination of the bone marrow from untreated and dox-treated animals on day 7 after tumor cell inoculation, at which time there was no evidence of radiographic osteolytic lesions, revealed that the number of tumor cell colonies that were recovered from the bone marrow of untreated mice was dramatically increased compared with that of dox-fed animals. In vitro, TWIST1 expression promoted tumor cell invasion and enhanced microRNA 10b (miR-10b) expression, a proinvasive factor, but was dispensable for growth of tumor cells. In vivo, the repression of miR-10b substantially decreased the presence of TWIST1-expressing breast cancer cells in the bone marrow. Overall, these results establish that TWIST1 facilitates breast cancer bone metastasis formation through a mechanism dependent of miR-10b, which leads to increase tumor burden and bone destruction. PMID:24619707

Croset, Martine; Goehrig, Delphine; Frackowiak, Agnieszka; Bonnelye, Edith; Ansieau, Stéphane; Puisieux, Alain; Clézardin, Philippe

2014-08-01

195

Role of RANKL-induced osteoclast formation and MMP-dependent matrix degradation in bone destruction by breast cancer metastasis.  

PubMed

Bone metastasis of breast cancer induces severe osteolysis with increased bone resorption. Osteoclast differentiation regulated by the receptor activator of NF-kappaB ligand (RANKL) in osteoblasts and matrix degradation induced by matrix metalloproteinases (MMPs) are thought to be involved in the process of bone resorption. When nude mice were inoculated with human breast cancer cells, MDA-MB-231(MDA-231), numerous osteoclasts resorbed bone and the degradation of the bone matrix markedly progressed in the femur and tibia with metastasis of the MDA-231 tumour. The expression of RANKL, MMP-13 and membrane-type 1-MMP mRNA was markedly elevated in bone with metastasis. When MDA-231 cells were cocultured with mouse calvaria, MDA-231 markedly induced bone resorption measured by calcium release from the calvaria, and the expression of RANKL, MMP-2 and MMP-13 was elevated in the calvaria after the coculture. The separation of MDA-231 from the calvaria using filter insert showed decreased bone resorption, suggesting that cell-to-cell interaction is essential for cancer-induced bone resorption. Adding MDA-231 cells to bone marrow cultures markedly induced osteoclast formation, and the expression of RANKL in osteoblasts was enhanced by contact with the cell surface of MDA-231 cells. These results indicate that RANKL-induced osteoclast formation and MMP-dependent matrix degradation are associated with osteolysis because of bone metastasis of breast cancer. PMID:12698202

Ohshiba, T; Miyaura, C; Inada, M; Ito, A

2003-04-22

196

Updating the Lamellar Hypothesis of Hippocampal Organization  

PubMed Central

Andersen et al. (1971) proposed that excitatory activity in the entorhinal cortex propagates topographically to the dentate gyrus, and on through a “trisynaptic circuit” lying within transverse hippocampal “slices” or “lamellae.” In this way, a relatively simple structure might mediate complex functions in a manner analogous to the way independent piano keys can produce a nearly infinite variety of unique outputs. The lamellar hypothesis derives primary support from the “lamellar” distribution of dentate granule cell axons (the mossy fibers), which innervate dentate hilar neurons and area CA3 pyramidal cells and interneurons within the confines of a thin transverse hippocampal segment. Following the initial formulation of the lamellar hypothesis, anatomical studies revealed that unlike granule cells, hilar mossy cells, CA3 pyramidal cells, and Layer II entorhinal cells all form axonal projections that are more divergent along the longitudinal axis than the clearly “lamellar” mossy fiber pathway. The existence of pathways with “translamellar” distribution patterns has been interpreted, incorrectly in our view, as justifying outright rejection of the lamellar hypothesis (Amaral and Witter, 1989). We suggest that the functional implications of longitudinally projecting axons depend not on whether they exist, but on what they do. The observation that focal granule cell layer discharges normally inhibit, rather than excite, distant granule cells suggests that longitudinal axons in the dentate gyrus may mediate “lateral” inhibition and define lamellar function, rather than undermine it. In this review, we attempt a reconsideration of the evidence that most directly impacts the physiological concept of hippocampal lamellar organization. PMID:23233836

Sloviter, Robert S.; L?mo, Terje

2012-01-01

197

Craniosynostosis-Associated Fgfr2C342Y Mutant Bone Marrow Stromal Cells Exhibit Cell Autonomous Abnormalities in Osteoblast Differentiation and Bone Formation  

PubMed Central

We recently reported that cranial bones of Fgfr2C342Y/+ craniosynostotic mice are diminished in density when compared to those of wild type mice, and that cranial bone cells isolated from the mutant mice exhibit inhibited late stage osteoblast differentiation. To provide further support for the idea that craniosynostosis-associated Fgfr mutations lead to cell autonomous defects in osteoblast differentiation and mineralized tissue formation, here we tested bone marrow stromal cells isolated from Fgfr2C342Y/+ mice for their ability to differentiate into osteoblasts. Additionally, to determine if the low bone mass phenotype of Crouzon syndrome includes the appendicular skeleton, long bones were assessed by micro CT. Fgfr2C342Y/+ cells showed increased osteoblastic gene expression during early osteoblastic differentiation but decreased expression of alkaline phosphatase mRNA and enzyme activity, and decreased mineralization during later stages of differentiation, when cultured under 2D in vitro conditions. Cells isolated from Fgfr2C342Y/+ mice also formed less bone when allowed to differentiate in a 3D matrix in vivo. Cortical bone parameters were diminished in long bones of Fgfr2C342Y/+ mice. These results demonstrate that marrow stromal cells of Fgfr2C342Y/+ mice have an autonomous defect in osteoblast differentiation and bone mineralization, and that the Fgfr2C342Y mutation influences both the axial and appendicular skeletons. PMID:23762837

Liu, J.; Kwon, T.-G.; Nam, H. K.; Hatch, N. E.

2013-01-01

198

Erythropoietin Mediated Bone Formation Is Regulated by mTOR Signaling  

PubMed Central

The role of erythropoietin (Epo) and Epo/Epo receptor (EpoR) signaling pathways for production of red blood cells are well established. However, little is known about Epo/EpoR signaling in non-hematopoietic cells. Recently, we demonstrated that Epo activates JAK/STAT signaling in hematopoietic stem cells (HSCs), leading to the production of bone morphogenetic protein 2 (BMP2) and bone formation and that Epo also directly activate mesenchymal cells to form osteoblasts in vitro. In this study, we investigated the effects of mTOR signaling on Epo-mediated osteoblastogenesis and osteoclastogenesis. We found that mTOR inhibition by rapamycin blocks Epo-dependent and -independent osteoblastic phenotypes in human bone marrow stromal cells (hBMSCs) and ST2 cells, respectively. Furthermore, we found that rapamycin inhibits Epo-dependent and -independent osteoclastogenesis in mouse bone marrow mononuclear cells and Raw264.7 cells. Finally, we demonstrated that Epo increases NFATc1 expression and decreases cathepsin K expression in an mTOR-independent manner, resulting in an increase of osteoclast numbers and a decrease in resorption activity. Taken together, these results strongly indicate that mTOR signaling plays an important role in Epo-mediated bone homeostasis. PMID:21898543

Kim, Jinkoo; Jung, Younghun; Sun, Hongli; Joseph, Jeena; Mishra, Anjali; Shiozawa, Yusuke; Wang, Jingcheng; Krebsbach, Paul H.; Taichman, Russell S.

2011-01-01

199

Fabrication and Characterization of Biomimetic Collagen-Apatite Scaffolds with Tunable Structures for Bone Tissue Engineering  

PubMed Central

The objective of the current study is to prepare a biomimetic collagen-apatite (Col-Ap) scaffold for improved bone repair and regeneration. A novel bottom-up approach has been developed, which combines a biomimetic self-assembly method with a controllable freeze casting technology. In this study, the mineralized collagen fibers were generated using a simple one-step co-precipitation method which involved collagen self-assembly and in situ apatite precipitation in a collagen-containing modified simulated body fluid (m-SBF). The precipitates were subjected to controllable freeze casting, forming scaffolds with either an isotropic equiaxed structure or a unidirectional lamellar structure. These scaffolds were comprised of collagen fibers and poorly crystalline bone-like carbonated apatite nanoparticles. The mineral content in the scaffold could be tailored in a range 0–54 wt% by simply adjusting the collagen content in the m-SBF. Further, the mechanisms of the formation of both the equiaxed and the lamellar scaffolds were investigated, and freezing regimes for equiaxed and lamellar solidification were established. Finally, bone forming capability of such prepared scaffolds was evaluated in vivo in a mouse calvarial defect model. It was confirmed that the scaffolds well support new bone formation. PMID:23567944

Xia, Zengmin; Yu, Xiaohua; Jiang, Xi; Brody, Harold D; Rowe, David W; Wei, Mei

2013-01-01

200

New bone formation enhanced by ADSCs overexpressing hRunx2 during mandibular distraction osteogenesis in osteoporotic rabbits.  

PubMed

Promoting new bone formation during distraction osteogenesis (DO) in elderly patients with osteoporosis is still a challenge. In this study, we investigated the effect of gene therapy using local Runt-related gene 2 on new bone formation during osteoporotic mandibular DO in rabbits. First, we successfully established a mandibular osteoporotic animal model by ovariectomizing rabbits. Second, the right mandibles of the osteoporotic rabbits were distracted after corticotomy. The distraction gap of the rabbits in Group A2 and B2 were injected with Adv-hRunx2-GFP-transfected adipose-derived stromal cells (ADSCs) and Adv-GFP-transfected ADSCs, respectively. Rabbits in Groups C2 (ovariectomized control) and D2 (sham surgery control) were injected with physiologic saline. New-generation bone tissue in the distraction gap was analyzed via plain radiographic examinations, micro-computed tomography, histological examinations, and biomechanical testing at weeks 3, 6, and 9 of the consolidation period. Results of above examinations showed that no ideal new bone formation was observed in Groups B2 and C2, but obvious ideal new bone formation was observed in Group A2 and D2. The results suggested that gene therapy using rhRunx2-modified ADSCs promoted new bone formation during osteoporotic mandibular DO and effectively compensated for the detrimental effects of systemic osteoporosis on new bone formation. PMID:24522890

Sun, Jing-Jing; Zheng, Xiao-Hui; Wang, Li-Ya; Liu, Lei; Jing, Wei; Lin, Yun-Feng; Tian, Weidong; Tang, Wei; Long, Jie

2014-05-01

201

Enhancement of ectopic bone formation by bone morphogenetic protein-2 released from a heparin-conjugated poly( l-lactic- co-glycolic acid) scaffold  

Microsoft Academic Search

In this study, a heparin-conjugated poly(l-lactic-co-glycolic acid) (HP-PLGA) scaffold was developed for the sustained delivery of bone morphogenetic protein-2 (BMP-2), and then used to address the hypothesis that BMP-2 delivered from this scaffold could enhance ectopic bone formation. We found the amount of heparin conjugated to the PLGA scaffolds could be increased up to 3.2-fold by using scaffolds made from

Oju Jeon; Su Jin Song; Sun-Woong Kang; Andrew J. Putnam; Byung-Soo Kim

2007-01-01

202

Evaluation of a Thiolated Chitosan Scaffold for Local Delivery of BMP-2 for Osteogenic Differentiation and Ectopic Bone Formation  

PubMed Central

Thiolated chitosan (Thio-CS) is a well-established pharmaceutical excipient for drug delivery. However, its use as a scaffold for bone formation has not been investigated. The aim of this study was to evaluate the potential of Thio-CS in bone morphogenetic protein-2 (BMP-2) delivery and bone formation. In vitro study showed that BMP-2 interacted with the Thio-CS and did not affect the swelling behavior. The release kinetics of BMP-2 from the Thio-CS was slightly delayed (70%) within 7 days compared with that from collagen gel (Col-gel, 85%), which is widely used in BMP-2 delivery. The BMP-2 released from Thio-CS increased osteoblastic cell differentiation but did not show any cytotoxicity until 21 days. Analysis of the in vivo ectopic bone formation at 4 weeks of posttransplantation showed that use of Thio-CS for BMP-2 delivery induced more bone formation to a greater extent (1.8 fold) than that of Col-gel. However, bone mineral density in both bones was equivalent, regardless of Thio-CS or Col-gel carrier. Taken together, Thio-CS system might be useful for delivering osteogenic protein BMP-2 and present a promising bone regeneration strategy. PMID:24024213

Bae, In-Ho; Jeong, Byung-Chul; Kim, Sun-Hun; Koh, Jeong-Tae

2013-01-01

203

Haversian bone formation rates determined by a new method in a mastodon, and in human diabetes mellitus and osteoporosis  

Microsoft Academic Search

Counts of the population densities of secondary osteons allow the determination of the haversian bone formation rate without the use of a tissue marker and can do so in paleontological as well as contemporary bone specimens. Using this technique, together with tetracycline markers, such rates were measured in 180 normal humans, in 10 diabetics, in 5 patients with osteogenesis imperfecta,

K. Wu; K. E. Schubeck; H. M. Frost; A. Villanueva

1970-01-01

204

Changes in markers of bone formation and resorption in a bed rest model of weightlessness  

NASA Technical Reports Server (NTRS)

To study the mechanism of bone loss in physical unloading, we examined indices of bone formation and bone resorption in the serum and urine of eight healthy men during a 7 day -6 degrees head-down tilt bed rest. Prompt increases in markers of resorption--pyridinoline (PD), deoxypyridinoline (DPD), and hydroxyproline (Hyp)/g creatinine--during the first few days of inactivity were paralleled by tartrate-resistant acid phosphatase (TRAP) with significant increases in all these markers by day 4 of bed rest. An index of formation, skeletal alkaline phosphatase (SALP), did not change during bed rest and showed a moderate 15% increase 1 week after reambulation. In contrast to SALP, serum osteocalcin (OC) began increasing the day preceding the increase in Hyp, remained elevated for the duration of the bed rest, and returned to pre-bed rest values within 5 days of reambulation. Similarly, DPD increased significantly at the onset of bed rest, remained elevated for the duration of bed rest, and returned to pre-bed rest levels upon reambulation. On the other hand, the other three indices of resorption, Hyp, PD, and TRAP, remained elevated for 2 weeks after reambulation. The most sensitive indices of the levels of physical activity proved to be the noncollagenous protein, OC, and the collagen crosslinker, DPD. The bed rest values of both these markers were significantly elevated compared to both the pre-bed rest values and the post-bed rest values. The sequence of changes in the circulating markers of bone metabolism indicated that increases in serum OC are the earliest responses of bone to head-down tilt bed rest.

Lueken, S. A.; Arnaud, S. B.; Taylor, A. K.; Baylink, D. J.

1993-01-01

205

Heparanase Expression and Activity Influences Chondrogenic and Osteogenic Processes During Endochondral Bone Formation  

PubMed Central

Endochondral bone formation is a highly orchestrated process involving coordination among cell-cell, cell-matrix and growth factor signaling that eventually results in the production of mineralized bone from a cartilage template. Chondrogenic and osteogenic differentiation occur in sequence during this process, and the temporospatial patterning clearly requires the activities of heparin binding growth factors and their receptors. Heparanase (HPSE) plays a role in osteogenesis, but the mechanism by which it does so is incompletely understood. We used a combination of ex vivo and in vitro approaches and a well described HPSE inhibitor, PI-88 to study HPSE in endochondral bone formation. In situ hybridization and immunolocalization with HPSE antibodies revealed that HPSE is expressed in the peri-chondrium, peri-osteum, and at the chondro-osseous junction, all sites of key signaling events and tissue morphogenesis. Transcripts encoding Hpse also were observed in the pre-hypertrophic zone. Addition of PI-88 to metatarsals in organ culture reduced growth and suggested that HPSE activity aids the transition from chondrogenic to osteogenic processes in growth of long bones. To study this, we used high density cultures of ATDC5 pre-chondrogenic cells grown under conditions favoring chondrogenesis or osteogenesis. Under chondrogenic conditions, HPSE/Hpse was expressed at high levels during the mid-culture period, at the onset of terminal chondrogenesis. PI-88 addition reduced chondrogenesis and accelerated osteogenesis, including a dramatic up-regulation of osteocalcin levels. In normal growth medium, addition of PI-88 reduced migration of ATDC-5 cells, suggesting that HPSE facilitates cartilage replacement by bone at the chondro-osseous junction by removing the HS component of proteoglycans, such as perlecan/HSPG2, that otherwise prevent osteogenic cells from remodeling hypertrophic cartilage. PMID:18589009

Brown, A. J.; Alicknavitch, M.; D'Souza, S.S.; Daikoku, T.; Kirn-Safran, C.B.; Marchetti, D.; Carson, D. D.; Farach-Carson, M.C.

2008-01-01

206

Efficiently engineered cell sheet using a complex of polyethylenimine-alginate nanocomposites plus bone morphogenetic protein 2 gene to promote new bone formation  

PubMed Central

Regeneration of large bone defects is a common clinical problem. Recently, stem cell sheet has been an emerging strategy in bone tissue engineering. To enhance the osteogenic potential of stem cell sheet, we fabricated bone morphogenetic protein 2 (BMP-2) gene-engineered cell sheet using a complex of polyethylenimine–alginate (PEI–al) nanocomposites plus human BMP-2 complementary(c)DNA plasmid, and studied its osteogenesis in vitro and in vivo. PEI–al nanocomposites carrying BMP-2 gene could efficiently transfect bone marrow mesenchymal stem cells. The cell sheet was made by culturing the cells in medium containing vitamin C for 10 days. Assays on the cell culture showed that the genetically engineered cells released the BMP-2 for at least 14 days. The expression of osteogenesis-related gene was increased, which demonstrated that released BMP-2 could effectively induce the cell sheet osteogenic differentiation in vitro. To further test the osteogenic potential of the cell sheet in vivo, enhanced green fluorescent protein or BMP-2-producing cell sheets were treated on the cranial bone defects. The results indicated that the BMP-2-producing cell sheet group was more efficient than other groups in promoting bone formation in the defect area. Our results suggested that PEI–al nanocomposites efficiently deliver the BMP-2 gene to bone marrow mesenchymal stem cells and that BMP-2 gene-engineered cell sheet is an effective way for promoting bone regeneration. PMID:24855355

Jin, Han; Zhang, Kai; Qiao, Chunyan; Yuan, Anliang; Li, Daowei; Zhao, Liang; Shi, Ce; Xu, Xiaowei; Ni, Shilei; Zheng, Changyu; Liu, Xiaohua; Yang, Bai; Sun, Hongchen

2014-01-01

207

Efficiently engineered cell sheet using a complex of polyethylenimine-alginate nanocomposites plus bone morphogenetic protein 2 gene to promote new bone formation.  

PubMed

Regeneration of large bone defects is a common clinical problem. Recently, stem cell sheet has been an emerging strategy in bone tissue engineering. To enhance the osteogenic potential of stem cell sheet, we fabricated bone morphogenetic protein 2 (BMP-2) gene-engineered cell sheet using a complex of polyethylenimine-alginate (PEI-al) nanocomposites plus human BMP-2 complementary(c)DNA plasmid, and studied its osteogenesis in vitro and in vivo. PEI-al nanocomposites carrying BMP-2 gene could efficiently transfect bone marrow mesenchymal stem cells. The cell sheet was made by culturing the cells in medium containing vitamin C for 10 days. Assays on the cell culture showed that the genetically engineered cells released the BMP-2 for at least 14 days. The expression of osteogenesis-related gene was increased, which demonstrated that released BMP-2 could effectively induce the cell sheet osteogenic differentiation in vitro. To further test the osteogenic potential of the cell sheet in vivo, enhanced green fluorescent protein or BMP-2-producing cell sheets were treated on the cranial bone defects. The results indicated that the BMP-2-producing cell sheet group was more efficient than other groups in promoting bone formation in the defect area. Our results suggested that PEI-al nanocomposites efficiently deliver the BMP-2 gene to bone marrow mesenchymal stem cells and that BMP-2 gene-engineered cell sheet is an effective way for promoting bone regeneration. PMID:24855355

Jin, Han; Zhang, Kai; Qiao, Chunyan; Yuan, Anliang; Li, Daowei; Zhao, Liang; Shi, Ce; Xu, Xiaowei; Ni, Shilei; Zheng, Changyu; Liu, Xiaohua; Yang, Bai; Sun, Hongchen

2014-01-01

208

Multiple myeloma presenting as plasmacytoma of the jaws showing prominent bone formation during chemotherapy  

PubMed Central

A 65-year-old female visited our hospital complaining of a swelling on the left cheek area of 2 years' duration. A panoramic radiograph revealed an ill-defined osteolytic radiolucent bony lesion involving the left mandibular angle, ascending ramus, coronoid process and condylar process. Histological examination showed the mandibular lesion to be a plasmacytoma, and a systemic work-up was obtained to rule out multiple myeloma. Contrast-enhanced CT images showed a well-defined and slightly enhanced round mass on the left ramal area, accompanied by the destruction of the left ramus and posterior maxilla. An 18F-fluorodeoxy-glucose positron emission tomography CT (18F-FDG PET/CT) scan revealed a hypermetabolic mass extending from the left mandible to the left maxillary sinus. The patient had M-protein in serum and urine, plasma cells up to 36.5% on bone marrow biopsy and anaemia as a clinical complication. The patient was diagnosed with multiple myeloma and received chemotherapy with thalidomide, cyclophosphamide and dexamethasone. A PET/CT scan taken 6 months later revealed that the hypermetabolic mass had disappeared and there was remarkable bone formation on the left mandible compared with a previous PET/CT scan. A panoramic radiograph taken 8 months later also demonstrated a prominent bone formation of the affected site. To the best of our knowledge, the current case is the first report of multiple myeloma presenting as plasmacytoma of the mandible with an FDG PET/CT scan. The lesion was solitary at diagnosis, and remarkable bone formation was newly observed on the radiographic examination during chemotherapy. PMID:23520399

An, S-Y; An, C-H; Choi, K-S; Heo, M-S

2013-01-01

209

Inhibition of apoptosis signal-regulating kinase 1 enhances endochondral bone formation by increasing chondrocyte survival.  

PubMed

Endochondral ossification is the result of chondrocyte differentiation, hypertrophy, death and replacement by bone. The careful timing and progression of this process is important for normal skeletal bone growth and development, as well as fracture repair. Apoptosis Signal-Regulating Kinase 1 (ASK1) is a mitogen-activated protein kinase (MAPK), which is activated by reactive oxygen species and other cellular stress events. Activation of ASK1 initiates a signaling cascade known to regulate diverse cellular events including cytokine and growth factor signaling, cell cycle regulation, cellular differentiation, hypertrophy, survival and apoptosis. ASK1 is highly expressed in hypertrophic chondrocytes, but the role of ASK1 in skeletal tissues has not been investigated. Herein, we report that ASK1 knockout (KO) mice display alterations in normal growth plate morphology, which include a shorter proliferative zone and a lengthened hypertrophic zone. These changes in growth plate dynamics result in accelerated long bone mineralization and an increased formation of trabecular bone, which can be attributed to an increased resistance of terminally differentiated chondrocytes to undergo cell death. Interestingly, under normal cell culture conditions, mouse embryonic fibroblasts (MEFs) derived from ASK1 KO mice show no differences in either MAPK signaling or osteogenic or chondrogenic differentiation when compared with wild-type (WT) MEFs. However, when cultured with stress activators, H2O2 or staurosporine, the KO cells show enhanced survival, an associated decrease in the activation of proteins involved in death signaling pathways and a reduction in markers of terminal differentiation. Furthermore, in both WT mice treated with the ASK1 inhibitor, NQDI-1, and ASK1 KO mice endochondral bone formation was increased in an ectopic ossification model. These findings highlight a previously unrealized role for ASK1 in regulating endochondral bone formation. Inhibition of ASK1 has clinical potential to treat fractures or to slow osteoarthritic progression by enhancing chondrocyte survival and slowing hypertrophy.Cell Death and Disease (2014) 5, e1522; doi:10.1038/cddis.2014.480; published online 13 November 2014. PMID:25393478

Eaton, G J; Zhang, Q-S; Diallo, C; Matsuzawa, A; Ichijo, H; Steinbeck, M J; Freeman, T A

2014-01-01

210

In vivo formation of bone and haematopoietic territories by transplanted human bone marrow stromal cells generated in medium with and without osteogenic supplements.  

PubMed

Autologous transplantation of human bone marrow stromal cells (BMSCs) has been successfully used for bone reconstruction. However, in order to advance this approach into the mainstream of bone tissue engineering, the conditions for BMSC cultivation and transplantation must be optimized. In a recent report, cultivation with dexamethasone (Dex) significantly increased bone formation by human BMSCs in vivo. Based on this important conclusion, we analysed the data accumulated by our laboratory, where human BMSCs have been routinely generated using media both with and without a combination of two osteogenic supplements: Dex at 10(-8) ?m and ascorbic acid phosphate (AscP) at 10(-4) ?m. Our data demonstrate that for 22/24 donors, BMSC strains propagated with and without Dex/AscP formed similar amounts of bone in vivo. Thus, human BMSCs do not appear to need to be induced to osteogenic differentiation ex vivo prior to transplantation. Similarly, for 12/14 donors, BMSC strains cultured with and without Dex/AscP formed haematopoietic territories to a comparable extent. While Dex/AscP did not increase bone formation, they significantly stimulated BMSC in vitro proliferation without affecting the number of BMSC colonies formed by the colony-forming units-fibroblasts. We conclude that for the substantial majority of donors, Dex/AscP have no effect on the ability of BMSCs to form bone and myelosupportive stroma in vivo. However, due to increased BMSC proliferation, the total osteogenic population obtained from a single marrow sample is larger after cultivation with Dex/AscP than without them. Secondary to increased BMSC proliferation, Dex/AscP may stimulate bone formation if BMSCs and/or the transplantation system are less than optimal. Published 2011. This article is a U.S. Government work and is in the public domain in the USA. PMID:22052864

Kuznetsov, Sergei A; Mankani, Mahesh H; Robey, Pamela Gehron

2013-03-01

211

Low-Intensity Pulsed Ultrasound Accelerates Osteoblast Differentiation and Promotes Bone Formation in an Osteoporosis Rat Model  

Microsoft Academic Search

Objective: We examined the effects of low-intensity pulsed ultrasound (LIPUS) on cell differentiation, bone mineralized nodule formation and core-binding factor A1 (Cbfa1) expression in a normal human osteoblast (NHOst) cell line and bone formation in an osteoporosis animal model. Methods: NHOst cells were cultured in vitro in medium with or without LIPUS stimulation. The ultrasound stimulation frequency was 1.0 MHz

Shuliang Wu; Yumi Kawahara; Tomotaka Manabe; Kazuyuki Ogawa; Masaya Matsumoto; Akira Sasaki; Louis Yuge

2009-01-01

212

Formation of a FGF-2 and calcium phosphate composite layer on a hydroxyapatite ceramic for promoting bone formation.  

PubMed

Fibroblast growth factor-2 (FGF-2) was immobilized on a hydroxyapatite (HAP) ceramic in supersaturated calcium phosphate solution prepared using solutions corresponding to clinically approved infusion fluids. To avoid the risk of FGF-2 denaturation, FGF-2 immobilization was carried out at 25 degrees C. FGF-2 was successfully immobilized on HAP ceramic surfaces by deposition with calcium phosphate to form a FGF-2 and calcium phosphate composite layer. A maximum of 2.72 +/- 0.01 microg cm(-2) of FGF-2 was immobilized in the composite layer formed on the HAP ceramic under the optimum condition. A FGF-2-immobilized HAP ceramic is likely to have the ability to release a sufficient amount of FGF-2 to promote bone formation. FGF-2 released from a FGF-2-immobilized HAP ceramic maintained its biological activity, since the proliferation of fibroblastic NIH3T3 was promoted. Therefore, the FGF-2-immobilized HAP ceramic is expected to be a useful material for promoting new bone formation. PMID:18458464

Sogo, Yu; Ito, Atsuo; Onoguchi, Masahiro; Oyane, Ayako; Tsurushima, Hideo; Ichinose, Noboru

2007-09-01

213

Kartogenin induces cartilage-like tissue formation in tendon–bone junction  

PubMed Central

Tendon–bone junctions (TBJs) are frequently injured, especially in athletic settings. Healing of TBJ injuries is slow and is often repaired with scar tissue formation that compromises normal function. This study explored the feasibility of using kartogenin (KGN), a biocompound, to enhance the healing of injured TBJs. We first determined the effects of KGN on the proliferation and chondrogenic differentiation of rabbit bone marrow stromal cells (BMSCs) and patellar tendon stem/progenitor cells (PTSCs) in vitro. KGN enhanced cell proliferation in both cell types in a concentration-dependent manner and induced chondrogenic differentiation of stem cells, as demonstrated by high expression levels of chondrogenic markers aggrecan, collagen II and Sox-9. Besides, KGN induced the formation of cartilage-like tissues in cell cultures, as observed through the staining of abundant proteoglycans, collagen II and osteocalcin. When injected into intact rat patellar tendons in vivo, KGN induced cartilage-like tissue formation in the injected area. Similarly, when KGN was injected into experimentally injured rat Achilles TBJs, wound healing in the TBJs was enhanced, as evidenced by the formation of extensive cartilage-like tissues. These results suggest that KGN may be used as an effective cell-free clinical therapy to enhance the healing of injured TBJs.

Zhang, Jianying; Wang, James H-C

2014-01-01

214

Resorption of, and bone formation from, new beta-tricalcium phosphate-monocalcium phosphate cements: an in vivo study.  

PubMed

Hard cylinders (4.7 x 10 mm) of two kinds of beta-tricalcium phosphate-monocalcium phosphate monohydrate-calcium sulfate hemihydrate (beta-TCP-MCPM-CSH) cements with and without beta-TCP granules (500-1000 microns) were implanted into holes drilled in rabbit femoral condyles for up to 16 weeks. Empty cavities were used as control. Cement resorption and new bone formation in the cylinders were evaluated with contact microradiography and quantified through an automatic image analysis system. At 4 weeks, both kinds of cement cylinders were surrounded by new bone. At 8 weeks, except for beta-TCP granules, both cement cylinders were almost completely resorbed and replaced by bone tissue. At 16 weeks the bone in the cavities of both cements recovered a trabecular pattern, but only the bone trabeculae in the initial cavity of the cement with beta-TCP granules became thick and mature. However, the cavities of the empty control were still empty and large. These results show that the beta-TCP-MCPM-CSH cements stimulate bone formation and are rapidly replaced by bone tissue. When added with nonresorbable beta-TCP granules, this cement maintains bone formation for a longer time. PMID:9019484

Ohura, K; Bohner, M; Hardouin, P; Lemaître, J; Pasquier, G; Flautre, B

1996-02-01

215

Si-Wu-tang extract stimulates bone formation through PI3K/Akt/NF-?B signaling pathways in osteoblasts  

PubMed Central

Background Si-Wu-Tang (SWT), a Traditional Chinese Medicine (TCM) formula, is widely used for the treatment of gynopathies diseases such as menstrual discomfort, climacteric syndrome, dysmenorrhea, and other estrogen-related diseases. Recent studies have shown that SWT can treat primary dysmenorrhea, have anti-pruritic anti-inflammatory effects, and protect against radiation-induced bone marrow damage in an animal model. It has been reported that anti-inflammatory and anti-oxidant agents have the potential to treat osteoporosis by increasing bone formation and/or suppressing bone resorption. However, the effect of SWT on bone cell function has not yet been reported. Methods Alkaline phosphatase (ALP), bone morphogenetic proteins (BMP)-2, and osteopontin (OPN) mRNA expression was analyzed by qPCR. The mechanism of action of SWT extract was investigated using western blotting. The in vivo anti-osteoporotic effect of SWT extract was assessed in ovariectomized mice. Results Here, we report that SWT increases ALP, BMP-2, and OPN expression as well as bone mineralization. In addition, we show that the PI3K, Akt, and NF-?B signaling pathways may be involved in the SWT-mediated increase in gene expression and bone mineralization. Notably, treatment of mice with SWT extract prevented bone loss induced by ovariectomy in vivo. Conclusion SWT may be used to stimulate bone formation for the treatment of osteoporosis. PMID:24156308

2013-01-01

216

Effect of estrogen/gestagen and 24R,25-dihydroxyvitamin D3 therapy on bone formation in postmenopausal women  

SciTech Connect

The effect of two different estrogen/gestagen regimens and 24R,25-(OH)2-cholecalciferol on bone formation was studied in a randomized trial with 144 healthy postmenopausal women. Urinary excretion (UE) of /sup 99m/technetium-diphosphonate and serum alkaline phosphatase (AP) was determined before and then once a year for 2 years of treatment. Both estimates of bone formation showed highly significant decreases (p less than .001) to normal premenopausal levels in women receiving unopposed 17 beta-estradiol or in a sequential combination with progestagen, whereas unchanged high values were found in the groups receiving 24R,25-(OH)2D3 and placebo. The data show that bone turnover increases in early postmenopausal women concomitantly with the loss of bone mass, and that hormonal substitutional therapy normalizes the total skeletal turnover as well as preventing bone loss.

Thomsen, K.; Riis, B.; Christiansen, C.

1986-12-01

217

NF-?B RELA-deficient bone marrow macrophages fail to support bone formation and to maintain the hematopoietic niche after lethal irradiation and stem cell transplantation.  

PubMed

Bone remodeling and hematopoiesis are interrelated and bone marrow (BM) macrophages are considered to be important for both bone remodeling and maintenance of the hematopoietic niche. We found that NF-?B Rela-deficient chimeric mice, generated by transplanting Rela (-/-) fetal liver cells into lethally irradiated hosts, developed severe osteopenia, reduced lymphopoiesis and enhanced mobilization of hematopoietic stem and progenitor cells when BM cells were completely substituted by Rela-deficient cells. Rela (-/-) hematopoietic stem cells from fetal liver had normal hematopoietic ability, but those harvested from the BM of osteopenic Rela (-/-) chimeric mice had reduced repopulation ability, indicating impairment of the microenvironment for the hematopoietic niche. Osteopenia in Rela (-/-) chimeric mice was due to reduced bone formation, even though osteoblasts differentiated from host cells. This finding indicates impaired functional coupling between osteoblasts and hematopoietic stem cell-derived cells. Rela-deficient BM macrophages exhibited an aberrant inflammatory phenotype, and transplantation with wild-type F4/80(+) BM macrophages recovered bone formation and ameliorated lymphopoiesis in Rela (-/-) chimeric mice. Therefore, RELA in F4/80(+) macrophages is important both for bone homeostasis and for maintaining the hematopoietic niche after lethal irradiation and hematopoietic stem cell transplantation. PMID:24908679

Mise-Omata, Setsuko; Alles, Neil; Fukazawa, Taro; Aoki, Kazuhiro; Ohya, Keiichi; Jimi, Eijiro; Obata, Yuichi; Doi, Takahiro

2014-11-01

218

Eldecalcitol improves mechanical strength of cortical bones by stimulating the periosteal bone formation in the senescence-accelerated SAM/P6 mice - a comparison with alfacalcidol.  

PubMed

Eldecalcitol (ELD), a 2?-hydroxypropyloxy derivative of 1?,25(OH)2D3, is a potent inhibitor of bone resorption that has demonstrated a greater effect at reducing the risk of fracture in osteoporotic patients than alfacalcidol (ALF). In the present study, we used the senescence-accelerated mouse strain P6 (SAM/P6), which has low bone mass caused by osteoblast dysfunction, to evaluate the effect of ELD on cortical bone in comparison with ALF. Four-month-old SAM/P6 mice were given either ELD (0.025 or 0.05?g/kg) or ALF (0.2 or 0.4?g/kg) by oral gavage 5 times/week for 6 weeks. Both ELD and ALF increased serum calcium (Ca) in a dose-dependent manner. Serum Ca levels in the ELD 0.05?g/kg group were comparable to those of the ALF 0.2?g/kg group. ELD 0.05?g/kg significantly improved the bone biomechanical properties of the femur compared with the vehicle control group (p<0.001) and the ALF 0.2?g/kg group (p<0.05) evaluated by 3-point bending test. The cortical area of the mid-femur in the ELD 0.05?g/kg group but not the ALF 0.2?g/kg group was significantly higher than those of the vehicle control group (p<0.001). Bone histomorphometry revealed that in the femoral endocortical surface, the suppression of bone resorption parameters (N.Oc/BS) and bone formation parameters (MS/BS) by ELD (0.05?g/kg) was greater than that by ALF (0.2?g/kg). In contrast, in the femoral periosteal surface, ELD 0.05?g/kg significantly increased bone formation parameters (BFR/BS, MS/BS) compared with the vehicle control group (p<0.05, p<0.01, respectively), whereas ALF 0.2?g/kg did not alter these parameters. These results indicate that ELD improved the biomechanical properties of femoral cortical bone not only by inhibiting endocortical bone resorption but also by stimulating the periosteal bone formation in SAM/P6 mice. This article is part of a Special Issue entitled '16th Vitamin D Workshop'. PMID:24189542

Shiraishi, Ayako; Sakai, Sadaoki; Saito, Hitoshi; Takahashi, Fumiaki

2014-10-01

219

Production of New Trabecular Bone in Osteopenic Ovariectomized Rats by Prostaglandin E2  

NASA Technical Reports Server (NTRS)

Serum chemistry and bone morphometry of the proximal tibial metaphysis were performed in 3 month-old double fluorescent-labeled, female Sprague-Dawley rats subjected to bilateral ovariectomy or sham surgery for 4 months prior to treatment with 0, 0.3, 1,3, or 6 mg of prostaglandin E2 (PGE2)/kg/day subcutaneously for 30 days. The 4 month postovariectomized rats possessed an osteopenic proximal tibial metaphysis with 7% trabecular area compared with controls (19%). PGE2 treatment elevated osteocalcin levels and augmented proximal tibial metaphyseal bone area in ovariectomized and sham-operated rats. Osteopenic, ovariectomized rats treated with 6 mg (PGE2)/kg/day for 30 days restored bone area to levels of agematched sham-operated rats. Morphometric analyses showed increased woven and lamellar bone area, fluorescent-labeled perimeter (osteoblastic recruitment), mineral apposition rate (osteoblastic activity), bone formation rate (BFR/BV), and longitudinal bone growth. These dramatic bone changes were all significantly increased at the doseresponse manner. This study showed that in vivo PGE2 is a powerful activator of bone remodeling, it increases both bone resorption and bone formation, and produces an anabolic effect by shifting bone balance to the positive direction. Furthermore, PGE2-induced augmentation of metaphyseal bone area in ovariectomized rats was at least two times greater than in sham-operated rats.

Mori, S.; Jee, W. S. S.; Li, X. J.

1992-01-01

220

Creep of Nearly Lamellar TiAl Alloy Containing W  

SciTech Connect

Effects of W on the creep resistance of two nearly fully lamellar TiAl alloys with 1.0 and 2.0 at.%W have been investigated. In the low stress regime (LS) a nearly quadratic (1.5formation of {beta} phase, which produces an adverse effect on the creep strength.

Hodge, A M; Hsiung, L M; Nieh, T

2004-04-08

221

The role of 1,25-dihydroxyvitamin D in the inhibition of bone formation induced by skeletal unloading  

NASA Technical Reports Server (NTRS)

Skeletal unloading results in osteopenia. To examine the involvement of vitamin D in this process, the rear limbs of growing rats were unloaded and alterations in bone calcium and bone histology were related to changes in serum calcium (Ca), inorganic phosphorus (P sub i), 25-hydroxyvitamin D (25-OH-D), 24,25-dihydroxyvitamin D (24,25(OH)2D and 1,25-dihydroxyvitamin D (1,25(OH)2D. Acute skeletal unloading induced a transitory inhibition of Ca accumulation in unloaded bones. This was accompanied by a transitory rise in serum Ca, a 21% decrease in longitudinal bone growth (P 0.01), a 32% decrease in bone surface lined with osteoblasts (P .05), no change in bone surface lined with osteoclasts and a decrease in circulating (1,25(OH)2D. No significant changes in the serum concentrations of P sub i, 25-OH-D or 24,25(OH)2D were observed. After 2 weeks of unloading, bone Ca stabilized at approximately 70% of control and serum Ca and 1,25(OH)2D returned to control values. Maintenance of a constant serum 1,25(OH)2D concentration by chronic infusion of 1,25(OH)2D (Alza osmotic minipump) throughout the study period did not prevent the bone changes induced by acute unloading. These results suggest that acute skeletal unloading in the growing rat produces a transitory inhibition of bone formation which in turn produces a transitory hypercalcemia.

Halloran, B. P.; Bikle, D. D.; Wronski, T. J.; GLOBUS. R.; Levens, M. J.; Morey-Holton, E.

1983-01-01

222

In vitro bone formation using muscle-derived cells: a new paradigm for bone tissue engineering using polymerbone  

E-print Network

morphogenetic protein; Muscle; Tissue engineering Over 800,000 bone grafting procedures are performed annually, a Johnson and Johnson Company, Raynham, MA, USA Received 10 April 2003 Abstract Over 800,000 bone grafting procedures are performed in the United States annually, creating a demand for viable alternatives

Lu, Helen H.

223

Analysis of the dynamics of bone formation, effect of cell seeding density, and potential of allogeneic cells in cell-based bone tissue engineering in goats.  

PubMed

After decades of research, relatively little is known about the role of bone marrow stromal cells (BMSCs) for bone tissue engineering. Although homogeneous cell seeding is regarded optimal, cell survival in large constructs is unlikely, except for the very periphery. Also no minimal and optimal BMSC densities have been identified. An interesting development is the use of allogeneic BMSCs. These have not yet been compared directly to autologous BMSCs. Culture-expanded BMSCs of 10 Dutch milk goats were cryopreserved and peroperatively seeded on 7 mm cubic scaffolds of 65% porous biphasic calcium phosphate (BCP). A range of BMSC densities (per cm3 scaffold) were prepared of 8E2 (= 8 x 10(2)), 8E3, 8E4, 8E5, 8E6 (considered the standard), and 1.6E7. Each goat received a control without cells, the six densities, and an 8E6 allogeneic BMSCs construct intramuscularly. After 3, 5, and 7 weeks, fluorochrome markers were administrated. At 9 weeks, implants were retrieved. The BCP scaffolds appeared to be autoinductive as the controls (without BMSCs) showed some bone. Early bone formation (before 3 weeks) appeared only at the peripheral 2mm of the BMSC-seeded constructs; the later 5- and 9-week labels were found more centrally, suggesting bone migration to the center. There was a minimum of 8E4 and optimum of 8E6 BMSCs/cm3. Allogeneic cells yielded comparable new bone. PMID:18558815

Kruyt, Moyo; De Bruijn, Joost; Rouwkema, Jeroen; Van Bliterswijk, Clemens; Oner, Cumhur; Verbout, Ab; Dhert, Wouter

2008-06-01

224

Heat and Radiofrequency Plasma Glow Discharge Pretreatment of a Titanium Alloy Promote Bone Formation and Osseointegration  

PubMed Central

Orthopedic and dental implants manifest increased failure rates when inserted into low density bone. We determined whether chemical pretreatments of a titanium alloy implant material stimulated new bone formation to increase osseointegration in vivo in trabecular bone using a rat model. Titanium alloy rods were untreated or pretreated with heat (600°C) or radiofrequency plasma glow discharge (RFGD). The rods were then coated with the extracellular matrix protein fibronectin (1 nM) or left uncoated and surgically implanted into the rat femoral medullary cavity. Animals were euthanized 3 or 6 weeks later, and femurs were removed for analysis. The number of trabeculae in contact with the implant surface, surface contact between trabeculae and the implant, and the length and area of bone attached to the implant were measured by histomorphometry. Implant shear strength was measured by a pull-out test. Both pretreatments and fibronectin enhanced the number of trabeculae bonding with the implant and trabeculae-to-implant surface contact, with greater effects of fibronectin observed with pretreated compared to untreated implants. RFGD pretreatment modestly increased implant shear strength, which was highly correlated (r2 = 0.87 – 0.99) with measures of trabecular bonding for untreated and RFGD-pretreated implants. In contrast, heat pretreatment increased shear strength 3 to 5-fold for both uncoated and fibronectin-coated implants at 3 and 6 weeks, suggesting a more rapid increase in implant-femur bonding compared to the other groups. In summary, our findings suggest that the heat and RFGD pretreatments can promote the osseointegration of a titanium alloy implant material. PMID:23649564

MacDonald, Daniel E.; Rapuano, Bruce E.; Vyas, Parth; Lane, Joseph M.; Meyers, Kathleen; Wright, Timothy

2013-01-01

225

Using poly(lactic-co-glycolic acid) microspheres to encapsulate plasmid of bone morphogenetic protein 2/polyethylenimine nanoparticles to promote bone formation in vitro and in vivo.  

PubMed

Repair of large bone defects is a major challenge, requiring sustained stimulation to continually promote bone formation locally. Bone morphogenetic protein 2 (BMP-2) plays an important role in bone development. In an attempt to overcome this difficulty of bone repair, we created a delivery system to slowly release human BMP-2 cDNA plasmid locally, efficiently transfecting local target cells and secreting functional human BMP-2 protein. For transfection, we used polyethylenimine (PEI) to create pBMP-2/PEI nanoparticles, and to ensure slow release we used poly(lactic-co-glycolic acid) (PLGA) to create microsphere encapsulated pBMP-2/PEI nanoparticles, PLGA@pBMP-2/PEI. We demonstrated that pBMP-2/PEI nanoparticles could slowly release from the PLGA@pBMP-2/PEI microspheres for a long period of time. The 3-15 ?m diameter of the PLGA@pBMP-2/PEI further supported this slow release ability of the PLGA@pBMP-2/PEI. In vitro transfection assays demonstrated that pBMP-2/PEI released from PLGA@pBMP-2/PEI could efficiently transfect MC3T3-E1 cells, causing MC3T3-E1 cells to secrete human BMP-2 protein, increase calcium deposition and gene expressions of alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), SP7 and I type collagen (COLL I), and finally induce MC3T3-E1 cell differentiation. Importantly, in vivo data from micro-computed tomography (micro-CT) and histological staining demonstrated that the human BMP-2 released from PLGA@pBMP-2/PEI had a long-term effect locally and efficiently promoted bone formation in the bone defect area compared to control animals. All our data suggest that our PLGA-nanoparticle delivery system efficiently and functionally delivers the human BMP-2 cDNA and has potential clinical application in the future after further modification. PMID:23990717

Qiao, Chunyan; Zhang, Kai; Jin, Han; Miao, Leiying; Shi, Ce; Liu, Xia; Yuan, Anliang; Liu, Jinzhong; Li, Daowei; Zheng, Changyu; Zhang, Guirong; Li, Xiangwei; Yang, Bai; Sun, Hongchen

2013-01-01

226

Exendin-4, a glucagon-like peptide-1 receptor agonist, prevents osteopenia by promoting bone formation and suppressing bone resorption in aged ovariectomized rats.  

PubMed

Osteoporosis mainly affects postmenopausal women and older men. Gastrointestinal hormones released after meal ingestion, such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide (GLP)-2, have been shown to regulate bone turnover. However, whether GLP-1, another important gastrointestinal hormone, and its analogues also have antiosteoporotic effects, especially in aged postmenopausal situation, has not been confirmed. In the present study, we evaluated the effects of the GLP-1 receptor agonist exendin-4 on ovariectomy (OVX)-induced osteoporosis in old rats. Twelve-month-old female Sprague-Dawley rats were subjected to OVX, and exendin-4 was administrated 4 weeks after the surgery and lasted for 16 weeks. Bone characters and related serum and gene biomarkers were analyzed. Sixteen weeks of treatment with exendin-4 slowed down body weight gain by decreasing fat mass and prevented the loss of bone mass in old OVX rats. Exendin-4 also enhanced bone strength and prevented the deterioration of trabecular microarchitecture. Moreover, exendin-4 decreased the urinary deoxypyridinoline (DPD)/creatinine ratio and serum C-terminal cross-linked telopeptides of type I collagen (CTX-I) and increased serum alkaline phosphatase (ALP), osteocalcin (OC), and N-terminal propeptide of type 1 procollagen (P1NP) levels, key biochemical markers of bone turnover. Interestingly, gene expression results further showed that exendin-4 not only inhibited bone resorption by increasing the osteoprotegerin (OPG)/receptor activator of NF-?B ligand (RANKL) ratio, but also promoted bone formation by increasing the expression of OC, Col1, Runx2, and ALP, which exhibited dual regulatory effects on bone turnover as compared with previous antiosteoporotic agents. In conclusion, these findings demonstrated for the first time the antiosteoporotic effects of exendin-4 in old OVX rats and that it might be a potential candidate for treatment of aged postmenopausal osteoporosis. PMID:23427056

Ma, Xue; Meng, Jingru; Jia, Min; Bi, Long; Zhou, Ying; Wang, Yukun; Hu, Jing; He, Gonghao; Luo, Xiaoxing

2013-07-01

227

Enhancement of ectopic bone formation by bone morphogenetic protein-2 delivery using heparin-conjugated PLGA nanoparticles with transplantation of bone marrow-derived mesenchymal stem cells  

Microsoft Academic Search

This study was performed to determine if a combination of previously undifferentiated bone marrow-derived mesenchymal stem\\u000a cells (BMMSCs) and exogenous bone morphogenetic protein-2 (BMP-2) delivered via heparin-conjugated PLGA nanoparticles (HCPNs)\\u000a would extensively regenerate bone in vivo. In vitro testing found that the HCPNs were able to release BMP-2 over a 2-week\\u000a period. Human BMMSCs cultured in medium containing BMP-2-loaded HCPNs

Sung Eun Kim; Oju Jeon; Jung Bok Lee; Min Soo Bae; Heoung-Jae Chun; Seong-Hwan Moon; Il Keun Kwon

2008-01-01

228

Adipose-derived stem cells transfected with pEGFP-OSX enhance bone formation during distraction osteogenesis.  

PubMed

This study was designed to investigate the effects of local delivery of adipose-derived stem cells (ADSCs) transfected with transcription factor osterix (OSX) on bone formation during distraction osteogenesis. New Zealand white rabbits (n=54) were randomly divided into three groups (18 rabbits per group). A directed cloning technique was used for the construction of recombinant plasmid pEGFP-OSX, where EGFP is the enhanced green fluorescence protein. After osteodistraction of the right mandible of all experimental rabbits, rabbits in group A were treated with ADSCs transfected with pEGFP-OSX, group B with ADSCs transfected with pEGFP-N1, and group C with physiological saline. Radiographic and histological examinations were processed after half of the animals within each group were humanely killed by injection of sodium pentothal at Week 2 or 6 after surgery. The distraction bone density was measured as its projectional bone mineral density (BMD). Three parameters were measured, namely, the thickness of new trabeculae (TNT), and the volumes of the newly generated cortical bone (NBV1) and the cancellous bone (NBV2) of the distracted regions. Good bone generation in the distraction areas was found in group A, which had the highest BMD, TNT, and NBV in the distraction zones among the groups. There was no significant difference in bone generation in the distraction areas between groups B and C. The results indicate that the transplantation of ADSCs transfected with pEGFP-OSX can effectively promote bone generation during distraction in vivo. PMID:24793766

Lai, Qing-guo; Sun, Shao-long; Zhou, Xiao-hong; Zhang, Chen-ping; Yuan, Kui-feng; Yang, Zhong-jun; Luo, Sheng-lei; Tang, Xiao-peng; Ci, Jiang-bo

2014-05-01

229

Adipose-derived stem cells transfected with pEGFP-OSX enhance bone formation during distraction osteogenesis*  

PubMed Central

This study was designed to investigate the effects of local delivery of adipose-derived stem cells (ADSCs) transfected with transcription factor osterix (OSX) on bone formation during distraction osteogenesis. New Zealand white rabbits (n=54) were randomly divided into three groups (18 rabbits per group). A directed cloning technique was used for the construction of recombinant plasmid pEGFP-OSX, where EGFP is the enhanced green fluorescence protein. After osteodistraction of the right mandible of all experimental rabbits, rabbits in group A were treated with ADSCs transfected with pEGFP-OSX, group B with ADSCs transfected with pEGFP-N1, and group C with physiological saline. Radiographic and histological examinations were processed after half of the animals within each group were humanely killed by injection of sodium pentothal at Week 2 or 6 after surgery. The distraction bone density was measured as its projectional bone mineral density (BMD). Three parameters were measured, namely, the thickness of new trabeculae (TNT), and the volumes of the newly generated cortical bone (NBV1) and the cancellous bone (NBV2) of the distracted regions. Good bone generation in the distraction areas was found in group A, which had the highest BMD, TNT, and NBV in the distraction zones among the groups. There was no significant difference in bone generation in the distraction areas between groups B and C. The results indicate that the transplantation of ADSCs transfected with pEGFP-OSX can effectively promote bone generation during distraction in vivo. PMID:24793766

Lai, Qing-guo; Sun, Shao-long; Zhou, Xiao-hong; Zhang, Chen-ping; Yuan, Kui-feng; Yang, Zhong-jun; Luo, Sheng-lei; Tang, Xiao-peng; Ci, Jiang-bo

2014-01-01

230

Impaired bone formation in male idiopathic osteoporosis: further reduction in the presence of concomitant hypercalciuria  

NASA Technical Reports Server (NTRS)

We present iliac bone histomorphometric data and related biochemical data from 16 nonalcoholic men (50 +/- 11 (SD) years) referred for evaluation of spontaneous skeletal and/or appendicular fractures and reduced spinal bone density. All men were eugonadal and had no known underlying disorder associated with osteopenia. For the group, mean serum chemistry values were within normal limits including immunoreactive parathyroid hormone, osteocalcin and serum 1,25-dihydroxyvitamin D [1,25(OH)2D]. Nine men demonstrated hypercalciuria (greater than or equal to 0.1 mmol/kg per day) while on a constant metabolic diet of 20 mmol/day Ca. Their 24-hour urinary calcium was significantly greater than that for the remaining 7 men (7.4 +/- 1.6 vs. 5.0 +/- 0.8 mmol/day, p = 0.003), as was their calciuric response to a 1 g oral calcium load (0.23 +/- 0.06 vs. 0.15 +/- 0.05 Ca/creatinine, p = 0.042). Serum parameters (including parathyroid hormone and 1,25(OH)2D) of hypercalciuric and normocalciuric men were not significantly different. Histomorphometric indices for cancellous bone demonstrated significant differences between the entire group of osteoporotic men and age-adjusted normal values for bone volume (11.4 +/- 4.0% vs. 23.2 +/- 4.4%), osteoid surface (5.6 +/- 3.9% vs. 12.1 +/- 4.6%), osteoblastic surface (2.0 +/- 2.3% vs. 3.9 +/- 1.9%), and mineralizing surface (1.9 +/- 2.4% vs. 5.1 +/- 2.7%); there were also significant differences in bone formation rate (total surface referent) (0.004 +/- 0.001 vs. 0.011 +/- 0.006 mm3/mm2 per year). Compared with the normocalciuric group the 9 hypercalciuric men had significantly lower osteoblastic surfaces (1.6 +/- 1.9% vs. 2.5 +/- 2.6%) and mineralizing surfaces (1.4 +/- 1.5% vs. 2.7 +/- 3.2%).(ABSTRACT TRUNCATED AT 250 WORDS).

Zerwekh, J. E.; Sakhaee, K.; Breslau, N. A.; Gottschalk, F.; Pak, C. Y.

1992-01-01

231

Semen astragali complanati- and rhizoma cibotii-enhanced bone formation in osteoporosis rats  

PubMed Central

Background Growing evidence shows that herb medicines have some anti-osteoporotic effects, the mechanism underlying is unknown. This study aims to investigate the therapeutic effect of Chinese herb supplements on rats that had osteoporosis-like symptom induced by ovariectomy (OVX). Methods OVX or sham operations were performed on virgin Wistar rats at three-month old, which were randomly divided into eight groups: sham (sham); OVX control group (OVX); OVX rats with treatments [either diethylstilbestrol (DES) or Semen Astragali Complanati decoction (SACD) or Rhizoma Cibotii decoction (RCD) or Herba Cistanches decoction (HCD) or Semen Allii Tuberosi decoction (SATD)]. Non-surgical rats were served as a normal control (NC). The treatments began 4 weeks after surgery, and lasted for 12 weeks. Bone mass and its turnover were analyzed by histomorphometry. Levels of protein and mRNA of osteoprotegerin (OPG) and receptor activator of nuclear factor ?B ligand (RANKL) in osteoblasts (OB) and bone marrow stromal cells (bMSC) were evaluated by immunohistochemistry and in situ hybridization. Results Compared to OVX control, TBV% in both SACD and RCD groups was increased significantly, while TRS%, TFS%, MAR, and mAR were decreased remarkably in the SACD group, only TRS% decreased dramatically in the RCD group. No significant changes in bone formation were observed in either HCD or SATD groups. OPG levels in both protein and mRNA were reduced consistantly in OB and bMSC from OVX control rats, in contrast, RANKL levels in both protein and mRNA were increased significantly. These effects were substantially reversed by treatments with either DES or SACD or RCD. No significant changes in both OPG and RANKL expression were observed in OB and bMSC from OVX rats treated with SATD and HCD. Conclusions Our study showed that SACD and RCD increased bone formation by stimulating OPG expression and downregulating RANKL expression in OB and bMSC. This suggests that SACD and RCD may be developed as alternative anti-osteoporotic agents for therapy of postmenopausal osteoporosis. PMID:23782721

2013-01-01

232

Uncoupling of growth plate maturation and bone formation in mice lacking both Schnurri-2 and Schnurri-3  

PubMed Central

Formation and remodeling of the skeleton relies on precise temporal and spatial regulation of genes expressed in cartilage and bone cells. Debilitating diseases of the skeletal system occur when mutations arise that disrupt these intricate genetic regulatory programs. Here, we report that mice bearing parallel null mutations in the adapter proteins Schnurri2 (Shn2) and Schnurri3 (Shn3) exhibit defects in patterning of the axial skeleton during embryogenesis. Postnatally, these compound mutant mice develop a unique osteochondrodysplasia. The deletion of Shn2 and Shn3 impairs growth plate maturation during endochondral ossification but simultaneously results in massively elevated trabecular bone formation. Hence, growth plate maturation and bone formation can be uncoupled under certain circumstances. These unexpected findings demonstrate that both unique and redundant functions reside in the Schnurri protein family that are required for proper skeletal patterning and remodeling. PMID:20404140

Jones, Dallas C.; Schweitzer, Michelle N.; Wein, Marc; Sigrist, Kirsten; Takagi, Tsuyoshi; Ishii, Shunsuke; Glimcher, Laurie H.

2010-01-01

233

Implantation of silicon dioxide-based nanocrystalline hydroxyapatite and pure phase beta-tricalciumphosphate bone substitute granules in caprine muscle tissue does not induce new bone formation  

PubMed Central

Background Osteoinductive bone substitutes are defined by their ability to induce new bone formation even at heterotopic implantation sites. The present study was designed to analyze the potential osteoinductivity of two different bone substitute materials in caprine muscle tissue. Materials and methods One gram each of either a porous beta-tricalcium phosphate (?-TCP) or an hydroxyapatite/silicon dioxide (HA/SiO2)-based nanocrystalline bone substitute material was implanted in several muscle pouches of goats. The biomaterials were explanted at 29, 91 and 181 days after implantation. Conventional histology and special histochemical stains were performed to detect osteoblast precursor cells as well as mineralized and unmineralized bone matrix. Results Both materials underwent cellular degradation in which tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like cells and TRAP-negative multinucleated giant cells were involved. The ß-TCP was completely resorbed within the observation period, whereas some granules of the HA-groups were still detectable after 180 days. Neither osteoblasts, osteoblast precursor cells nor extracellular bone matrix were found within the implantation bed of any of the analyzed biomaterials at any of the observed time points. Conclusions This study showed that ß-TCP underwent a faster degradation than the HA-based material. The lack of osteoinductivity for both materials might be due to their granular shape, as osteoinductivity in goat muscle has been mainly attributed to cylindrical or disc-shaped bone substitute materials. This hypothesis however requires further investigation to systematically analyze various materials with comparable characteristics in the same experimental setting. PMID:23286366

2013-01-01

234

Optimisation of the differing conditions required for bone formation in vitro by primary osteoblasts from mice and rats  

PubMed Central

The in vitro culture of calvarial osteoblasts from neonatal rodents remains an important method for studying the regulation of bone formation. The widespread use of transgenic mice has created a particular need for a reliable, simple method that allows the differentiation and bone-forming activity of murine osteoblasts to be studied. In the present study, we established such a method and identified key differences in optimal culture conditions between mouse and rat osteoblasts. Cells isolated from neonatal rodent calvariae by collagenase digestion were cultured for 14–28 days before staining for tissue non-specific alkaline phosphatase (TNAP) and bone mineralisation (alizarin red). The reliable differentiation of mouse osteoblasts, resulting in abundant TNAP expression and the formation of mineralised ‘trabecular-shaped’ bone nodules, occurred only following culture in ? minimum essential medium (?MEM) and took 21–28 days. Dexamethasone (10 nM) inhibited bone mineralisation in the mouse osteoblasts. By contrast, TNAP expression and bone formation by rat osteoblasts were observed following culture in both ?MEM and Dulbecco’s modified Eagle’s medium (DMEM) after approximately 14 days (although ~3-fold more effectively in ?MEM) and was strongly dependent on dexamethasone. Both the mouse and rat osteoblasts required ascorbate (50 ?g/ml) for osteogenic differentiation and ?-glycerophosphate (2 mM) for mineralisation. The rat and mouse osteoblasts showed similar sensitivity to the well-established inhibitors of mineralisation, inorganic pyrophosphate (PPi) and adenosine triphosphate (ATP; 1–100 ?M). The high efficiency of osteogenic differentiation observed following culture in ?MEM, compared with culture in DMEM possibly reflects the richer formulation of the former. These findings offer a reliable technique for inducing mouse osteoblasts to form bone in vitro and a more effective method for culturing bone-forming rat osteoblasts. PMID:25200658

ORRISS, ISABEL R.; HAJJAWI, MARK O.R.; HUESA, CARMEN; MACRAE, VICKY E.; ARNETT, TIMOTHY R.

2014-01-01

235

Evaluation of circulating levels of inflammatory and bone formation markers in axial spondyloarthritis.  

PubMed

Studies have demonstrated the important role of bone remodelling and osteoimmunology in the progression of inflammatory lesions in axial spondyloarthritis (SpA) disease. This study was conducted to evaluate the inflammatory response by analysis of the serum levels of pro-inflammatory and new bone formation markers in patients with axial SpA who were treated or not treated with anti-tumour necrosis factor-? (anti-TNF-?) or non-steroidal drugs (NSAIDs) and to identify whether these drugs modify the activity and severity of the disease. The serum levels of myeloperoxidase (MPO), adenosine deaminase (ADA), nitric oxide metabolites (NOx), bone alkaline phosphatase (BAP), Dickkopf-1 (DKK-1), and osteoprotegerin (OP) were measured in 52 SpA patients who were treated or not with anti-TNF-? or NSAIDs and in 26 healthy controls using colourimetric and enzyme immunoassay tests. The activity and the severity of illness in patients with SpA were assessed using questionnaires (Bath Ankylosing Spondylitis Metrology Index (BASMI), Bath Ankylosing Spondylitis Functional Index (BASFI), and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)). A significant difference between the controls and the patients without medication was observed in relation to NOx, BAP, and OP (p<0.01). When the patients were compared with regard to their treatment, there were no clinically significant differences between the groups (p>0.05). In conclusion, The NOx, BAP, and OP are emerging as important inflammatory pathways in axial SpA. Also the anti-TNF-? or non-steroidal drugs reduce the inflammation and destructions, however these treatments do not modify the serum levels of these biomarkers. PMID:24925756

de Andrade, Kenia Rodrigues; de Castro, Gláucio Ricardo Werner; Vicente, Geison; da Rosa, Julia Salvan; Nader, Marina; Pereira, Ivanio Alves; Fröde, Tânia Silvia

2014-08-01

236

Thai traditional massage increases biochemical markers of bone formation in postmenopausal women: a randomized crossover trial  

PubMed Central

Background The effect of massage therapy on bone metabolism in adults has only scarcely been explored. In a randomized crossover trial, we investigated the skeletal effect of Thai traditional massage by examining the changes in biochemical markers of bone turnover. Methods Forty-eight postmenopausal women participated in the study. All volunteers were randomized to a 2-hour session of Thai traditional massage twice a week for 4 weeks and a 4-week control period after a 2-week washout, or vice versa. Twenty-one subjects were allocated to receiving Thai traditional massage first, followed by the control period, while 27 were initially allocated to the control period. Results Serum P1NP increased significantly after Thai traditional massage (P <0.01), while there was no change in serum osteocalcin or CTX. During the control period, there was no significant change in P1NP, osteocalcin or CTX compared to baseline. When age and height were taken into account, P1NP in postmenopausal women whose ages were in the middle and higher tertiles and whose heights were in the lower and middle tertiles (n = 22) had a 14.8 ± 3.3% increase in P1NP after massage (P <0.001), while no change in P1NP was found in the rest of the women (n = 26). Conclusions Thai traditional massage results in an increase in bone formation as assessed by serum P1NP, particularly in postmenopausal women who are older and have a smaller body build. Future studies with larger samples and additional design features are warranted. Trial registration ClinicalTrials.gov : NCT01627028 PMID:23530566

2013-01-01

237

Generation of an rhBMP-2-loaded beta-tricalcium phosphate/hydrogel composite and evaluation of its efficacy on peri-implant bone formation.  

PubMed

Dental implant insertion on a site with low bone quality or bone defect should be preceded by a bone graft or artificial bone graft insertion to heal the defect. We generated a beta-tricalcium phosphate (?-TCP) and poloxamer 407-based hydrogel composite and penetration of the ?-TCP/hydrogel composite into the peri-implant area of bone was evaluated by porous bone block experiments. The maximum penetration depth for porous bone blocks and dense bone blocks were 524??m and 464??m, respectively. We report the in-vivo performance of a composite of ?-TCP/hydrogel composite as a carrier of recombinant human bone morphogenetic protein (rhBMP-2), implanted into a rabbit tibial defect model. Three holes drilled into each tibia of eight male rabbits were (1) grafted with dental implant fixtures; (2) filled with ?-TCP/hydrogel composite (containing 5??g of rhBMP-2), followed by grafting of the dental implant fixtures. Four weeks later, bone-implant contact ratio and peri-implant bone formation were analyzed by radiography, micro-CT and histology of undecalcified specimens. The micro-CT results showed a significantly higher level of trabecular thickness and new bone and peri-implant new bone formation in the experimental treatment compared to the control treatment. Histomorphometry revealed a significantly higher bone-implant contact ratio and peri-implant bone formation with the experimental treatment. The use of ?-TCP/poloxamer 407 hydrogel composite as a carrier of rhBMP-2 significantly promoted new bone formation around the dental implant fixture and it also improved the quality of the new bone formed in the tibial marrow space. PMID:25135209

Lee, Jae Hyup; Ryu, Mi Young; Baek, Hae-Ri; Seo, Jun-Hyuk; Lee, Kyung-Mee; Lee, Ji-Ho

2014-10-01

238

Loss of Prostaglandin E2-induced Extra Cortical Bone After its Withdrawal in Rats  

NASA Technical Reports Server (NTRS)

The object of this study was to determine the fate of PGE2-(Prostaglandin E2) induced new cortical bone mass after withdrawal of PGE2 administration. Seven-month-old male Sprague-Dawley rats were given subcutaneous injections of 1, 3 and 6 mg PGE2/kg/day for 60 days and then withdrawn for 60 and 120 days (on/off treatment). Histomorphometric analyses were performed on double-fluorescent-labeled undecalcified tibial shaft sections (proximal to the tibiofibular junction). In a previous report we showed that after 60, 120 and 180 days of daily PGE2 (on)treatment, a new steady state was achieved marked by increased total bone area (+16%, +25% and +34% with 1, 3 and 6 mg PGE2/kg/day) when compared to age-matched controls. The continuous PGE2 treatment stimulated periosteal and endocortical lamellar bone formation, activated endocortical woven trabecular bone formation and intracortical bone resorption. These responses increased cortical bone mass since the bone formation exceeded bone resorption. The current study showed that after withdrawal of PGE2 for 60 and 120 days, the extra endocortical bone, which was induced by the first 60-days treatment, was resorbed, but the new subperiosteal bone persisted resulting in a tibial shaft with larger cross sectional and marrow areas. Despite that, there was still the same amount of bone mass in these shafts as in age-related controls. A new steady state was achieved after 60 days of withdrawal, in which the bone mass and bone formation activity approximated that of age-related controls. It was concluded that maintaining the extra PGE2-induced cortical bone mass depends on continuous daily administration of PGE2.

Jee, Webster S. S.; Ke, Hua Zhu; Li, Xiao Jian

1992-01-01

239

Loss of Prostaglandin E2-induced Extra Cortical Bone after its Withdrawal in Rats  

NASA Technical Reports Server (NTRS)

The object of this study was to determine the fate of PGE2-induced new cortical bone mass after withdrawal of PGE2 administration. Seven-month-old male Sprague-Dawley rats were given subcutaneous injections of 1, 3 and 6 mg PGE2/kg/day for 60 days and then withdrawn for 60 and 120 days (on/off treatment). Histomorphometric analyses were performed on double-fluorescent-labeled undecalcified tibial shaft sections (proximal to the tibiofibular junction). In a previous report we showed that after 60, 120 and 180 days of daily PGE2 (on)treatment, a new steady state was achieved marked by increased total bone area (+ 16%, +25% and + 34% with 1, 3 and 6 mg PGE2/kg/day) when compared to age-matched controls. The continuous PGE2 treatment stimulated periosteal and endocortical lamellar bone formation, activated endocortical woven trabecular bone formation and intracortical bone resorption. These responses increased cortical bone mass since the bone formation exceeded bone resorption. The current study showed that after withdrawal of PGE2 for 60 and 120 days, the extra endocortical bone, which was induced by the first 60-days treatment, was resorbed, but the new subperiosteal bone persisted resulting in a tibial shaft with larger cross sectional and marrow areas. Despite that, there was still the same amount of bone mass in these shafts as in age-related controls. A new steady state was achieved after 60 days of withdrawal, in which the bone mass and bone formation activity approximated that of age-related controls. It was concluded that maintaining the extra PGE2-induced cortical bone mass depends on continuous daily administration of PGE2.

Jee, Webster S. S.; Ke, Hua Zhu; Li, Xiao Jian

1992-01-01

240

Bio-activated titanium surface utilizable for mimetic bone implantation in dentistry—Part III: Surface characteristics and bone implant contact formation  

NASA Astrophysics Data System (ADS)

This study was carried out to quantify the effect of an alkali-modified surface on the bone implant interface formation during healing using an animal model. A total of 24 screw-shaped, self-tapping, (c.p.) titanium dental implants, divided into test group B—implants with alkali-modified surface (Bio surface) and control group M—implants with turned, machined surface, were inserted without pre-tapping in the tibiae of three beagle dogs. The animals were sacrificed after 2, 5 and 12 weeks and the bone implant contact (BIC%) was evaluated histometrically. The surface characteristics that differed between the implant surfaces, i.e. specific surface area, contact angle, may represent factors that influence the rate of osseointegration and the secondary implant stability. The alkali-treated surface enhances the BIC formation during the first 2 5 weeks of healing compared to the turned, machined surface.

Strnad, Jakub; Strnad, Zden?k; Šesták, Jaroslav; Urban, Karel; Povýšil, Ctibor

2007-05-01

241

The Mesenchymal Stem Cell Marker CD248 (Endosialin) Is a Negative Regulator of Bone Formation in Mice  

PubMed Central

Objective CD248 (tumor endothelial marker 1/endosialin) is found on stromal cells and is highly expressed during malignancy and inflammation. Studies have shown a reduction in inflammatory arthritis in CD248-knockout (CD248?/?) mice. The aim of the present study was to investigate the functional effect of genetic deletion of CD248 on bone mass. Methods Western blotting, polymerase chain reaction, and immunofluorescence were used to investigate the expression of CD248 in humans and mice. Micro-computed tomography and the 3-point bending test were used to measure bone parameters and mechanical properties of the tibiae of 10-week-old wild-type (WT) or CD248?/? mice. Human and mouse primary osteoblasts were cultured in medium containing 10 mM ?-glycerophosphate and 50 ?g/ml ascorbic acid to induce mineralization, and then treated with platelet-derived growth factor BB (PDGF-BB). The mineral apposition rate in vivo was calculated by identifying newly formed bone via calcein labeling. Results Expression of CD248 was seen in human and mouse osteoblasts, but not osteoclasts. CD248?/? mouse tibiae had higher bone mass and superior mechanical properties (increased load required to cause fracture) compared to WT mice. Primary osteoblasts from CD248?/? mice induced increased mineralization in vitro and produced increased bone over 7 days in vivo. There was no decrease in bone mineralization and no increase in proliferation of osteoblasts in response to stimulation with PDGF-BB, which could be attributed to a defect in PDGF signal transduction in the CD248?/? mice. Conclusion There is an unmet clinical need to address rheumatoid arthritis–associated bone loss. Genetic deletion of CD248 in mice results in high bone mass due to increased osteoblast-mediated bone formation, suggesting that targeting CD248 in rheumatoid arthritis may have the effect of increasing bone mass in addition to the previously reported effect of reducing inflammation. PMID:22674221

Naylor, Amy J.; Azzam, Eman; Smith, Stuart; Croft, Adam; Poyser, Callum; Duffield, Jeremy S.; Huso, David L.; Gay, Steffen; Ospelt, Caroline; Cooper, Mark S.; Isacke, Clare; Goodyear, Simon R.; Rogers, Michael J.; Buckley, Christopher D.

2014-01-01

242

A computational model of clavicle bone formation: a mechano-biochemical hypothesis.  

PubMed

Clavicle development arises from mesenchymal cells condensed as a cord extending from the acromion towards the sternal primordium. First two primary ossification centers form, extending to develop the body of the clavicle through intramembranous ossification. However, at its ends this same bone also displays endochondral ossification. So how can the clavicle be formed by both types of ossification? Developmental events associated with clavicle formation have mainly used histological studies as supporting evidence. Nonetheless, mechanisms of biological events such as molecular and mechanical effects remain to be determined. The objective of this work was to provide a mathematical explanation of embryological events based on two serial phases: first formation of an ossified matrix by intramembranous ossification based on three factors: systemic, local biochemical, and mechanical factors. After this initial phase expansion of the ossified matrix follows with mesenchymal cell differentiation into chondrocytes for posterior endochondral ossification. Our model provides strong evidence for clavicle formation integrating molecules and mechanical stimuli through partial differentiation equations using finite element analysis. PMID:24444803

Garzon-Alvarado, Diego A; Gutiérrez, María Lucía; Calixto, Luis Fernando

2014-04-01

243

Evidence for estrogen receptor expression during medullary bone formation and resorption in estrogen-treated male Japanese quails (Coturnix coturnix japonica).  

PubMed

The temporal expression of estrogen receptor (ER)-? and ER-? mRNA was examined in male Japanese quails. Femurs of quails receiving 17?-estradiol underwent RT-PCR and histochemical analysis 1 to 15 days after treatment. Untreated quails were used as controls (day 0). Between days 0 and 5, cells lining the bone endosteal surface differentiated into osteoblasts, which in turn formed medullary bone. Expression of ER-? was already observed on day 0 and increased slightly during bone formation whereas ER-? was hardly detected throughout this process. After osteoclasts appeared on the medullary bone surface, this type of bone disappeared from the bone marrow cavity (days 7˜15). ER-? expression simultaneously decreased slightly and ER-? levels remained very low. These results suggest that estrogen activity mediated by ER-? not only affects medullary bone formation but also bone resorption. PMID:23000578

Hiyama, Shinji; Sugiyama, Toshie; Kusuhara, Seiji; Uchida, Takashi

2012-09-01

244

Evidence for estrogen receptor expression during medullary bone formation and resorption in estrogen-treated male Japanese quails (Coturnix coturnix japonica)  

PubMed Central

The temporal expression of estrogen receptor (ER)-? and ER-? mRNA was examined in male Japanese quails. Femurs of quails receiving 17?-estradiol underwent RTPCR and histochemical analysis 1 to 15 days after treatment. Untreated quails were used as controls (day 0). Between days 0 and 5, cells lining the bone endosteal surface differentiated into osteoblasts, which in turn formed medullary bone. Expression of ER-? was already observed on day 0 and increased slightly during bone formation whereas ER-? was hardly detected throughout this process. After osteoclasts appeared on the medullary bone surface, this type of bone disappeared from the bone marrow cavity (days 7~15). ER-? expression simultaneously decreased slightly and ER-? levels remained very low. These results suggest that estrogen activity mediated by ER-? not only affects medullary bone formation but also bone resorption. PMID:23000578

Sugiyama, Toshie; Kusuhara, Seiji; Uchida, Takashi

2012-01-01

245

Recent Advances in the Use of Serological Bone Formation Markers to Monitor Callus Development and Fracture Healing  

PubMed Central

The failure of an osseous fracture to heal, or the development of a nonunion, is common; however, current diagnostic measures lack the capability of early and reliable detection of such events. Analyses of radiographic imaging and clinical examination, in combination, remain the gold standard for diagnosis; however, these methods are not reliable for early detection. Delayed diagnosis of a nonunion is costly from both the patient and treatment standpoints. In response, repeated efforts have been made to identify bone metabolic markers as diagnostic or prognostic tools for monitoring bone healing. Thus far, the evidence regarding a correlation between the kinetics of most bone metabolic markers and nonunion is very limited. With the aim of classifying the role of biological pathways of bone metabolism and of understanding bone conditions in the development of osteoporosis, advances have been made in our knowledge of the molecular basis of bone remodeling, fracture healing, and its failure. Procollagen type I amino-terminal propeptide has been shown to be a reliable bone formation marker in osteoporosis therapy and its kinetics during fracture healing has been recently described. In this article, we suggest that procollagen type I amino-terminal propeptide presents a good opportunity for early detection of nonunion. We also review the role and potential of serum PINP, as well as other markers, as indications of fracture healing. PMID:21133841

Coulibaly, Marlon O.; Sietsema, Debra L.; Burgers, Travis A.; Mason, Jim; Williams, Bart O.; Jones, Clifford B.

2011-01-01

246

Effects of cigarette smoke inhalation and coffee consumption on bone formation and osseous integration of hydroxyapatite implant.  

PubMed

The present study aims to assess the effects of cigarette smoke inhalation and/or coffee consumption on bone formation and osseous integration of a dense hydroxyapatite (DHA) implant in rats. For this study, 20 male rats were divided into four groups (n = 5): CT (control) group, CE (coffee) group, CI (cigarette) group and CC (coffee + cigarette) group. During 16 weeks, animals in the CI group were exposed to cigarette smoke inhalation equivalent to 6 cigarettes per day; specimens in the CE group drank coffee as liquid diet; and rats in the CC group were submitted to both substances. In the 6th week a 5 mm slit in the parietal bone and a 4 mm slit in the tibia were performed on the left side: the former was left open while the latter received a DHA implant. As soon as surgeries were finished, the animals returned to their original protocols and after 10 weeks of exposure they were euthanised (ethically sacrificed) and the mentioned bones collected for histological processing. Data showed that exposure to cigarette smoke inhalation and coffee consumption did not interfere in weight gain and that solid and liquid diet consumption was satisfactory. Rats in the CC group showed a decrease in bone neoformation around the tibial DHA implant (31.8 ± 2.8) as well as in bone formation in the parietal slit (28.6 ± 2.2). On their own, cigarette smoke inhalation or coffee consumption also led to diminished bone neoformation around the implant and delayed the bone repair process in relation to the CT group. However, reduction in the bone repair process was accentuated with exposure to both cigarette smoke inhalation and coffee consumption in this study. PMID:23644799

Andrade, A R; Sant'Ana, D C M; Mendes, J A; Moreira, M; Pires, G C; Santos, M P; Fernandes, G J M; Nakagaki, W R; Garcia, J A D; Lima, C C; Soares, E A

2013-02-01

247

In vitro and in vivo evaluation of bone formation using solid freeform fabrication-based bone morphogenic protein-2 releasing PCL/PLGA scaffolds.  

PubMed

The aim of this study was to develop novel polycaprolactone/poly(lactic-co-glycolic acid) (PCL/PLGA) scaffolds with a heparin-dopamine (Hep-DOPA) conjugate for controlled release of bone morphogenic protein-2 (BMP-2) to enhance osteoblast activity in vitro and also bone formation in vivo. PCL/PLGA scaffolds were prepared by a solid freeform fabrication method. The PCL/PLGA scaffolds were functionalized with Hep-DOPA and then BMP-2 was sequentially coated onto the Hep-DOPA/PCL/PLGA scaffolds. The characterization and surface elemental composition of all scaffolds were evaluated by scanning electron microscope and x-ray photoelectron spectroscopy. The osteoblast activities on all scaffolds were assessed by cell proliferation, alkaline phosphatase (ALP) activity and calcium deposition in vitro. To demonstrate bone formation in vivo, plain radiograph, micro-computed tomography (micro-CT) evaluation and histological studies were performed after the implantation of all scaffolds on a rat femur defect. Hep-DOPA/PCL/PLGA had more controlled release of BMP-2, which was quantified by enzyme-linked immunosorbent assay, compared with Hep/PCL/PLGA. The in vitro results showed that osteoblast-like cells (MG-63 cells) grown on BMP-2/Hep-DOPA/PCL/PLGA had significantly enhanced ALP activity and calcium deposition compared with those on BMP-2/Hep/PCL/PLGA and PCL/PLGA. In addition, the plain radiograph, micro-CT evaluation and histological studies demonstrated that the implanted BMP-2/Hep-DOPA/PCL/PLGA on rat femur had more bone formation than BMP-2/Hep/PCL/PLGA and PCL/PLGA in vivo. PMID:24518200

Kim, Tae-Hoon; Yun, Young-Pil; Park, Young-Eun; Lee, Suk-Ha; Yong, Woonjae; Kundu, Joydip; Jung, Jin Woo; Shim, Jin-Hyung; Cho, Dong-Woo; Kim, Sung Eun; Song, Hae-Ryong

2014-04-01

248

Long-Term Symptoms Onset and Heterotopic Bone Formation around a Total Temporomandibular Joint Prosthesis: a Case Report  

PubMed Central

ABSTRACT Background The literature on total alloplastic temporomandibular joint (TMJ) reconstructions is encouraging, and studies on total alloplastic TMJ replacements outcomes showed acceptable improvements in terms of both pain levels and jaw function. Nevertheless, some adverse events, such as heterotopic bone formation around the implanted prosthesis, may occur. In consideration of that, the present manuscript describes a case of heterotopic bone formation around a total temporomandibular joint prosthesis, which occurred several years after the implant. Methods The present manuscript describes a case of heterotopic bone formation around a total TMJ prosthesis, which occurred several years after the implant in patients, who previously underwent multiple failed TMJ surgeries. Results Ten years after the surgical TMJ replacement to solve an ankylotic bone block, the patient came to our attention again referring a progressive limitation in mouth opening. A computerized tomography showed evidence of marked heterotopic bone formation in the medial aspects of the joint, where a new-born ankylotic block occupied most part of the gap created by resecting the coronoid process at the time of the TMJ prosthesis insertion. Conclusions Despite this adverse event has been sometimes described in the literature, this is the first case in which its occurrence happened several years after the temporomandibular joint replacement. It can be suggested that an accurate assessment of pre-operative risk factors for re-ankylosis (e.g., patients with multiple failed temporomandibular joint surgeries) and within-intervention prevention (e.g., strategies to keep the bone interfaces around the implant separated) should be better standardized and define in future studies. PMID:24800055

Guarda-Nardini, Luca; Manfredini, Daniele; Ferronato, Giuseppe

2014-01-01

249

The role of middle ear effusions and epidermal growth factor in cholesteatoma formation in the gerbilline temporal bone  

Microsoft Academic Search

To study the process of aural cholesteatoma formation, we used gerbilline temporal bones to examine histologically the early stages of spontaneous cholesteatomas associated with experimentally induced otitis media with effusion (OME) following electric cauterizations of the eustachian tube. Epidermal growth factor (EGF) was then localized immunohistochemically in the pars flaccida of normal ears and the forming spontaneous cholesteatomas. Findings in

F. Omura; K. Makino; M. Amatsu; H. Itoh

1995-01-01

250

Slope sedimentation associated with a vertically building shelf, Bone Spring Formation, Mescalero Escarpe Field, southeast New Mexico  

Microsoft Academic Search

Mescalero Escarpe field contains slope strata in the Bone Spring formation which provide insight into development of the Northwestern shelf to the north and the Delaware basin to the south. During the Leonardian (Permian), the Northwestern shelf grew vertically due to regional subsidence and cyclic sedimentation. Slope facies include (1) dolomitized peloid-bioclast packstone, (2) dolomite megabreccia, (3) laminated dolomitic mudstone,

A. H. Saller; J. W. Barton; R. E. Barton

1987-01-01

251

Optimal lamellar arrangement in fish gills.  

PubMed

Fish respire through gills, which have evolved to extract aqueous oxygen. Fish gills consist of filaments with well-ordered lamellar structures, which play a role in maximizing oxygen diffusion. It is interesting that when we anatomically observe the gills of various fish species, gill interlamellar distances (d) vary little among them, despite large variations in body mass (Mb). Noting that the small channels formed by densely packed lamellae cause significant viscous resistance to water flow, we construct and test a model of oxygen transfer rate as a function of the lamellar dimensions and pumping pressure, which allows us to predict the optimal interlamellar distance that maximizes the oxygen transfer rate in the gill. Comparing our theory with biological data supports the hypothesis that fish gills have evolved to form the optimal interlamellar distances for maximizing oxygen transfer. This explains the weak scaling dependence of d on Mb: d ? Mb(1/6). PMID:24847065

Park, Keunhwan; Kim, Wonjung; Kim, Ho-Young

2014-06-01

252

Royal jelly stimulates bone formation: physiologic and nutrigenomic studies with mice and cell lines.  

PubMed

Royal jelly (RJ) has diverse physiological and pharmacological functions. We observed its weak estrogenic activity in the previous study. RJ stimulated the proliferation of mouse osteoblast-like MC3T3-E1 cells at 0.1 mg/ml, and the effect was blocked by the specific estrogen receptor antagonist ICI 182,780. The addition of 0.1-1.0 mg/ml RJ enhanced collagen production in culture medium. Oral administration of RJ to normal female mice for 9 weeks increased the ash content of their tibiae. DNA microarray analysis revealed significant changes in gene expression related to extracellular matrix formation when the femurs of mice fed RJ were analyzed. Quantitative reverse transcriptase-PCR (RT-PCR) confirmed up-regulation of procollagen I alpha1 gene expression. These data suggest that RJ as a whole or some of its individual components stimulates production of type I collagen and other activities for bone formation through action on osteoblasts. PMID:17031045

Narita, Yukio; Nomura, Johji; Ohta, Shozo; Inoh, Yoshikazu; Suzuki, Kazu-Michi; Araki, Yoko; Okada, Shinji; Matsumoto, Ichiro; Isohama, Yoichiro; Abe, Keiko; Miyata, Takeshi; Mishima, Satoshi

2006-10-01

253

Cell sheet transplantation of cultured mesenchymal stem cells enhances bone formation in a rat nonunion model  

Microsoft Academic Search

Orthopedic surgeons have long been troubled by cases involving nonunion of fractured bones. This study aimed to enhance bone union by cell sheet transplantation of mesenchymal stem cells. A nonunion model was made in rat femur, and rat bone marrow cells were cultured in medium containing dexamethasone and ascorbic acid phosphate to create a cell sheet that could be scraped

Akifumi Nakamura; Manabu Akahane; Hideki Shigematsu; Mika Tadokoro; Yusuke Morita; Hajime Ohgushi; Yoshiko Dohi; Tomoaki Imamura; Yasuhito Tanaka

2010-01-01

254

Why Rest Stimulates Bone Formation: A Hypothesis Based on Complex Adaptive Phenomenon  

PubMed Central

Moderate exercise is an ineffective strategy to build bone mass. The authors present data demonstrating that allowing bone to rest between each load cycle transforms low- and moderate-magnitude mechanical loading into a signal that potently induces bone accretion. They hypothesize that the osteogenic nature of rest-inserted loading arises by enabling osteocytes to communicate as a small world network. PMID:14748543

Gross, Ted S.; Poliachik, Sandra L.; Ausk, Brandon J.; Sanford, David A.; Becker, Blair A.; Srinivasan, Sundar

2006-01-01

255

Natural variation in the extent of phosphorylation of bone phosphoproteins as a function of in vivo new bone formation induced by demineralized bone matrix in soft tissue and bony environments.  

PubMed Central

Implants of allogenic demineralized bone matrix were placed in distinct in vivo environments, i.e. calvarial (bony) and subcutaneous (soft tissue) sites. Detailed analyses of the biochemical components were performed. Quantitative levels of osteopontin (OPN), bone sialoprotein (BSP) and calcium phosphate (Ca-P) deposition within each implant environment varied as a function of new bone formation, and were substantially different in samples from calvarial and subcutaneous sites. Quantification of the extent of phosphorylation of affinity-purified OPN and BSP from such implants indicated that: (i) the number of mols of phosphoserine (P-Ser)/mol of affinity-purified OPN or BSP varied as a function of implant time and bone formation within both implant sites, and (ii) the 'effective P-Ser concentration' provided by the total OPN and BSP within each implant site varied and increased as a function of time, being approx. 5-fold higher for BSP in calvarial compared with subcutaneous implants. Peak levels of mols of P-Ser/mol of BSP coincided with maximum rates of Ca-P deposition in calvarial implants. Levels of OPN phosphorylation from both calvarial and subcutaneous implants also indicated fluctuations as a function of bone formation. Hence the present study, for the first time, provides direct evidence of natural variation in the extent of phosphorylation of both OPN and BSP as a function of time of mineralized tissue formation. Further evaluation of the data provides the first evidence of a direct and linear relationship between the rate of Ca-P deposition and the ratio of P-Ser-BSP/P-Ser-OPN for calvarial implants. Data for subcutaneous implants failed to provide such correlation. Overall, the present work demonstrates that the natural biological progression of the process of biomineralization follows strict criteria consistent with the anatomical location. Biomineralization fails to proceed in the same way in a soft tissue environment. PMID:12023890

Salih, Erdjan; Wang, Jinxi; Mah, James; Fluckiger, Rudolf

2002-01-01

256

Phenytoin and fluoride act in concert to stimulate bone formation and to increase bone volume in adult male rats  

Microsoft Academic Search

We have recently demonstrated that phenytoin is an osteogenic agent at low doses. The present paper describes observations that a mitogenic dose (i.e., 20 µM in BGJb medium) of fluoride significantly augments the phenytoin-dependent stimulation of normal human bone cell proliferation and alkaline phosphatase (ALP) activity in cell culture. Additionally, the present study was designed to investigate whether fluoride and

T. Ohta; J. E. Wergedal; T. Matsuyama; D. J. Baylink; K.-H. Wiliam Lau

1995-01-01

257

Effective immobilization of BMP-2 mediated by polydopamine coating on biodegradable nanofibers for enhanced in vivo bone formation.  

PubMed

Although bone morphogenic proteins (BMPs) have been widely used for bone regeneration, the ideal delivery system with optimized dose and minimized side effects is still active area of research. In this study, we developed bone morphogenetic protein-2(BMP-2) immobilized poly(l-lactide) (PLLA) nanofibers inspired by polydopamine, which could be ultimately used as membranes for guided bone regeneration, and investigated their effect on guidance of in vitro cell behavior and in vivo bone formation. Surface chemical analysis of the nanofibers confirmed successful immobilization of BMP-2 mediated by polydopamine, and about 90% of BMP-2 was stably retained on the nanofiber surface for at least 28 days. The alkaline phosphatase activity and calcium mineralization of human mesenchymal stem cells (hMSCs) after 14 days of in vitro culture was significantly enhanced on nanofibers immobilized with BMP-2. More importantly, BMP-2 at a relatively small dose was highly active following implantation to the critical-sized defect in the cranium of mice; radiographic analysis demonstrated that 77.8 ± 11.7% of newly formed bone was filled within the defect for a BMP-2-immobilized groups at the concentration of 124 ± 9 ng/cm(2), as compared to 5.9 ± 1.0 and 34.1 ± 5.5% recovery, for a defect-only and a polydopamine-only group, respectively. Scanning and transmission electron microscopy of samples from the BMP-2 immobilized group showed fibroblasts and osteoblasts with nanofiber strands in the middle of regenerated bone tissue, revealing the importance of interaction between implanted nanofibers and the neighboring extracellular environment. Taken together, our data support that the presentation of BMP-2 on the surface of nanofibers as immobilized by utilizing polydopamine chemistry may be an effective method to direct bone growth at relatively low local concentration. PMID:24942379

Cho, Hyeong-jin; Perikamana, Sajeesh Kumar Madhurakkat; Lee, Ji-hye; Lee, Jinkyu; Lee, Kyung-Mi; Shin, Choongsoo S; Shin, Heungsoo

2014-07-23

258

Nanohydroxyapatite shape and its potential role in bone formation: an analytical study.  

PubMed

Bone cells (osteoblasts) produce a collagen-rich matrix called osteoid, which is mineralized extracellularly by nanosized calcium phosphate (CaP). Synthetically produced CaP nanoparticles (NPs) have great potential for clinical application. However few studies have compared the effect of CaP NPs with different properties, such as shape and aspect ratio, on the survival and behaviour of active bone-producing cells, such as primary human osteoblasts (HOBs). This study aimed to investigate the biocompatibility and ultrastructural effects of two differently shaped hydroxyapatite [Ca10(PO4)6(OH)2] nanoparticles (HA NPs), round- (aspect ratio 2.12, AR2) and rice-shaped (aspect ratio 3.79, AR4). The ultrastructural response and initial extracellular matrix (ECM) formation of HOBs to HA NPs were observed, as well as matrix vesicle release. A transmission electron microscopy (TEM)-based X-ray microanalytical technique was used to measure cytoplasmic ion levels, including calcium (Ca), phosphorus (P), sodium (Na) and potassium (K). K/Na ratios were used as a measure of cell viability. Following HA NP stimulation, all measured cytoplasmic ion levels increased. AR2 NPs had a greater osteogenic effect on osteoblasts compared with AR4 NPs, including alkaline phosphatase activity and matrix vesicle release. However, they produced only a moderate increase in intracellular Ca and P levels compared with AR4. This suggests that particular Ca and P concentrations may be required for, or indicative of, optimal osteoblast activity. Cell viability, as measured by Na and K microanalysis, was best maintained in AR2. Initial formation of osteoblast ECM was altered in the presence of either HA NP, and immuno-TEM identified fibronectin and matrilin-3 as two ECM proteins affected. Matrilin-3 is here described for the first time as being expressed by cultured osteoblasts. In summary, this novel and in-depth study has demonstrated that HA NP shape can influence a range of different parameters related to osteoblast viability and activity. PMID:24478288

Kalia, Priya; Vizcay-Barrena, Gema; Fan, Jian Ping; Warley, Alice; Di Silvio, Lucy; Huang, Jie

2014-04-01

259

Autologous serum improves bone formation in a primary stable silica-embedded nanohydroxyapatite bone substitute in combination with mesenchymal stem cells and rhBMP-2 in the sheep model  

PubMed Central

New therapeutic strategies are required for critical size bone defects, because the gold standard of transplanting autologous bone from an unharmed area of the body often leads to several severe side effects and disadvantages for the patient. For years, tissue engineering approaches have been seeking a stable, axially vascularized transplantable bone replacement suitable for transplantation into the recipient bed with pre-existing insufficient conditions. For this reason, the arteriovenous loop model was developed and various bone substitutes have been vascularized. However, it has not been possible thus far to engineer a primary stable and axially vascularized transplantable bone substitute. For that purpose, a primary stable silica-embedded nanohydroxyapatite (HA) bone substitute in combination with blood, bone marrow, expanded, or directly retransplanted mesenchymal stem cells, recombinant human bone morphogenetic protein 2 (rhBMP-2), and different carrier materials (fibrin, cell culture medium, autologous serum) was tested subcutaneously for 4 or 12 weeks in the sheep model. Autologous serum lead to an early matrix change during degradation of the bone substitute and formation of new bone tissue. The best results were achieved in the group combining mesenchymal stem cells expanded with 60 ?g/mL rhBMP-2 in autologous serum. Better ingrowth of fibrovascular tissue could be detected in the autologous serum group compared with the control (fibrin). Osteoclastic activity indicating an active bone remodeling process was observed after 4 weeks, particularly in the group with autologous serum and after 12 weeks in every experimental group. This study clearly demonstrates the positive effects of autologous serum in combination with mesenchymal stem cells and rhBMP-2 on bone formation in a primary stable silica-embedded nano-HA bone grafting material in the sheep model. In further experiments, the results will be transferred to the sheep arteriovenous loop model in order to engineer an axially vascularized primary stable bone replacement in clinically relevant size for free transplantation.

Boos, Anja M; Weigand, Annika; Deschler, Gloria; Gerber, Thomas; Arkudas, Andreas; Kneser, Ulrich; Horch, Raymund E; Beier, Justus P

2014-01-01

260

Total extract of Korean red ginseng facilitates human bone marrow hematopoietic colony formation in vitro  

PubMed Central

Background The number of CD34+ cells in a peripheral blood stem cell collection is the key factor in predicting successful treatment of hematologic malignancies. Korean Red Ginseng (KRG) (Panax ginseng C.A. Meyer) is the most popular medicinal herb in Korea. The objective of this study was to determine the effect of KRG on hematopoietic colony formation. Methods Bone marrow (BM) samples were obtained from 8 human donors after acquiring informed consent. BM mononuclear cells (MNCs) were isolated, and CD34+ cells were sorted using magnetic beads. The sorted CD34+ cells were incubated with or without total extract of KRG (50 µg/mL, 100 µg/mL) or Ginsenoside Rg1 (100 µg/mL), and the hematopoietic colony assay was performed using methylcellulose semisolid medium. The CD34+ cell counts were measured by a single platform assay using flow cytometry. Results The numbers of human BM-MNCs and CD34+ cells obtained after purification were variable among donors (5.6×107 and 1.3-48×107 and 8.9×104 and 1.8-80×104, respectively). The cells expanded 1,944 times after incubation for 12 d. Total extract of KRG added to the hematopoietic stem cell (HSC)-specific medium increased CD34+ cell counts 3.6 times compared to 2.6 times when using HSC medium alone. Total numbers of hematopoietic colonies in KRG medium were more than those observed in conventional medium, especially that of erythroid colonies such as burst forming unit-erythroid. Conclusion Total extract of KRG facilitated CD34+ cell expansion and hematopoietic colony formation, especially of the erythroid lineage.

Kim, Sang-Gyung; Bae, Sung Hwa; Kim, Seong-Mo; Lee, Ji-Hye; Kim, Min Ji; Jang, Hae-Bong

2014-01-01

261

The effect of rhBMP-2 and PRP delivery by biodegradable ?-tricalcium phosphate scaffolds on new bone formation in a non-through rabbit cranial defect model  

PubMed Central

This study evaluated whether the combination of biodegradable ?-tricalcium phosphate (?-TCP) scaffolds with recombinant human bone morphogenetic protein-2 (rhBMP-2) or platelet-rich plasma (PRP) could accelerate bone formation and increase bone height using a rabbit non-through cranial bone defect model. Four non-through cylindrical bone defects with a diameter of 8-mm were surgically created on the cranium of rabbits. ?-TCP scaffolds in the presence and absence of impregnated rhBMP-2 or PRP were placed into the defects. At 8 and 16 weeks after implantation, samples were dissected and fixed for analysis by microcomputed tomography and histology. Only defects with rhBMP-2 impregnated ?-TCP scaffolds showed significantly enhanced bone formation compared to non-impregnated ?-TCP scaffolds (p<0.05). Although new bone was higher than adjacent bone at 8 weeks after implantation, vertical bone augmentation was not observed at 16 weeks after implantation, probably due to scaffold resorption occurring concurrently with new bone formation. PMID:23779152

Lim, Hyun-Pil; Mercado-Pagan, Angel E.; Yun, Kwi-Dug; Kang, Seong-Soo; Choi, Taek-Hue; Bishop, Julius; Koh, Jeong-Tae; Maloney, William; Lee, Kwang-Min; Yang, Yunzhi; Park, Sang-Won

2013-01-01

262

Characterization of new bone formation in gout: a quantitative site-by-site analysis using plain radiography and computed tomography  

PubMed Central

Introduction Radiographic descriptions of gout have noted the tendency to hypertrophic bone changes. The aim of this study was to characterize the features of new bone formation (NBF) in gout, and to determine the relationship between NBF and other radiographic features of disease, particularly erosion and tophus. Methods Paired plain radiographs (XR) and computed tomography (CT) scans of 798 individual hand and wrist joints from 20 patients with gout were analyzed. Following a structured review of a separate set of images, films were scored for the presence of the following features of NBF: spur, osteophyte, periosteal NBF, ankylosis and sclerosis. The relationship between NBF and other radiographic features was analyzed. Results The most frequent forms of NBF were bone sclerosis and osteophyte. Spur and periosteal NBF were less common, and ankylosis was rare. On both XR and CT, joints with bone erosion were more likely to have NBF; for CT, if erosion was present, the odds ratios (OR) was 45.1 for spur, 3.3 for osteophyte, 16.6 for periosteal NBF, 26.6 for ankylosis and 32.3 for sclerosis, P for all < 0.01. Similarly, on CT, joints with intraosseous tophus were more likely to have NBF; if tophus was present, the OR was 48.4 for spur, 3.3 for osteophyte, 14.5 for periosteal NBF, 35.1 for ankylosis and 39.1 for sclerosis; P for all < 0.001. Conclusions This detailed quantitative analysis has demonstrated that NBF occurs more frequently in joints affected by other features of gout. This work suggests a connection between bone loss, tophus, and formation of new bone during the process of joint remodelling in gout. PMID:22794662

2012-01-01

263

Bone remodelling in osteoporosis  

Microsoft Academic Search

Summary Bone remodelling, a highly regulated succession of events, is the temporal sequence of osteoclastic bone resorption and osteoblastic bone formation. Bone loss with age and in osteoporotic patients is due to a desequilibrium between both processus. Bone histomorphometry was the method used to measure these events. Its shows clearly that, with age, the quantity of bone formed in one

M. C. de VERNEJOUL

1989-01-01

264

ABCC5 supports osteoclast formation and promotes breast cancer metastasis to bone  

PubMed Central

Introduction Bone is the most common site of breast cancer metastasis, and complications associated with bone metastases can lead to a significantly decreased patient quality of life. Thus, it is essential to gain a better understanding of the molecular mechanisms that underlie the emergence and growth of breast cancer skeletal metastases. Methods To search for novel molecular mediators that influence breast cancer bone metastasis, we generated gene-expression profiles from laser-capture microdissected trephine biopsies of both breast cancer bone metastases and independent primary breast tumors that metastasized to bone. Bioinformatics analysis identified genes that are differentially expressed in breast cancer bone metastases compared with primary, bone-metastatic breast tumors. Results ABCC5, an ATP-dependent transporter, was found to be overexpressed in breast cancer osseous metastases relative to primary breast tumors. In addition, ABCC5 was significantly upregulated in human and mouse breast cancer cell lines with high bone-metastatic potential. Stable knockdown of ABCC5 substantially reduced bone metastatic burden and osteolytic bone destruction in mice. The decrease in osteolysis was further associated with diminished osteoclast numbers in vivo. Finally, conditioned media from breast cancer cells with reduced ABCC5 expression failed to induce in vitro osteoclastogenesis to the same extent as conditioned media from breast cancer cells expressing ABCC5. Conclusions Our data suggest that ABCC5 functions as a mediator of breast cancer skeletal metastasis. ABCC5 expression in breast cancer cells is important for efficient osteoclast-mediated bone resorption. Hence, ABCC5 may be a potential therapeutic target for breast cancer bone metastasis. PMID:23174366

2012-01-01

265

A correlation analysis between bone formation rate and bioelectric potentials in rabbit tibia  

Microsoft Academic Search

Summary  The origin of the bioelectric potentials in unstressed living bones is still an open question. Blood-flow in vessels, stationary\\u000a potentials on peripheral nerves, muscle injury potentials, and viability of bone cells are claimed to be possible sites of\\u000a origin of the electric potentials recorded on bone surface.\\u000a \\u000a The present data show that the topographic quantitative distribution of tetracycline labeling at

A. Rubinacci; L. Tessari

1983-01-01

266

A comparative histological study of fossil and recent bone tissues  

E-print Network

, Eleutherodactylus (Plate XIII, fig. 5), Ascaphus (Plate XIII, fig. 8), and Seaphiopus (Plate XIII, fig. 9) differ from the primary vascular pattern found in most Rana and Bufo. The bone tissues of these amphibians are entirely simple lamellar in structure..., Eleutherodactylus (Plate XIII, fig. 5), Ascaphus (Plate XIII, fig. 8), and Seaphiopus (Plate XIII, fig. 9) differ from the primary vascular pattern found in most Rana and Bufo. The bone tissues of these amphibians are entirely simple lamellar in structure...

Enlow, Donald H.

2013-10-04

267

Divergent Resorbability and Effects on Osteoclast Formation of Commonly Used Bone Substitutes in a Human In Vitro-Assay  

PubMed Central

Bioactive bone substitute materials are a valuable alternative to autologous bone transplantations in the repair of skeletal defects. However, clinical studies have reported varying success rates for many commonly used biomaterials. While osteoblasts have traditionally been regarded as key players mediating osseointegration, increasing evidence suggests that bone-resorbing osteoclasts are of crucial importance for the longevity of applied biomaterials. As no standardized data on the resorbability of biomaterials exists, we applied an in vitro-assay to compare ten commonly used bone substitutes. Human peripheral blood mononuclear cells (PBMCs) were differentiated into osteoclasts in the co-presence of dentin chips and biomaterials or dentin alone (control) for a period of 28 days. Osteoclast maturation was monitored on day 0 and 14 by light microscopy, and material-dependent changes in extracellular pH were assessed twice weekly. Mature osteoclasts were quantified using TRAP stainings on day 28 and their resorptive activity was determined on dentin (toluidin blue staining) and biomaterials (scanning electron microscopy, SEM). The analyzed biomaterials caused specific changes in the pH, which were correlated with osteoclast multinuclearity (r?=?0.942; p?=?0.034) and activity on biomaterials (r?=?0.594; p?=?0.041). Perossal led to a significant reduction of pH, nuclei per osteoclast and dentin resorption, whereas Tutogen bovine and Tutobone human strikingly increased all three parameters. Furthermore, natural biomaterials were resorbed more rapidly than synthetic biomaterials leading to differential relative resorption coefficients, which indicate whether bone substitutes lead to a balanced resorption or preferential resorption of either the biomaterial or the surrounding bone. Taken together, this study for the first time compares the effects of widely used biomaterials on osteoclast formation and resorbability in an unbiased approach that may now aid in improving the preclinical evaluation of bone substitute materials. PMID:23071629

Busse, Bjorn; Schilling, Arndt F.; Schinke, Thorsten; Amling, Michael; Lange, Tobias

2012-01-01

268

Ascorbic acid insufficiency induces the severe defect on bone formation via the down-regulation of osteocalcin production  

PubMed Central

The L-gulono-?-lactone oxidase gene (Gulo) encodes an essential enzyme in the synthesis of ascorbic acid from glucose. On the basis of previous findings of bone abnormalities in Gulo-/- mice under conditions of ascorbic acid insufficiency, we investigated the effect of ascorbic acid insufficiency on factors related to bone metabolism in Gulo-/- mice. Four groups of mice were raised for 4 weeks under differing conditions of ascorbic acid insufficiency, namely, wild type; ascorbic acid-sufficient Gulo-/- mice, 3-week ascorbic acid-insufficient Gulo-/- mice, and 4-week ascorbic acid-insufficient Gulo-/- mice. Four weeks of ascorbic acid insufficiency resulted in significant weight loss in Gulo-/- mice. Interestingly, average plasma osteocalcin levels were significantly decreased in Gulo-/- mice after 3 weeks of ascorbic acid insufficiency. In addition, the tibia weight in ascorbic acid-sufficient Gulo-/- mice was significantly higher than that in the other three groups. Moreover, significant decreases in trabecular bone volume near to the growth plate, as well as in trabecular bone attachment to the growth plate, were evident in 3- or 4-week ascorbic acid-insufficient Gulo-/-. In summary, ascorbic acid insufficiency in Gulo-/- mice results in severe defects in normal bone formation, which are closely related to a decrease in plasma osteocalcin levels. PMID:24386598

Kim, Won; Bae, Seyeon; Kim, Hyemin; Kim, Yejin; Choi, Jiwon; Lim, Sun Young; Lee, Hei Jin; Lee, Jihyuk; Choi, Jiyea; Jang, Mirim; Lee, Kyoung Eun; Chung, Sun G.; Hwang, Young-il

2013-01-01

269

Rat adipose-derived stromal cells expressing BMP4 induce ectopic bone formation in vitro and in vivo  

Microsoft Academic Search

Aim:Bone morphogenetic protein 4 (BMP4) is one of the main local contributing factors in callus formation in the early phase of fracture healing. Adipose-derived stromal cells (ADSC) are multipotent cells. The present study was conducted to investigate the osteogenic potential of ADSC when exposed to adenovirus containing BMP4 cDNA (Ad-BMP4).Methods:ADSC were harvested from Sprague-Dawley rats. After exposure to Ad-BMP4, ADSC

Lin Lin; Xin Fu; Xin Zhang; Lian-xu Chen; Ji-ying Zhang; Chang-long Yu; Kang-tao Ma; Chun-yan Zhou

2006-01-01

270

Bone-like apatite formation on HA\\/316L stainless steel composite surface in simulated body fluid  

Microsoft Academic Search

HA\\/316L stainless steel(316L SS) biocomposites were prepared by hot-pressing technique. The formation of bone-like apatite on the biocomposite surfaces in simulated body fluid(SBF) was analyzed by digital pH meter, plasma emission spectrometer, scanning electron microscope(SEM) and energy dispersive X-ray energy spectrometer(EDX). The results indicate that the pH value in SBF varies slightly during the immersion. It is a dynamic process

Xin FAN; Jian CHEN; Jian-peng ZOU; Qian WAN; Zhong-cheng ZHOU; Jian-ming RUAN

2009-01-01

271

The effect of devitalized trabecular bone on the formation of osteochondral tissue-engineered constructs  

PubMed Central

In the current study, evidence is presented demonstrating that devitalized trabecular bone has an inhibitory effect on in vitro chondral tissue development when used as a base material for the tissue-engineering of osteochondral constructs for cartilage repair. Chondrocyte-seeded agarose hydrogel constructs were cultured alone or attached to an underlying bony base in a chemically defined medium formulation that has been shown to yield engineered cartilaginous tissue with native Young's modulus (EY) and glycosaminoglycan (GAG) content. By day 42 in culture the incorporation of a bony base significantly reduced these properties (EY = 87 ± 12 kPa, GAG = 1.9 ± 0.8%ww) compared to the gel-alone group (EY = 642 ± 97 kPa, GAG = 4.6 ± 1.4%ww). Similarly, the mechanical and biochemical properties of chondrocyte-seeded agarose constructs were inhibited when co-cultured adjacent to bone (unattached), suggesting that soluble factors rather than direct cell–bone interactions mediate the chondro-inhibitory bone effects. Altering the method of bone preparation, including demineralization, or the timing of bone introduction in co-culture did not ameliorate the effects. In contrast, osteochondral constructs with native cartilage properties (EY = 730 ± 65 kPa, GAG = 5.2 ± 0.9%ww) were achieved when a porous tantalum metal base material was adopted instead of bone. This work suggests that devitalized bone may not be a suitable substrate for long-term cultivation of osteochondral grafts. PMID:18718655

Lima, Eric G.; Chao, Pen-hsiu Grace; Ateshian, Gerard A.; Bal, B. Sonny; Cook, James L.; Vunjak-Novakovic, Gordana; Hung, Clark T.

2008-01-01

272

The Fos-related antigen Fra-1 is an activator of bone matrix formation  

PubMed Central

Ectopic expression of the transcription factor Fra-1 in transgenic mice leads to osteosclerosis, a bone disorder characterized by increased bone mass. The molecular basis for this phenotype is unknown and Fra-1 functions cannot be studied by a conventional loss-of-function approach, since fra-1-knockout mice die in utero likely due to placental defects. Here we show that the lethality of fra-1-knockout mice can be rescued by specific deletion of Fra-1 only in the mouse embryo and not in the placenta. Mice lacking Fra-1 (fra-1?/?) are viable and develop osteopenia, a low bone mass disease. Long bones of fra-1?/? mice appear to have normal osteoclasts but express reduced amounts of bone matrix components produced by osteoblasts and chondrocytes such as osteocalcin, collagen1a2 and matrix Gla protein. The gene for matrix Gla protein seems to be a specific target of Fra-1 since its expression was markedly increased in the long bones of fra-1-transgenic mice. These results uncover a novel function of Fra-1 in regulating bone mass through bone matrix production by osteoblasts and chondrocytes. PMID:15229648

Eferl, Robert; Hoebertz, Astrid; Schilling, Arndt F; Rath, Martina; Karreth, Florian; Kenner, Lukas; Amling, Michael; Wagner, Erwin F

2004-01-01

273

Castor oil polymer induces bone formation with high matrix metalloproteinase-2 expression.  

PubMed

The aim of this study was to evaluate the modulation of matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) expression in newly formed bone tissue at the interface between implants derived from castor oil (Ricinus communis) polymer and the tibia medullary canal. Forty-four rabbits were assigned to either Group 1 (n?=?12; control) or Group 2 (n?=?30), which had the tibial medullary canals reamed bilaterally and filled with polymer. CT scans showed no space between the material surface and the bone at the implant/bone marrow interface, and the density of the tissues at this interface was similar to the density measured of other regions of the bone. At 90 days postimplantation, the interface with the polymer presented a thick layer of newly formed bone tissue rich in osteocytes. This tissue exhibited ongoing maturation at 120 and 150 days postimplantation. Overall, bone remodeling process was accompanied by positive modulation of MMP-2 and low MMP-9 expression. Differently, in control group, the internal surface close to the medullary canal was lined by osteoblasts, followed by a bone tissue zone with few lacunae filled with osteocytes. Maturation of the tissue of the medullary internal surface occurred in the inner region, with the bone being nonlamellar. PMID:23670892

Saran, Wallace Rocha; Chierice, Gilberto Orivaldo; da Silva, Raquel Assed Bezerra; de Queiroz, Alexandra Mussolino; Paula-Silva, Francisco Wanderley Garcia; da Silva, Léa Assed Bezerra

2014-02-01

274

A New Piezoelectric Actuator Induces Bone Formation In Vivo: A Preliminary Study  

PubMed Central

This in vivo study presents the preliminary results of the use of a novel piezoelectric actuator for orthopedic application. The innovative use of the converse piezoelectric effect to mechanically stimulate bone was achieved with polyvinylidene fluoride actuators implanted in osteotomy cuts in sheep femur and tibia. The biological response around the osteotomies was assessed through histology and histomorphometry in nondecalcified sections and histochemistry and immunohistochemistry in decalcified sections, namely, through Masson's trichrome, and labeling of osteopontin, proliferating cell nuclear antigen, and tartrate-resistant acid phosphatase. After one-month implantation, total bone area and new bone area were significantly higher around actuators when compared to static controls. Bone deposition rate was also significantly higher in the mechanically stimulated areas. In these areas, osteopontin increased expression was observed. The present in vivo study suggests that piezoelectric materials and the converse piezoelectric effect may be used to effectively stimulate bone growth. PMID:22701304

Reis, Joana; Frias, Clara; Canto e Castro, Carlos; Botelho, Maria Luisa; Marques, Antonio Torres; Simoes, Jose Antonio Oliveira; Capela e Silva, Fernando; Potes, Jose

2012-01-01

275

Ectopic bone formation by marrow stromal osteoblast transplantation using poly(DL-lactic-co-glycolic acid) foams implanted into the rat mesentery  

NASA Technical Reports Server (NTRS)

Porous biodegradable poly(DL-lactic-co-glycolic acid) foams were seeded with rat marrow stromal cells and implanted into the rat mesentery to investigate in vivo bone formation at an ectopic site. Cells were seeded at a density of 6.83 x 10(5) cells/cm2 onto polymer foams having pore sizes ranging from either 150 to 300 to 710 microns and cultured for 7 days in vitro prior to implantation. The polymer/cell constructs were harvested after 1, 7, 28, or 49 days in vivo and processed for histology and gel permeation chromatography. Visual observation of hematoxylin and eosin-stained sections and von Kossa-stained sections revealed the formation of mineralized bonelike tissue in the constructs within 7 days postimplantation. Ingrowth of vascular tissue was also found adjacent to the islands of bone, supplying the necessary metabolic requirements to the newly formed tissue. Mineralization and bone tissue formation were investigated by histomorphometry. The average penetration depth of mineralized tissue in the construct ranged from 190 +/- 50 microns for foams with 500-710-microns pores to 370 +/- 160 microns for foams with 150-300-microns pores after 49 days in vivo. The mineralized bone volume per surface area and total bone volume per surface area had maximal values of 0.28 +/- 0.21 mm (500-710-microns pore size, day 28) and 0.038 +/- 0.024 mm (150-300-microns, day 28), respectively. As much as 11% of the foam volume penetrated by bone tissue was filled with mineralized tissue. No significant trends over time were observed for any of the measured values (penetration depth, bone volume/surface area, or percent mineralized bone volume). These results suggest the feasibility of bone formation by osteoblast transplantation in an orthotopic site where not only bone formation from transplanted cells but also ingrowth from adjacent bone may occur.

Ishaug-Riley, S. L.; Crane, G. M.; Gurlek, A.; Miller, M. J.; Yasko, A. W.; Yaszemski, M. J.; Mikos, A. G.; McIntire, L. V. (Principal Investigator)

1997-01-01

276

Comparison of effect of BMP2, -4, and -6 on in vitro cartilage formation of human adult stem cells from bone marrow stroma  

Microsoft Academic Search

The human adult stem cells from bone marrow stroma referred to as mesenchymal stem cells or marrow stromal cells (MSCs) are of interest because they are easily isolated and expanded and are capable of multipotential differentiation. Here, we examined the ability of recombinant human bone morphogenetic protein (BMP)-2, -4, and -6 to enhance in vitro cartilage formation of MSCs. Human

Ichiro Sekiya; Benjamin L. Larson; Jussi T. Vuoristo; Roxanne L. Reger; Darwin J. Prockop

2005-01-01

277

Targeted overexpression of parathyroid hormone-related peptide in chondrocytes causes chondrodysplasia and delayed endochondral bone formation.  

PubMed Central

Parathyroid hormone-related peptide (PTHrP) was initially identified as a product of malignant tumors that mediates paraneoplastic hypercalcemia. It is now known that the parathyroid hormone (PTH) and PTHrP genes are evolutionarily related and that the products of these two genes share a common receptor, the PTH/PTHrP receptor. PTHrP and the PTH/PTHrP receptor are widely expressed in both adult and fetal tissues, and recent gene-targeting and disruption experiments have implicated PTHrP as a developmental regulatory molecule. Apparent PTHrP functions include the regulation of endochondral bone development, of hair follicle formation, and of branching morphogenesis in the breast. Herein, we report that overexpression of PTHrP in chondrocytes using the mouse type II collagen promoter induces a novel form of chondrodysplasia characterized by short-limbed dwarfism and a delay in endochondral ossification. This features a delay in chondrocyte differentiation and in bone collar formation and is sufficiently marked that the mice are born with a cartilaginous endochondral skeleton. In addition to the delay, chondrocytes in the transgenic mice initially become hypertrophic at the periphery of the developing long bones rather than in the middle, leading to a seeming reversal in the pattern of chondrocyte differentiation and ossification. By 7 weeks, the delays in chondrocyte differentiation and ossification have largely corrected, leaving foreshortened and misshapen but histologically near-normal bones. These findings confirm a role for PTHrP as an inhibitor of the program of chondrocyte differentiation. PTHrP may function in this regard to maintain the stepwise differentiation of chondrocytes that initiates endochondral ossification in the midsection of endochondral bones early in development and that also permits linear growth at the growth plate later in development. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8816783

Weir, E C; Philbrick, W M; Amling, M; Neff, L A; Baron, R; Broadus, A E

1996-01-01

278

Magnetic nanorods confined in a lamellar lyotropic phase  

E-print Network

Magnetic nanorods confined in a lamellar lyotropic phase Keevin B�eneut, Doru Constantin , Patrick, CNRS, UMR 7574, F-75252, Paris Cedex 05, France. May 7, 2008 Abstract The dilute lamellar phase of the nonionic surfactant C12EO5 was doped with goethite (iron oxide) nanorods up to a fraction of 5 vol

Paris-Sud XI, Université de

279

Structure, Stability, and Thermodynamics of Lamellar DNA-Lipid Complexes  

E-print Network

of parallel strands of DNA intercalated in the water layers of lamellar stacks of mixed lipid bilayers, with the parallel DNA strands intercalated between. Quite different morphologies are expected to arise for otherStructure, Stability, and Thermodynamics of Lamellar DNA-Lipid Complexes Daniel Harries,* Sylvio

Harries, Daniel

280

IL-23 Is Critical for Induction of Arthritis, Osteoclast Formation, and Maintenance of Bone Mass  

PubMed Central

The role of IL-23 in the development of arthritis and bone metabolism was studied using systemic IL-23 exposure in adult mice via hydrodynamic delivery of IL-23 minicircle DNA in vivo and in mice genetically deficient in IL-23. Systemic IL-23 exposure induced chronic arthritis, severe bone loss, and myelopoiesis in the bone marrow and spleen, which resulted in increased osteoclast differentiation and systemic bone loss. The effect of IL-23 was partly dependent on CD4+ T cells, IL-17A, and TNF, but could not be reproduced by overexpression of IL-17A in vivo. A key role in the IL-23–induced arthritis was made by the expansion and activity of myeloid cells. Bone marrow macrophages derived from IL-23p19?/? mice showed a slower maturation into osteoclasts with reduced tartrate-resistant acid phosphatase-positive cells and dentine resorption capacity in in vitro osteoclastogenesis assays. This correlated with fewer multinucleated osteoclast-like cells and more trabecular bone volume and number in 26-wk-old male IL-23p19?/? mice compared with control animals. Collectively, our data suggest that systemic IL-23 exposure induces the expansion of a myeloid lineage osteoclast precursor, and targeting IL-23 pathway may combat inflammation-driven bone destruction as observed in rheumatoid arthritis and other autoimmune arthritides. The Journal of Immunology, 2011, 187: 951–959. PMID:21670317

Adamopoulos, Iannis E.; Tessmer, Marlowe; Chao, Cheng-Chi; Adda, Sarvesh; Gorman, Dan; Petro, Mary; Chou, Chuan-Chu; Pierce, Robert H.; Yao, Wei; Lane, Nancy E.; Laface, Drake; Bowman, Edward P.

2014-01-01

281

Focal osteoporotic hematopoietic bone marrow defect formation around a dental implant: a case report.  

PubMed

Focal osteoporotic bone marrow defects usually appear as asymptomatic radioluencies in the edentulous posterior mandible of middle-aged women. The exact causative factor in the majority of focal osteoporotic bone marrow defects is still unknown. Because of their radiological similarity with many intraosseous lesions, accurate diagnosis is possible only with histopathological examination. A focal osteoporotic bone marrow defect that occurred 2 years postoperatively apical to an implant is presented with clinical, radiographic, and histopathologic features. According to the literature scan, this is the first case report of this phenomenon caused by a dental implant. Int J Oral Maxillofac Implants 2011;26:e1-e4. PMID:21365033

Sencimen, Metin; Delilbasi, Cagri; Gulses, Aydin; Okcu, Kemel Murat; Gunhan, Omer; Varol, Altan

2011-01-01

282

Blunt scissors stromal dissection technique for deep anterior lamellar keratoplasty  

PubMed Central

Objective We describe a modified technique for performing lamellar dissection in deep anterior lamellar keratoplasty after failure to achieve a “big bubble” detachment of Descemet’s membrane (DM) with deep intrastromal pneumatic injection. Methods The technique utilizes blunt lamellar dissection with blunt-tipped corneal mini scissors as an alternative to a crescent blade, which can be difficult for surgeons to master and is associated with a high risk of perforation. Results Other techniques of blunt dissection, such as the Melles technique, cannot be utilized after failure to achieve a big bubble, as emphysema in the stroma prevents visualization of the spatula. In contrast, our blunt scissors lamellar dissection technique takes advantage of the emphysema and microdetachments of DM created by the pneumatic injection. Conclusion This technique provides deep anterior lamellar keratoplasty surgeons with a simple, alternative method of baring DM or achieving a pre-DM plane with minimal residual stroma, after failure to achieve a big bubble. PMID:25258506

Anwar, Didar S; Kruger, Matthew M; Mootha, V Vinod

2014-01-01

283

Chain confinement, phase transitions, and lamellar structure in semicrystalline polymers, polymer blends and polymer nanocomposites  

NASA Astrophysics Data System (ADS)

Recent studies suggest that there are three phase fractions in semicrystalline polymers, the crystalline, the mobile amorphous and the rigid amorphous phases. Due to the distinct properties of the rigid amorphous fraction, RAF, it has been investigated for more than twenty years. In this thesis, a general method using quasi-isothermal temperature-modulated differential scaning calorimetry, DSC, is provided for the first time to obtain the temperature dependent RAF and the other two fractions, crystalline fraction and mobile amorphous fraction, MAF. For poly(ethylene terephthalate), PET, our results show RAF was vitrified during quasi-isothermal cooling after crystallization had been completed and became totally devitrified during quasi-isothermal heating before the start of melting. Several years after people initially discovered the existence of RAF, another issue arose relating to the physical location of RAF and mobile amorphous fraction, MAF, within a lamellar stack model. Two very different models to describe the location of RAF were proposed. In the Heterogeneous Stack Model, HET, RAF is located outside the lamellar stacks. In the Homogeneous Stack Model, HSM, RAF was located inside the lamellar stacks. To determine the lamellar structure of semicrystalline polymers comprising three phase, a general method is given in this thesis by using a combination of the DSC and small angle X-ray scattering, SAXS techniques. It has been applied to Nylon 6, isotactic polystyrene, iPS, and PET. It was found for all of these materials, the HSM model is correct to describe the lamellar structure. In addition to the determination of lamellar structures, this method can also provide the exact fraction of MAF inside and outside lamellar stacks for binary polymer blends. For binary polymer blends, MAF, normally is located partially inside and partially outside the lamellar stacks. However, the quantification of the MAF inside and outside the lamellar stacks has now been provided and is applied to the iPS/atactic polystyrene, aPS, blends. The fractions of MAF inside and outside the lamellar stacks were quantified for the first time. For A/B binary polymer blends, it has been reported that if B is already crystalline, the crystalline fraction would serve as a restriction on the subsequent growth of the crystallizable partner A, while amorphous fraction could be diffused from the crystalline growth front of the crystallizing A component. Considering the effect of RAF on binary blends, a new concept is provided: like the crystals, the RAF of one polymer component may inhibit the growth of crystals of the other blend partner. The non-isothermal crystallization of PET/poly(lactic acid), PLA, blends were investigated and the results confirmed the new concept is correct: PET forms a large amount of RAF and inhibits crystal formation in PLA. Then, we broadened the concept of RAF and investigated the RAF in recent 'hot' materials, polymer nanocomposites. It was found the fraction of RAF greatly increased with a small amount of multi-wall carbon nanotubes, MWCNT, loading in PET electrospun, ES, fibers. A general model is given for polymer ES fibers with MWCNTs: the addition of MWCNTs causes polymer chains in the ES fibers to become more extended, (ie, more stretched), resulting in more confinement of PET chains and an increase in the RAF.

Chen, Huipeng

284

In vitro and in vivo studies of surface-structured implants for bone formation  

PubMed Central

Background and methods Micronanoscale topologies play an important role in implant osteointegration and determine the success of an implant. We investigated the effect of three different implant surface topologies on osteoblast response and bone regeneration. In this study, implants with nanotubes and micropores were used, and implants with flat surfaces were used as the control group. Results Our in vitro studies showed that the nanostructured topologies improved the proliferation, differentiation, and development of the osteoblastic phenotype. Histological analysis further revealed that the nanotopology increased cell aggregation at the implant-tissue interfaces and enhanced bone-forming ability. Pushout testing indicated that the nanostructured topology greatly increased the bone-implant interfacial strength within 4 weeks of implantation. Conclusion Nanotopography may improve regeneration of bone tissue and shows promise for dental implant applications. PMID:23028216

Xia, Lu; Feng, Bo; Wang, Peizhi; Ding, Siyang; Liu, Zhiyuan; Zhou, Jie; Yu, Rong

2012-01-01

285

Applications of Mössbauer Spectroscopy to Lamellar Magnetism  

NASA Astrophysics Data System (ADS)

Nanosize lamellar structures that form in slowly cooled igneous and metamorphic rocks can have unusually high natural magnetic remanence that is stable over timescales of one billion years or more. This behavior has been attributed to lamellar magnetism in the system hematite-ilmenite, where ferrimagnetic contact layers form between paramagnetic ilmenite and antiferromagnetic hematite. Such stable magnetic memory is of importance for planetary magnetism, particularly for planets such as Mars where the magnetic field is no longer present, and for potential industrial applications such as the development of highly stable magnetic storage units. Mössbauer spectroscopy provides a unique probe of the iron environment, enabling the quantitative determination of iron distribution and abundance, with insight into parameters that determine the magnetic properties. To investigate the role of iron in lamellar magnetism, we have undertaken a study of rocks from several different regions using Mössbauer spectroscopy. Titanohaematite grains were identified optically on polished thin sections of slowly cooled rocks from Lerhuvud and Gödestad (both in southern Sweden) and the Russell Belt (Adirondack Mountains, USA). Grains were removed from thin sections with a microdrill, and mounted on a Mössbauer spectrometer fitted with a point source. Room-temperature Mössbauer spectra are dominated by magnetically ordered Fe3+ in hematite, with a smaller absorption corresponding to paramagnetic Fe2+ in ilmenite. Minor absorption is also observed from magnetite and pyrite in some grains. There is no evidence for superparamagnetic hematite in any of the spectra. Comparison of Mössbauer spectra of the natural samples with those from synthetic hematite-rich titanohematite solid solutions provides a measure of the iron environment in natural titanohematite, showing that there is only moderate deviation from the ideal hematite local environment. The absence of Fe3+ in ilmenite indicates that ilmenite lamellae are close to the endmember composition. All grains taken from the same thin sections show similar ilmenite:hematite area ratios, and the two different samples from Gödestad also show similar ratios, suggesting a similar bulk composition. Based on models of cation and magnetic ordering, the proportion of iron involved in the contact layers can be determined, and combined with information from the Mössbauer spectra, provide insight into the density of lamellae, which effectively controls the magnetization.

McCammon, C.; McEnroe, S.; Robinson, P.

2005-12-01

286

Recombinant human bone morphogenetic protein-type 2 (rhBMP-2) enhances local bone formation in the lumbar spine of osteoporotic sheep.  

PubMed

The failure of orthopedic implants in osteoporotic patients is attributed to the lack of sufficient bone stock and regenerative capacity but most treatments for osteoporosis fail to address this issue. rhBMP-2 is known to promote bone formation under normal conditions but has not been used clinically in the osteoporotic condition. Osteoporosis was induced in 19 ewes using ovariectomy, low calcium diet, and steroid injection. After induction, the steroid was withdrawn and pellets containing inert carrier with rhBMP-2 in either slow or fast-release formulation were implanted into the lumbar vertebrae of each animal. After 2, 3, and 6 months the spines were harvested and assessed for changes in BMD and histomorphometric indices. BMD did not change after cessation of steroid treatment. After 2 months BV/TV increased in the vicinity of the pellets containing the fast-release rhBMP-2 and was sustained for the duration of the study. Focal voids surrounding all implants, particularly the slow-release formulation, were observed initially but resolved with time. Increased BV/TV adjacent to rhBMP-2 pellets suggests it could be used for localized treatment of osteoporosis. Refinement of the delivery system and supplementary treatments may be necessary to overcome the initial catabolic effects of rhBMP-2. PMID:23737220

Zarrinkalam, Mohammad Reza; Schultz, Christopher G; Ardern, David W; Vernon-Roberts, Barrie; Moore, Robert J

2013-09-01

287

Helium embrittlement of a lamellar titanium aluminide  

NASA Astrophysics Data System (ADS)

Embrittlement by helium was investigated in a lamellar TiAl alloy under two conditions: Specimens were implanted to various amounts of helium up to 762 appm at temperatures from 630 °C to 1000 °C and some of them subsequently creep-tested at the same temperature under stresses from 150 to 300 MPa. The microstructure and fracture surfaces of creep-deformed and non-creep-deformed specimens were then studied by transmission electron microscopy (TEM) and by scanning electron microscopy (SEM), respectively. Specimens were implanted to various amounts of helium at a low temperature (150 °C) and post-implantation annealed at elevated temperatures for TEM studies. Embrittlement was revealed by reduction in time- and strain-to-rupture and by a transition in fracture surface from ductile to an inter-lamellar appearance. Embrittlement occurred above a critical He concentration, which decreased from about 10 appm at 700 °C to below 6 appm at 900 °C. TEM showed that embrittlement could be associated to reaching a critical bubble diameter of about 5 nm. Bubble diameters increased with increasing temperature ranging in high-temperature implanted specimens from about 3 nm (630 °C) to 20 nm (1000 °C) and in post-implantation annealed ones from 1.2 nm (600 °C) to 2.2 nm (900 °C), respectively. With increasing temperature, the bubble distribution grew less homogenous with a lower density of larger bubbles situated preferentially at interfaces and sinks. This was ascribed to a change in bubble nucleation mode from homogeneous di-atomic nucleation at lower temperatures to multi-atomic nucleation at sinks at higher temperature.

Magnusson, P.; Chen, J.; Jung, P.; Sauvage, T.; Hoffelner, W.; Spätig, Ph.

2013-03-01

288

Overexpression of H1 Calponin in Osteoblast Lineage Cells Leads to a Decrease in Bone Mass by Disrupting Osteoblast Function and Promoting Osteoclast Formation  

PubMed Central

H1 calponin (CNN1) is known as a smooth muscle-specific, actin-binding protein which regulates smooth muscle contractive activity. Although previous studies have shown that CNN1 has effect on bone, the mechanism is not well defined. To investigate the role of CNN1 in maintaining bone homeostasis, we generated transgenic mice overexpressing Cnn1 under the control of the osteoblast-specific 3.6-kb Col1a1 promoter. Col1a1-Cnn1 transgenic mice showed delayed bone formation at embryonic stage and decreased bone mass at adult stage. Morphology analyses showed reduced trabecular number, thickness and defects in bone formation. The proliferation and migration of osteoblasts were decreased in Col1a1-Cnn1 mice due to alterations in cytoskeleton. The early osteoblast differentiation of Col1a1-Cnn1 mice was increased, but the late stage differentiation and mineralization of osteoblasts derived from Col1a1-Cnn1 mice were significantly decreased. In addition to impaired bone formation, the decreased bone mass was also associated with enhanced osteoclastogenesis. Tartrate-resistant acid phosphatase (TRAP) staining revealed increased osteoclast numbers in tibias of 2-month-old Col1a1-Cnn1 mice, and increased numbers of osteoclasts co-cultured with Col1a1-Cnn1 osteoblasts. The ratio of RANKL to OPG was significantly increased in Col1a1-Cnn1 osteoblasts. These findings reveal a novel function of CNN1 in maintaining bone homeostasis by coupling bone formation to bone resorption. PMID:23044709

Su, Nan; Chen, Maomao; Chen, Siyu; Li, Can; Xie, Yangli; Zhu, Ying; Zhang, Yaozong; Zhao, Ling; He, Qifen; Du, Xiaolan; Chen, Di; Chen, Lin

2013-01-01

289

Nanoparticle size controls aggregation in lamellar nonionic surfactant mesophase.  

PubMed

We show that the size of silica nanoparticles influences the nature of their aggregation in an aqueous solution of a relatively hydrophobic nonionic surfactant, C12E4. We present results for dispersions of silica nanoparticles with sizes varying from 8 to 26 nm, in a 75: 25 C12E4/water system, that forms a lamellar phase, L?, at room temperature. Addition of silica particles does not affect the formation of the L? phase. Nanoparticles smaller than about 11 nm aggregate irreversibly in the C12E4/water system. However, nanoparticles larger than about 15 nm aggregate in the L? phase, but are dispersed at temperatures above the L? order-disorder temperature. Thus, in contrast to the smaller particles, aggregation of silica nanoparticles larger than about 15 nm is reversible with temperature. We use small-angle neutron scattering (SANS) to demonstrate that these results can be explained by the size-dependent wrapping of nanoparticles by surfactant bilayers. Larger particles, above 15 nm in size, are sterically stabilized by the formation of an adsorbed surfactant bilayer. The cost of bilayer bending inhibits adsorption onto the highly curved surfaces of smaller particles, and these "bare" particles aggregate irreversibly. PMID:23845138

Venugopal, Edakkal; Aswal, Vinod K; Kumaraswamy, Guruswamy

2013-08-01

290

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

PubMed Central

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

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

2013-01-01

291

The Nell-1 Growth Factor Stimulates Bone Formation by Purified Human Perivascular Cells  

PubMed Central

The search for novel sources of stem cells other than bone marrow mesenchymal stem cells (MSCs) for bone regeneration and repair has been a critical endeavor. We previously established an effective protocol to homogeneously purify human pericytes from multiple fetal and adult tissues, including adipose, bone marrow, skeletal muscle, and pancreas, and identified pericytes as a primitive origin of human MSCs. In the present study, we further characterized the osteogenic potential of purified human pericytes combined with a novel osteoinductive growth factor, Nell-1. Purified pericytes grown on either standard culture ware or human cancellous bone chip (hCBC) scaffolds exhibited robust osteogenic differentiation in vitro. Using a nude mouse muscle pouch model, pericytes formed significant new bone in vivo as compared to scaffold alone (hCBC). Moreover, Nell-1 significantly increased pericyte osteogenic differentiation, both in vitro and in vivo. Interestingly, Nell-1 significantly induced pericyte proliferation and was observed to have pro-angiogenic effects, both in vitro and in vivo. These studies suggest that pericytes are a potential new cell source for future efforts in skeletal regenerative medicine, and that Nell-1 is a candidate growth factor able to induce pericyte osteogenic differentiation. PMID:21615216

Zhang, Xinli; Péault, Bruno; Chen, Weiwei; Li, Weiming; Corselli, Mirko; James, Aaron W.; Lee, Min; Siu, Ronald K.; Shen, Pang; Zheng, Zhong; Shen, Jia; Kwak, Jinny; Zara, Janette N.; Chen, Feng; Zhang, Hong; Yin, Zack; Wu, Ben; Ting, Kang

2011-01-01

292

FTY720 Promotes Local Microvascular Network Formation and Regeneration of Cranial Bone Defects  

PubMed Central

The calvarial bone microenvironment contains a unique progenitor niche that should be considered for therapeutic manipulation when designing regeneration strategies. Recently, our group demonstrated that cells isolated from the dura are multipotent and exhibit expansion potential and robust mineralization on biodegradable constructs in vitro. In this study, we evaluate the effectiveness of healing critical-sized cranial bone defects by enhancing microvascular network growth and host dura progenitor trafficking to the defect space pharmacologically by delivering drugs targeted to sphingosine 1-phosphate (S1P) receptors. We demonstrate that delivery of pharmacological agonists to (S1P) receptors S1P1 and S1P3 significantly increase bone ingrowth, total microvessel density, and smooth muscle cell investment on nascent microvessels within the defect space. Further, in vitro proliferation and migration studies suggest that selective activation of S1P3 promotes recruitment and growth of osteoblastic progenitors from the meningeal dura mater. PMID:20038198

Aronin, Caren E. Petrie; Sefcik, Lauren S.; Tholpady, Sunil S.; Tholpady, Ashok; Sadik, Karim W.; Macdonald, Timothy L.; Peirce, Shayn M.; Wamhoff, Brian R.; Lynch, Kevin R.; Ogle, Roy C.

2010-01-01

293

Nell-1 Protein Promotes Bone Formation in a Sheep Spinal Fusion Model  

PubMed Central

Bone morphogenetic proteins (BMPs) are widely used as bone graft substitutes in spinal fusion, but are associated with numerous adverse effects. The growth factor Nel-like molecule-1 (Nell-1) is mechanistically distinct from BMPs and can minimize complications associated with BMP therapies. This study evaluates the efficacy of Nell-1 combined with demineralized bone matrix (DBM) as a novel bone graft material for interbody spine fusion using sheep, a phylogenetically advanced animal with biomechanical similarities to human spine. Nell-1+sheep DBM or Nell-1+heat-inactivated DBM (inDBM) (to determine the osteogenic effect of residual growth factors in DBM) were implanted in surgical sites as follows: (1) DBM only (control) (n=8); (2) DBM+0.3?mg/mL Nell-1 (n=8); (3) DBM+0.6?mg/mL Nell-1 (n=8); (4) inDBM only (control) (n=4); (5) inDBM+0.3?mg/mL Nell-1 (n=4); (6) inDBM+0.6?mg/mL Nell-1 (n=4). Fusion was assessed by computed tomography, microcomputed tomography, and histology. One hundred percent fusion was achieved by 3 months in the DBM+0.6?mg/mL Nell-1 group and by 4 months in the inDBM+0.6?mg/mL Nell-1 group; bone volume and mineral density were increased by 58% and 47%, respectively. These fusion rates are comparable to published reports on BMP-2 or autograft bone efficacy in sheep. Nell-1 is an independently potent osteogenic molecule that is efficacious and easily applied when combined with DBM. PMID:21128865

Siu, Ronald K.; Lu, Steven S.; Li, Weiming; Whang, Julie; McNeill, Gabriel; Zhang, Xinli; Wu, Benjamin M.; Turner, A. Simon; Seim, Howard B.; Hoang, Paul; Wang, Jeffrey C.; Gertzman, Arthur A.; Ting, Kang

2011-01-01

294

The role of scaffold architecture and composition on the bone formation by adipose-derived stem cells.  

PubMed

Scaffold architecture and composition are crucial parameters determining the initial cell spatial distribution and consequently bone tissue formation. Three-dimensional poly-?-caprolactone (PCL) scaffolds with a 0/90° lay-down pattern were plotted and subjected to (1) an oxygen plasma (PCL O) or (2) a postargon plasma modification with gelatin and fibronectin (PCL Fn). These scaffolds with an open pore structure were compared with more compact scaffolds fabricated by conventional processing techniques: oxidized polylactic acid (LA O) and collagen (COL) scaffolds. Human adipose tissue-derived stem cell/scaffold interactions were studied. The study revealed that the biomimetic surface modification of plotted scaffolds did not increase the seeding efficiency. The proliferation and colonization was superior for PCL Fn in comparison with PCL O. The plotted PCL Fn was completely colonized throughout the scaffold, whereas conventional scaffolds only at the edge. Protein-based scaffolds (PCL Fn and COL) enhanced the differentiation, although plotted scaffolds showed a delay in their differentiation compared with compact scaffolds. In conclusion, protein modification of plotted PCL scaffolds enhances uniform tissue formation, but shows a delayed differentiation in comparison with compact scaffolds. The present study demonstrates that biomimetic PCL scaffolds could serve as a guiding template to obtain a uniform bone tissue formation in vivo. PMID:23998529

Declercq, Heidi A; Desmet, Tim; Dubruel, Peter; Cornelissen, Maria J

2014-01-01

295

Effects of prostaglandin F2 alpha on bone formation and resorption in cultured neonatal mouse calvariae: Role of prostaglandin E2 production  

SciTech Connect

Although most studies show that prostaglandin E2 (PGE2) is the most potent and effective of the prostanoids in bone, recent data in cell culture suggest that PGF2 alpha may have unique effects, particularly on cell replication. The present study was undertaken to compare the effects of PGF2 alpha and PGE2 in cultured neonatal mouse parietal bones by simultaneous measurement of bone resorption as release of previously incorporated 45Ca, bone formation as incorporation of (3H)proline into collagenase-digestible (CDP) and noncollagen protein, and DNA synthesis as incorporation of (3H)thymidine. PGF2 alpha was less effective than PGE2 as a stimulator of bone resorption, and its effects were partially inhibited by indomethacin and markedly inhibited by glucocorticoids. In contrast, the resorptive response to PGE2 was unaffected by indomethacin and only partially inhibited by cortisol. PGF2 alpha had little effect on bone formation, in contrast to the biphasic effect of PGE2, which inhibited labeling of CDP in the absence of cortisol and stimulated CDP labeling in the presence of cortisol. PGF2 alpha increased thymidine incorporation into DNA, but the effect was smaller than that of PGE2 and was inhibited by indomethacin. These observations suggested that PGF2 alpha might act in part by stimulating PGE2 production. By RIA, PGE2 concentrations were increased in the medium of bones treated with PGF2 alpha, and this increase was blocked by indomethacin. By HPLC, bones prelabeled with (3H)arachidonic acid showed an increase in labeled PGE2 release, and RIA showed an increase in PGE2 after PGF2 alpha treatment. These results indicate that PGF2 alpha is a relatively weak agonist in bone compared to PGE2 and that some of the effects of PGF2 alpha on bone resorption, formation, and cell replication may be mediated by an increase in endogenous PGE2 production.

Raisz, L.G.; Alander, C.B.; Fall, P.M.; Simmons, H.A. (Univ. of Connecticut Health Center, Farmington (USA))

1990-02-01

296

A potent analog of 1 ,25-dihydroxyvitamin D3 selectively induces bone formation  

E-print Network

defect associated with vitamin D deficiency is due directly to insufficient calcium and phosphorusLuca, August 6, 2002 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] is a principal regulator of calcium and phosphorus-mediated bone calcium mobilization while being only slightly more potent in supporting intestinal calcium

Pike, J. Wesley

297

Controlled delivery of platelet-rich plasma-derived growth factors for bone formation  

E-print Network

, the recruitment of mesenchymal stem cells and progenitor cells to the site of bone regeneration is mediated of Dental Medicine, Columbia University, New York, New York 10032 Received 20 February 2007; revised 14 phosphatase (ALP) activity of human osteoblast-like cells were also evaluated. It was found that factor

Lu, Helen H.

298

Low Magnitude and High Frequency Mechanical Loading Prevents Decreased Bone Formation Responses  

E-print Network

to osteoporosis or disuse such as in paraplegia or microgravity is a significant health problem. As a treatment for osteoporosis, brief exposure of intact animals or humans to low magnitude and high frequency (LMHF) mechanical osteoporosis or disuse-induced bone loss. J. Cell. Biochem. 106: 306­ 316, 2009. � 2009 Wiley-Liss, Inc. KEY

299

Scalp malignant peripheral nerve sheath tumor (MPNST) with bony involvement and new bone formation: case report  

Microsoft Academic Search

Malignant peripheral nerve sheath tumors (MPNSTs) are rare neoplasms, usually arising from somatic soft tissues or peripheral nerves. Primary MPNST of the scalp is extremely rare, with only a single case reported so far. Here, we describe an unusual case of scalp MPNST in a 50-year-old male. The tumor was associated with bony projection, intracranial extension and underlying bone destruction.

A Garg; V Gupta; S. B Gaikwad; N. K Mishra; B. K Ojha; M Chugh; M. C Sharma

2004-01-01

300

Ectopic bone formation in severely combat-injured orthopedic patients -- a hematopoietic niche.  

PubMed

Combat-related heterotopic ossification (HO) has emerged as a common and problematic complication of modern wartime extremity injuries, contributing to substantial patient morbidity and loss of function. We have previously reported that HO-forming patients exhibit a more pronounced systemic and local inflammatory response very early in the wound healing process. Moreover, traumatized muscle-derived mesenchymal progenitor cells from these patients have a skewed differentiation potential toward bone. Here, we demonstrate that HO lesions excised from this patient population contain highly vascularized, mature, cancellous bone containing adipogenic marrow. Histologic analysis showed immature hematopoietic cells located within distinct foci in perivascular regions. The adipogenic marrow often contained low numbers of functional erythroid (BFU-E), myeloid (CFU-GM, CFU-M) and multilineage (CFU-GEMM) colony-forming hematopoietic progenitor cells (HPCs). Conversely, tissue from control muscle and non-HO traumatic wound granulation tissue showed no evidence of hematopoietic progenitor cell activity. In summary, our findings suggest that ectopic bone can provide an appropriate hematopoietic microenvironment for supporting the proliferation and differentiation of HPCs. This reactive and vibrant cell population may help maintain normal hematopoietic function, particularly in those with major extremity amputations who have sustained both massive blood loss, prompting systemic marrow stimulation, as well as loss of available native active marrow space. These findings begin to characterize the functional biology of ectopic bone and elucidate the interactions between HPC and non-hematopoietic cell types within the ectopic intramedullary hematopoietic microenvironmental niche identified. PMID:23727270

Davis, Thomas A; Lazdun, Yelena; Potter, Benjamin K; Forsberg, Jonathan A

2013-09-01

301

Hydroxyapatite-poly(L-lactide) nanohybrids via surface-initiated ATRP for improving bone-like apatite-formation abilities  

NASA Astrophysics Data System (ADS)

It is important to improve the compatibility of hydroxyapatite (HA) nanoparticles in biodegradable polyesters to obtain desirable nanocomposites for bone tissue engineering applications. Polymer grafting has been proven an efficient way to get nanohybrids with good dispersibility in polymeric matrixes. In this paper, a new strategy to prepare HA-poly(L-lactide) (PLLA) nanohybrids was developed, where PLLA oligomers were grafted from HA nanoparticle surfaces via surface-initiated atom transfer radical polymerization (ATRP) of methylacrylate group terminated PLLA macromonomers (PLLA-MA). HA with the derived ATRP initiators was obtained by (1) preparation of HA from precursors in the presence of 3-aminopropyl-triethoxysilane (APTS) to produce the HA surface with terminal sbnd NH2 groups (HA-NH2) and (2) reaction of the sbnd NH2 groups of the HA-NH2 nanoparticles with 2-bromoisobutyryl bromide (BIBB) to produce the 2-bromoisobutyryl-immobilized nanoparticles (HA-Br). The obtained HA-PLLA nanohybrids demonstrated good dispersibility in chloroform. With the good dispersion of HA-PLLA nanohybrids in PLLA matrix, the resultant PLLA/HA-PLLA nanocomposites could much faster induce bone-like apatite-formation in simulated body fluids (SBF) than the PLLA/HA counterparts where the HA nanoparticles aggregated heavily. With the versatility of ATRP, properly, grafting oligomeric PLLA chains from HA nanoparticle surfaces is an effective means for the design of novel HA-polymer biohybrids for future bone tissue engineering applications.

He, Jiqing; Yang, Xiaoping; Mao, Jiaofu; Xu, Fujian; Cai, Qing

2012-07-01

302

Prednisolone alone, or in combination with estrogen or dietary calcium deficiency or immobilization, inhibits bone formation but does not induce bone loss in mature rats  

Microsoft Academic Search

Glucocorticoid use has long been recognized as a risk factor for bone loss, resulting in an increased fracture incidence in humans. However, steroid-treated patients often present with other complications that predispose to bone loss, such as immobilization, and little is known about the interaction of these other risk factors for bone loss and glucocorticoids. In the present study, mature female

V. Shen; R. Birchman; X. G. Liang; D. D. Wu; R. Lindsay; D. W. Dempster

1997-01-01

303

Magnetic nanorods confined in a lamellar lyotropic phase.  

PubMed

The dilute lamellar phase of the nonionic surfactant C 12EO 5 was doped with goethite (iron oxide) nanorods up to a fraction of 5 vol %. The interaction between the inclusions and the host phase was studied by polarized optical microscopy (with or without an applied magnetic field) and by small-angle X-ray scattering. We find that, when the orientation of the nanorods is modified using the magnetic field, the texture of the lamellar phase changes accordingly; one can thus induce a homeotropic-planar reorientation transition. On the other hand, the lamellar phase induces an attractive interaction between the nanorods. In more concentrated lamellar phases (under stronger confinement) the particles form aggregates. This behavior is not encountered for a similar system doped with spherical particles, emphasizing the role of particle shape in the interaction between doping particles and the host phase. PMID:18590288

Béneut, Keevin; Constantin, Doru; Davidson, Patrick; Dessombz, Arnaud; Chanéac, Corinne

2008-08-01

304

Biomimetic Templating of Porous Lamellar Silicas by Vesicular Surfactant Assemblies  

NASA Astrophysics Data System (ADS)

A biomimetic templating approach to the synthesis of lamellar silicas is demonstrated. The procedure is based on the hydrolysis and cross-linking of a neutral silicon alkoxide precursor in the interlayered regions of multilamellar vesicles formed from a neutral diamine bola-amphiphile. Unlike earlier surfactant-templating approaches, this method produces porous lamellar silicas (designated MSU-V) with vesicular particle morphology, exceptional thermal stability, a high degree of framework cross-linking, unusually high specific surface area and pore volume, and sorption properties that are typical of pillared lamellar materials. This approach circumvents the need for a separate pillaring step in building porosity into a lamellar host structure and offers new opportunities for the direct fabrication of adsorbents, catalysts, and nanoscale devices.

Tanev, Peter T.; Pinnavaia, Thomas J.

1996-03-01

305

Measuring the number of lamellar body particles in amniotic fluid.  

PubMed

We describe a method for determining the number and size distribution of lamellar bodies and compare the results prospectively with other tests for fetal lung maturity: lecithin-sphingomyelin ratio (L/S), phosphatidylglycerol, and fluorescence polarization. The technique uses an electronic particle counter calibrated for a size range of 1.7-7.3 fL. The number of lamellar bodies in amniotic fluid samples varied from 3800-166,000 particles per microliter and correlated strongly with L/S ratio (r = 0.75; N = 144) and fluorescence polarization (r = -0.78; N = 165). Amniotic fluid samples stored for up to 10 days at 4C had stable lamellar body counts (within +/- 11%). Longer storage tended to decrease the counts. Addition of more than 1% (v/v) whole blood significantly decreased the lamellar body counts. This technique shows promise for the rapid assessment of fetal lung maturity. PMID:2300359

Ashwood, E R; Oldroyd, R G; Palmer, S E

1990-02-01

306

Biosilica-glass formation using enzymes from sponges [silicatein]: Basic aspects and application in biomedicine [bone reconstitution material and osteoporosis  

NASA Astrophysics Data System (ADS)

In the last 15 years biomineralization, in particular biosilicification (i.e., the formation of biogenic silica, SiO2), has become an exciting source of inspiration for the development of novel bionic approaches, following "Nature as model". Among the silica forming organisms there are the sponges that have the unique property to catalyze their silica skeletons by a specific enzyme termed silicatein. In the present review we summarize the present state of knowledge on silicatein-mediated "biosilica" formation in marine sponges, the involvement of further molecules in silica metabolism and their potential application in biomedicine. Recent advancements in the production of bone replacement material and in the potential use as a component in the treatment of osteoporosis are highlighted.

Wang, Shun-Feng; Wang, Xiao-Hong; Gan, Lu; Wiens, Matthias; Schröder, Heinz C.; Müller, Werner E. G.

2011-09-01

307

Molecular dynamics simulation of the phase behavior of lamellar amphiphilic model systems  

NASA Astrophysics Data System (ADS)

Using efficient simplified continuum amphiphile models-AB dimers, A2B2 tetramers, and A4B4 octamers-as models for diblock copolymers, surfactants and liquid crystals, the phase behavior of the corresponding lamellar systems is investigated by large-scale parallelized dissipative particle dynamics type of molecular dynamics simulation. We not only observe the first order nature of the order-disorder transition, but also find that this first order phase transition becomes weaker as the block length of the models increases. The theoretically predicted ``chain stretching'' effect is reproduced as the like-monomer attractive potential well depth is increased. At the order-disorder transition point, a singular discontinuous jump in the stretching amplitude is accompanied with a distinctive orientation-induced stretching effect in the layer normal direction and an orientation induced-compressing effect in the layer plane directions. The configuration of the lamellar phase is very sensitive to the commensurability of its equilibrium layer spacing with the cell size. Too large layer spacings lead to the formation of a slightly tilted lamellar structure in the ``quasistatic-cooling'' process and to an undulation instability in the ``quasistatic-heating'' process. The relation between equilibrium layer spacing and like-monomer attraction is examined.

Guo, Hongxia; Kremer, Kurt

2003-11-01

308

Plumbagin attenuates cancer cell growth and osteoclast formation in the bone microenvironment of mice  

PubMed Central

Aim: To investigate the effects of plumbagin, a naphthoquinone derived from the medicinal plant Plumbago zeylanica, on human breast cancer cell growth and the cancer cell-induced osteolysis in the bone microenvironment of mice. Methods: Human breast cancer cell subline MDA-MB-231SA with the ability to spread and grow in the bone was tested. The cell proliferation was determined using the CCK-8 assay. Apoptosis was detected with Annexin V/PI double-labeled flow cytometry. Red fluorescent protein-labeled MDA-MB-231SArfp cells were injected into the right tibia of female BALB/c-nu/nu mice. Three days after the inoculation, the mice were injected with plumbagin (2, 4, or 6 mg/kg, ip) 5 times per week for 7 weeks. The growth of the tumor cells was monitored using an in vivo imaging system. After the mice were sacrificed, the hind limbs were removed for radiographic and histological analyses. Results: Plumbagin (2.5–20 ?mol/L) concentration-dependently inhibited the cell viability and induced apoptosis of MDA-MB-231SA cells in vitro (the IC50 value of inhibition of cell viability was 14.7 ?mol/L). Administration of plumbagin to breast cancer bearing mice delayed the tumor growth by 2–3 weeks and reduced the tumor volume by 44%–74%. The in vivo imaging study showed that plumbagin dose-dependently inhibited MDA-MB-231SArfp cell growth in bone microenvironment. Furthermore, X-ray images and micro-CT study demonstrated that plumbagin reduced bone erosion area and prevented a decrease in bone tissue volume. Histological studies showed that plumbagin dose-dependently inhibited the breast cancer cell growth, enhanced the cell apoptosis and reduced the number of TRAcP-positive osteoclasts. Conclusion: Plumbagin inhibits the cell growth and induces apoptosis in human breast cancer cells in mice bone microenvironment, leading to significant reduction in osteolytic lesions caused by the tumor cells. PMID:24384612

Yan, Wei; Wang, Ting-yu; Fan, Qi-ming; Du, Lin; Xu, Jia-ke; Zhai, Zan-jing; Li, Hao-wei; Tang, Ting-ting

2014-01-01

309

Bone Marrow-Derived Matrix Metalloproteinase-9 Is Associated with Fibrous Adhesion Formation after Murine Flexor Tendon Injury  

PubMed Central

The pathogenesis of adhesions following primary tendon repair is poorly understood, but is thought to involve dysregulation of matrix metalloproteinases (Mmps). We have previously demonstrated that Mmp9 gene expression is increased during the inflammatory phase following murine flexor digitorum (FDL) tendon repair in association with increased adhesions. To further investigate the role of Mmp9, the cellular, molecular, and biomechanical features of healing were examined in WT and Mmp9?/? mice using the FDL tendon repair model. Adhesions persisted in WT, but were reduced in Mmp9?/? mice by 21 days without any decrease in strength. Deletion of Mmp9 resulted in accelerated expression of neo-tendon associated genes, Gdf5 and Smad8, and delayed expression of collagen I and collagen III. Furthermore, WT bone marrow cells (GFP+) migrated specifically to the tendon repair site. Transplanting myeloablated Mmp9?/? mice with WT marrow cells resulted in greater adhesions than observed in Mmp9?/? mice and similar to those seen in WT mice. These studies show that Mmp9 is primarily derived from bone marrow cells that migrate to the repair site, and mediates adhesion formation in injured tendons. Mmp9 is a potential target to limit adhesion formation in tendon healing. PMID:22792383

Loiselle, Alayna E.; Frisch, Benjamin J.; Wolenski, Matthew; Jacobson, Justin A.; Calvi, Laura M.; Schwarz, Edward M.; Awad, Hani A.; O'Keefe, Regis J.

2012-01-01

310

Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation  

PubMed Central

SUMMARY Parathyroid hormone (PTH) suppresses Dickkopf 1 (Dkk1) expression in osteoblasts. To determine whether this suppression is essential for PTH-mediated Wnt signaling and bone formation, we examined mice that overexpress Dkk1 in osteoblasts (Dkk1 mice). Dkk1 mice were osteopenic due to abnormal osteoblast and osteoclast activity. When fed a low calcium diet, and in two other models of hyperparathyroidism, these mice failed to develop the peritrabecular stromal cell response (“osteitis fibrosis”) and new bone formation seen in wild type mice. Despite these effects of Dkk1 overexpression, PTH still activated Wnt signaling in Dkk1 mice and in osteoblastic cells cultured from these mice. In cultured MC3T3E1 preosteoblastic cells, PTH dramatically suppressed Dkk1 expression, induced PKA-mediated phosphorylation of ?-catenin and significantly enhanced Lef1 expression. Our findings indicate that the full actions of PTH require intact Wnt signaling but that PTH can activate the Wnt pathway despite overexpression of Dkk1. PMID:20142103

Guo, Jun; Liu, Minlin; Yang, Dehong; Bouxsein, Mary L; Saito, Hiroaki; Galvin, R J Sells; Kuhstoss, Stuart A.; Thomas, Clare C; Schipani, Ernestina; Baron, Roland; Bringhurst, F Richard; Kronenberg, Henry M.

2010-01-01

311

Quantification of ovine bone adaptation to altered load: morphometry, density, and surface strain.  

PubMed

Mechanical loading in the sheep proximal radius was increased by ulnar osteotomy (Group O), decreased by Steinmann pinning (Group P) and unaltered in sham operated controls (Group C). A series of intravenous fluochromes was given to label bone formation and the adaptive response was measured at intervals up to 24 weeks. Surface strains, measured in an in vitro rig, were reduced in Group P and increased significantly in Group O. Cross-sectional area (CSA) peaked in all groups at 6 weeks consistent with a regional acceleratory phenomenon (RAP) and the formation of fibrolamellar bone of low density. In Groups C and P the extent of the RAP was related to the degree of operative trauma and the newly-formed bone was subsequently resorbed. In Group P, CSA fell below control levels suggesting negative adaptation. The increase in area was sustained in Group O and bone density increased due to mineralisation and infilling. Periosteal labelling of the scaffold of parallel-fibred bone peaked at 10 weeks, followed by labelling of lamellar bone filling the gaps in the structure. This adaptive response reduced surface strains to near normal levels by 24 weeks in Group O. Positive adaptation was distinguished from the non-specific RAP due to surgical trauma. The adaptive response is both 'intelligent', in that it utilises and adds to the RAP, and accurate, as no further increase in cross-sectional area was required after 6 weeks. PMID:16225262

Lee, T C; Taylor, D

2003-01-01

312

Bony defect repair in rabbit using hybrid rapid prototyping polylactic-co-glycolic acid/?-tricalciumphosphate collagen I/apatite scaffold and bone marrow mesenchymal stem cells  

PubMed Central

Background: In bone tissue engineering, extracellular matrix exerts critical influence on cellular interaction with porous biomaterial and the apatite playing an important role in the bonding process of biomaterial to bone tissue. The aim of this study was to observe the therapeutic effects of hybrid rapid prototyping (RP) scaffolds comprising polylactic-co-glycolic acid (PLGA), ?-tricalciumphosphate (?-TCP), collagen I and apatite (PLGA/?-TCP-collagen I/apatite) on segmental bone defects in conjunction with combination with bone marrow mesenchymal stem cells (BMSCs). Materials and Methods: BMSCs were seeded into the hybrid RP scaffolds to repair 15 mm defect in the radius of rabbits. Radiograph, microcomputed tomography and histology were used to evaluate new bone formation. Results: Radiographic analysis done from 12 to 36 weeks postoperative period demonstrated that new bone formed at the radial defect site and continues to increase until the medullary cavity is recanalized and remodelling is complete. The bone defect remained unconnected in the original RP scaffolds (PLGA/?-TCP) during the whole study. Histological observations conformed to the radiographic images. In hybrid RP scaffold group, woven bone united the radial defect at 12 weeks and consecutively remodeled into lamellar bone 24 weeks postoperation and finally matured into cortical bone with normal marrow cavity after another 12 weeks. No bone formation but connective tissue has been detected in RP scaffold at the same time. Conclusion: Collagen I/apatite sponge composite coating could improve new bone formation in vivo. The hybrid RP scaffold of PLGA/?-TCP skeleton with collagen I/apatite sponge composite coating is a promising candidate for bone tissue engineering. PMID:23960284

Pang, Long; Hao, Wei; Jiang, Ming; Huang, Jianguo; Yan, Yongnian; Hu, Yunyu

2013-01-01

313

Tissue Inhibitor of Metalloproteinase-3 (TIMP-3) Regulates Hematopoiesis and Bone Formation In Vivo  

PubMed Central

Background Tissue inhibitor of metalloproteinases-3 (TIMP-3) inhibits matrix metalloproteinases and membrane-bound sheddases. TIMP-3 is associated with the extracellular matrix and is expressed in highly remodeling tissues. TIMP-3 function in the hematopoietic system is unknown. Methodology/Principal Findings We now report that TIMP-3 is highly expressed in the endosteal region of the bone marrow (BM), particularly by osteoblasts, endothelial and multipotent mesenchymal stromal cells which are all important cellular components of hematopoietic stem cell (HSC) niches, whereas its expression is very low in mature leukocytes and hematopoietic stem and progenitor cells. A possible role of TIMP-3 as an important niche component was further suggested by its down-regulation during granulocyte colony-stimulating factor-induced mobilization. To further investigate TIMP-3 function, mouse HSC were retrovirally transduced with human TIMP-3 and transplanted into lethally irradiated recipients. TIMP-3 overexpression resulted in decreased frequency of B and T lymphocytes and increased frequency of myeloid cells in blood and BM, increased Lineage-negative Sca-1+KIT+ cell proliferation in vivo and in vitro and increased colony-forming cell trafficking to blood and spleen. Finally, over-expression of human TIMP-3 caused a late onset fatal osteosclerosis. Conclusions/Significance Our results suggest that TIMP-3 regulates HSC proliferation, differentiation and trafficking in vivo, as well as bone and bone turn-over, and that TIMP-3 is expressed by stromal cells forming HSC niches within the BM. Thus, TIMP-3 may be an important HSC niche component regulating both hematopoiesis and bone remodeling. PMID:20941363

Shen, Yi; Winkler, Ingrid G.; Barbier, Valerie; Sims, Natalie A.; Hendy, Jean; Levesque, Jean-Pierre

2010-01-01

314

ESR study of MMA polymerization by a peroxide/amine system: bone cement formation.  

PubMed

Electron spin resonance (ESR) spectroscopy was used to gain insight at the molecular level into the curing of bone cement. Methyl methacrylate was polymerized using a N,N-dimethyl-p-toluidine (TD)/benzoyl peroxide (BPO) redox system in the presence of polymethyl methacrylate (PMMA) powder. The conventional nine-line ESR spectrum for the growing polymer radical was detected at the gel stage of polymerization. While the optimum free radical concentration was observed near the equimolar amine/BPO concentration, excess amine led to a change in the chemical structure of the trapped radical and inhibited the polymerization process. At a high amine/BPO ratio the nine-line signal disappeared and a three-line nitroxide-based radical appeared. The appearance of this nitroxide signal seems to depend on the amine/BPO molar ratio and on the presence of PMMA. An excess amount of amine with respect to BPO was found to inhibit the polymerization process. When BPO was removed, the system still polymerized but with a longer gelation time and a lower radical concentration. These results demonstrate that trapped free radicals in the bulk polymerization of MMA convert to polymeric peroxides that act as initiators in bone cement. When the accelerator 4-dimethylamino phenethyl alcohol (TDOH) was used, a higher radical concentration was observed in the polymerizing system. TDOH shows potential for being a more effective accelerator than TD for bone cement curing. PMID:10397948

Oldfield, F F; Yasuda, H K

1999-03-15

315

Load transfer in bovine plexiform bone determined by synchrotron x-ray diffraction.  

SciTech Connect

High-energy synchrotron x-ray diffraction (XRD) has been used to quantify load transfer in bovine plexiform bone. By using both wide-angle and small-angle XRD, strains in the mineral as well as the collagen phase of bone were measured as a function of applied compressive stress. We suggest that a greater proportion of the load is borne by the more mineralized woven bone than the lamellar bone as the applied stress increases. With a further increase in stress, load is shed back to the lamellar regions until macroscopic failure occurs. The reported data fit well with reported mechanisms of microdamage accumulation in bovine plexiform bone.

Akhtar, R.; Daymond, M.; Almer, J.; Mummery, P.; The Univ. of Manchester; Queen's Univ.

2008-02-01

316

Focal Adhesion Kinase Plays a Role in Osteoblast Mechanotransduction In Vitro but Does Not Affect Load-Induced Bone Formation In Vivo  

PubMed Central

A healthy skeleton relies on bone's ability to respond to external mechanical forces. The molecular mechanisms by which bone cells sense and convert mechanical stimuli into biochemical signals, a process known as mechanotransduction, are unclear. Focal adhesions play a critical role in cell survival, migration and sensing physical force. Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that controls focal adhesion dynamics and can mediate reparative bone formation in vivo and osteoblast mechanotransduction in vitro. Based on these data, we hypothesized that FAK plays a role in load-induced bone formation. To test this hypothesis, we performed in vitro fluid flow experiments and in vivo bone loading studies in FAK?/? clonal lines and conditional FAK knockout mice, respectively. FAK?/? osteoblasts showed an ablated prostaglandin E2 (PGE2) response to fluid flow shear. This effect was reversed with the re-expression of wild-type FAK. Re-expression of FAK containing site-specific mutations at Tyr-397 and Tyr-925 phosphorylation sites did not rescue the phenotype, suggesting that these sites are important in osteoblast mechanotransduction. Interestingly, mice in which FAK was conditionally deleted in osteoblasts and osteocytes did not exhibit altered load-induced periosteal bone formation. Together these data suggest that although FAK is important in mechanically-induced signaling in osteoblasts in vitro, it is not required for an adaptive response in vivo, possibly due to a compensatory mechanism that does not exist in the cell culture system. PMID:23028449

Castillo, Alesha B.; Blundo, Jennifer T.; Chen, Julia C.; Lee, Kristen L.; Yereddi, Nikitha Reddy; Jang, Eugene; Kumar, Shefali; Tang, W. Joyce; Zarrin, Sarah; Kim, Jae-Beom; Jacobs, Christopher R.

2012-01-01

317

Radial extracorporeal shock wave therapy (rESWT) induces new bone formation in vivo: results of an animal study in rabbits.  

PubMed

The aim of this study was to investigate if radial extracorporeal shock wave therapy (rESWT) induces new bone formation and to study the time course of ESWT-induced osteogenesis. A total of 4000 impulses of radial shock waves (0.16 mJ/mm²) were applied to one hind leg of 13 New Zealand white rabbits with the contralateral side used for control. Treatment was repeated after 7 days. Fluorochrome sequence labeling of new bone formation was performed by subcutaneous injection of tetracycline, calcein green, alizarin red and calcein blue. Animals were sacrificed 2 weeks (n = 4), 4 weeks (n = 4) and 6 weeks (n = 5) after the first rESWT and bone sections were analyzed by fluorescence microscopy. Deposits of fluorochromes were classified and analyzed for significance with the Fisher exact test. rESWT significantly increased new bone formation at all time points over the 6-week study period. Intensity of ossification reached a peak after 4 weeks and declined at the end of the study. New bone formation was significantly higher and persisted longer at the ventral cortex, which was located in the direction to the shock wave device, compared with the dorsal cortex, emphasizing the dose-dependent process of ESWT-induced osteogenesis. No traumata, such as hemorrhage, periosteal detachment or microfractures, were observed by histologic and radiologic assessment. This is the first study demonstrating low-energy radial shock waves to induce new bone formation in vivo. Based on our results, repetition of ESWT in 6-week intervals can be recommended. Application to bone regions at increased fracture risk (e.g., in osteoporosis) are possible clinical indications. PMID:23122639

Gollwitzer, Hans; Gloeck, Timo; Roessner, Michaela; Langer, Rupert; Horn, Carsten; Gerdesmeyer, Ludger; Diehl, Peter

2013-01-01

318

Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression  

PubMed Central

Lymphatic vessels (LVs) play critical roles in the maintenance of fluid homeostasis and in pathological conditions, including cancer metastasis. Although mutations in ALK1, a member of the transforming growth factor (TGF)-?/bone morphogenetic protein (BMP) receptor family, have been linked to hereditary hemorrhagic telangiectasia, a human vascular disease, the roles of activin receptor-like kinase 1 (ALK-1) signals in LV formation largely remain to be elucidated. We show that ALK-1 signals inhibit LV formation, and LVs were enlarged in multiple organs in Alk1-depleted mice. These inhibitory effects of ALK-1 signaling were mediated by BMP-9, which decreased the number of cultured lymphatic endothelial cells. Bmp9-deficient mouse embryos consistently exhibited enlarged dermal LVs. BMP-9 also inhibited LV formation during inflammation and tumorigenesis. BMP-9 downregulated the expression of the transcription factor prospero-related homeobox 1, which is necessary to maintain lymphatic endothelial cell identity. Furthermore, silencing prospero-related homeobox 1 expression inhibited lymphatic endothelial cell proliferation. Our findings reveal a unique molecular basis for the physiological and pathological roles of BMP-9/ALK-1 signals in LV formation. PMID:24133138

Yoshimatsu, Yasuhiro; Lee, Yulia G.; Akatsu, Yuichi; Taguchi, Luna; Suzuki, Hiroshi I.; Cunha, Sara I.; Maruyama, Kazuichi; Suzuki, Yuka; Yamazaki, Tomoko; Katsura, Akihiro; Oh, S. Paul; Zimmers, Teresa A.; Lee, Se-Jin; Pietras, Kristian; Koh, Gou Young; Miyazono, Kohei; Watabe, Tetsuro

2013-01-01

319

Convergence of bone morphogenetic protein and laminin-1 signaling pathways promotes proliferation and colony formation by fetal mouse pancreatic cells  

SciTech Connect

We previously reported that bone morphogenetic proteins (BMPs), members of the transforming growth factor superfamily, together with the basement membrane glycoprotein laminin-1 (Ln-1), promote proliferation of fetal pancreatic cells and formation of colonies containing peripheral insulin-positive cells. Here, we further investigate the cross-talk between BMP and Ln-1 signals. By RT-PCR, receptors for BMP (BMPR) (excepting BMPR-1B) and Ln-1 were expressed in the fetal pancreas between E13.5 and E17.5. Specific blocking antibodies to BMP-4 and -6 and selective BMP antagonists partially inhibited colony formation by fetal pancreas cells. Colony formation induced by BMP-6 and Ln-1 was completely abolished in a dose-dependent manner by blocking Ln-1 binding to its {alpha}{sub 6} integrin and {alpha}-dystroglycan receptors or by blocking the Ln-1 signaling molecules, phosphatidyl-inositol-3-kinase (P13K) and MAP kinase kinase-1. These results demonstrate a convergence of BMP and Ln-1 signaling through P13K and MAP kinase pathways to induce proliferation and colony formation in E15.5 fetal mouse pancreatic cells.

Jiang Fangxu [Autoimmunity and Transplantation Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3050 (Australia)]. E-mail: jiang@wehi.edu.au; Harrison, Leonard C. [Autoimmunity and Transplantation Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3050 (Australia)

2005-08-01

320

BMP-Non-Responsive Sca1+CD73+CD44+ Mouse Bone Marrow Derived Osteoprogenitor Cells Respond to Combination of VEGF and BMP-6 to Display Enhanced Osteoblastic Differentiation and Ectopic Bone Formation  

PubMed Central

Clinical trials on fracture repair have challenged the effectiveness of bone morphogenetic proteins (BMPs) but suggest that delivery of mesenchymal stem cells (MSCs) might be beneficial. It has also been reported that BMPs could not increase mineralization in several MSCs populations, which adds ambiguity to the use of BMPs. However, an exogenous supply of MSCs combined with vascular endothelial growth factor (VEGF) and BMPs is reported to synergistically enhance fracture repair in animal models. To elucidate the mechanism of this synergy, we investigated the osteoblastic differentiation of cloned mouse bone marrow derived MSCs (D1 cells) in vitro in response to human recombinant proteins of VEGF, BMPs (-2, -4, -6, -9) and the combination of VEGF with BMP-6 (most potent BMP). We further investigated ectopic bone formation induced by MSCs pre-conditioned with VEGF, BMP-6 or both. No significant increase in mineralization, phosphorylation of Smads 1/5/8 and expression of the ALP, COL1A1 and osterix genes was observed upon addition of VEGF or BMPs alone to the cells in culture. The lack of CD105, Alk1 and Alk6 expression in D1 cells correlated with poor response to BMPs indicating that a greater care in the selection of MSCs is necessary. Interestingly, the combination of VEGF and BMP-6 significantly increased the expression of ALP, COL1A1 and osterix genes and D1 cells pre-conditioned with VEGF and BMP-6 induced greater bone formation in vivo than the non-conditioned control cells or the cells pre-conditioned with either VEGF or BMP-6 alone. This enhanced bone formation by MSCs correlated with higher CADM1 expression and OPG/RANKL ratio in the implants. Thus, combined action of VEGF and BMP on MSCs enhances osteoblastic differentiation of MSCs and increases their bone forming ability, which cannot be achieved through use of BMPs alone. This strategy can be effectively used for bone repair. PMID:25048464

Madhu, Vedavathi; Li, Ching-Ju; Dighe, Abhijit S.; Balian, Gary; Cui, Quanjun

2014-01-01

321

[Bone metabolic markers for evaluation of bone metastases].  

PubMed

Bone metabolic markers consist of bone formation markers, which are secreted from osteoblasts (BAP, OC, P1CP, P1NP) , and bone resorption markers, which are metabolites of bone type 1 collagen or secreted from osteoclasts (PYD, DPD, NTX, CTX, 1CTP, TRACP) . Those bone metabolic markers are useful for : (1) diagnosis of bone metastases, (2) follow-up during treatment of bone metastases, and (3)predicting prognosis of bone metastases. PMID:23445893

Takahashi, Shunji

2013-03-01

322

Microcellular polyHIPE polymer supports osteoblast growth and bone formation in vitro.  

PubMed

A novel micro-cellular polymer with a well-defined and uniform micro-architecture has been developed as a three-dimensional support matrix for in vitro tissue engineering applications. This material is manufactured through a high internal phase emulsion (HIPE) polymerization route and may be modified with hydroxyapatite. The generic form of the support is known as PolyHIPE Polymer (PHP). By changing the chemical composition of the emulsion and the processing conditions, the pore size can be altered from sub-micron range to a few hundred microns and the porosity varied from 70% to 97%. Our work has investigated the use of this micro-porous polymer as a biomaterial to support the growth of osteoblasts, the bone forming cells in vitro. Three groups of polymers were used that had pore sizes of 40, 60 and 100 microm. Results demonstrated in vitro cell-polymer compatibility, with osteoblasts forming multicellular layers on the polymer surface and also migrating to a maximum depth of 1.4mm inside the scaffold after 35 days in culture. PHP was also able to support the differentiation of osteoblasts and the production of a bone-like matrix. The effect of modifying the polymer with hydroxyapatite was also studied and showed that there was a significant increase in osteoblast numbers penetrating into the polymer. There were few differences, between the pore sizes studied, on the overall penetration of osteoblasts into the polymer but the rate of movement into 100 microm PHP was significantly higher compared to the other sizes investigated. This study shows that osteoblasts seeded onto PHP demonstrate cellular attachment, proliferation and ingrowth leading to the support of an osteoblastic phenotype. Therefore this highly porous scaffold has a potential for bone tissue engineering. PMID:15046889

Akay, G; Birch, M A; Bokhari, M A

2004-08-01

323

Local delivery of FTY720 accelerates cranial allograft incorporation and bone formation  

Microsoft Academic Search

Endogenous stem cell recruitment to the site of skeletal injury is key to enhanced osseous remodeling and neovascularization.\\u000a To this end, this study utilized a novel bone allograft coating of poly(lactic-co-glycolic acid) (PLAGA) to sustain the release\\u000a of FTY720, a selective agonist for sphingosine 1-phosphate (S1P) receptors, from calvarial allografts. Uncoated allografts,\\u000a vehicle-coated, low dose FTY720 in PLAGA (1:200 w:w)

Cynthia Huang; Anusuya Das; Daniel Barker; Sunil Tholpady; Tiffany Wang; Quanjun Cui; Roy Ogle; Edward Botchwey

324

ERR? Is Not Required for Skeletal Development but Is a RUNX2-Dependent Negative Regulator of Postnatal Bone Formation in Male Mice  

PubMed Central

To assess the effects of the orphan nuclear Estrogen receptor-related receptor gamma (ERR?) deficiency on skeletal development and bone turnover, we utilized an ERR? global knockout mouse line. While we observed no gross morphological anomalies or difference in skeletal length in newborn mice, by 8 weeks of age ERR? +/? males but not females exhibited increased trabecular bone, which was further increased by 14 weeks. The increase in trabecular bone was due to an increase in active osteoblasts on the bone surface, without detectable alterations in osteoclast number or activity. Consistent with the histomorphometric results, we observed an increase in gene expression of the bone formation markers alkaline phosphatase (Alp) and bone sialoprotein (Bsp) in bone and increase in serum ALP, but no change in the osteoclast regulators receptor activator of NF-?B ligand (RANKL) and osteoprotegerin (OPG) or the resorption marker carboxy-terminal collagen crosslinks (CTX). More colony forming units-alkaline phosphatase and -osteoblast (CFU-ALP, CFU-O respectively) but not CFU-fibroblast (CFU-F) formed in ERR? +/? versus ERR? +/+ stromal cell cultures, suggesting that ERR? negatively regulates osteoblast differentiation and matrix mineralization but not mesenchymal precursor number. By co-immunoprecipitation experiments, we found that ERR? and RUNX2 interact in an ERR? DNA binding domain (DBD)-dependent manner. Treatment of post-confluent differentiating bone marrow stromal cell cultures with Runx2 antisense oligonucleotides resulted in a reduction of CFU-ALP/CFU-O in ERR? +/? but not ERR? +/+ mice compared to their corresponding sense controls. Our data indicate that ERR? is not required for skeletal development but is a sex-dependent negative regulator of postnatal bone formation, acting in a RUNX2- and apparently differentiation stage-dependent manner. PMID:25313644

Cardelli, Marco; Aubin, Jane E.

2014-01-01

325

Runx2-I Isoform Contributes to Fetal Bone Formation Even in the Absence of Specific N-Terminal Amino Acids  

PubMed Central

The Runt-related transcription factor 2 (Runx2) gene encodes the transcription factor Runx2, which is the master regulator of osteoblast development; insufficiency of this protein causes disorders of bone development such as cleidocranial dysplasia. Runx2 has two isoforms, Runx2-II and Runx2-I, and production of each isoform is controlled by a unique promoter: a distal promoter (P1) and a proximal promoter (P2), respectively. Although several studies have focused on differences and similarities between the two Runx2 isoforms, their individual roles in bone formation have not yet been determined conclusively, partly because a Runx2-I-targeted mouse model is not available. In this study, we established a novel Runx2-manipulated mouse model in which the first ATG of Runx2-I was replaced with TGA (a stop codon), and a neomycin-resistant gene (neo) cassette was inserted at the first intron of Runx2-I. Homozygous Runx2-Ineo/neo mice showed severely reduced expression of Runx2-I, whereas Runx2-II expression was largely retained. Runx2-Ineo/neo mice showed neonatal lethality, and in these mice, intramembranous ossification was more severely defective than endochondral ossification, presumably because of the greater involvement of Runx2-I, compared with that of Runx2-II in intramembranous ossification. Interestingly, the depletion of neo rescued the above-described phenotypes, indicating that the isoform-specific N-terminal region of Runx2-I is not functionally essential for bone development. Taken together, our results provide a novel clue leading to a better understanding of the roles of Runx2 isoforms in osteoblast development. PMID:25244033

Okura, Hideaki; Sato, Shintaro; Kishikawa, Sari; Kaneto, Satoshi; Nakashima, Tomoki; Yoshida, Nobuaki; Takayanagi, Hiroshi; Kiyono, Hiroshi

2014-01-01

326

Runx2-I isoform contributes to fetal bone formation even in the absence of specific N-terminal amino acids.  

PubMed

The Runt-related transcription factor 2 (Runx2) gene encodes the transcription factor Runx2, which is the master regulator of osteoblast development; insufficiency of this protein causes disorders of bone development such as cleidocranial dysplasia. Runx2 has two isoforms, Runx2-II and Runx2-I, and production of each isoform is controlled by a unique promoter: a distal promoter (P1) and a proximal promoter (P2), respectively. Although several studies have focused on differences and similarities between the two Runx2 isoforms, their individual roles in bone formation have not yet been determined conclusively, partly because a Runx2-I-targeted mouse model is not available. In this study, we established a novel Runx2-manipulated mouse model in which the first ATG of Runx2-I was replaced with TGA (a stop codon), and a neomycin-resistant gene (neo) cassette was inserted at the first intron of Runx2-I. Homozygous Runx2-Ineo/neo mice showed severely reduced expression of Runx2-I, whereas Runx2-II expression was largely retained. Runx2-Ineo/neo mice showed neonatal lethality, and in these mice, intramembranous ossification was more severely defective than endochondral ossification, presumably because of the greater involvement of Runx2-I, compared with that of Runx2-II in intramembranous ossification. Interestingly, the depletion of neo rescued the above-described phenotypes, indicating that the isoform-specific N-terminal region of Runx2-I is not functionally essential for bone development. Taken together, our results provide a novel clue leading to a better understanding of the roles of Runx2 isoforms in osteoblast development. PMID:25244033

Okura, Hideaki; Sato, Shintaro; Kishikawa, Sari; Kaneto, Satoshi; Nakashima, Tomoki; Yoshida, Nobuaki; Takayanagi, Hiroshi; Kiyono, Hiroshi

2014-01-01

327

Enhanced healing of rat calvarial critical size defect with selenium-doped lamellar biocomposites.  

PubMed

A 3D porous lamellar selenium-containing nano-hydroxyapatite (SeHAN)/chitosan (CS) biocomposite was synthesized. The selenium-containing hydroxyapatite (HA) grains of 150~200 nm in length and 20~30 nm in width were observed by dynamic light scattering and transmission electron microscopy. A combination of X-ray diffraction, Fourier-transform infrared spectroscopy, and SEM indicated that HA particles were uniformly dispersed in chitosan matrix and there was a chemical interaction between chitosan and HA. Then, a standard critical size calvarial bone defect was created in Wistar rats. In group 1, no implant was made in the defect. In groups 2 and 3, HA nanoparticles (HAN)/CS biocomposite and SeHAN/CS biocomposite were implanted into the defect, respectively. After 4 weeks, the histological assessment clearly exhibited no significant changes, only found some living cells anchored in the periphery of the implants. After 8 and 12 weeks, most newly formed osteoid tissue was found in the SeHAN/CS implant group. Additionally, the newly formed osteoid tissue, both at the edge and in the center of implants, was bioactive and neovascularized. Microfocus computerized tomography measurements also confirmed the much better quality of the newly formed bone tissue in SeHAN/CS implant group than that in HAN/CS implant group (p < 0.01). Collectively, the SeHAN/CS biocomposite, as a bioactive bone grafting substitute, significantly enhanced the repair of bone defect. PMID:23892698

Wang, Yanhua; Lv, Peng; Ma, Zhe; Zhang, Jingcheng

2013-10-01

328

Effects of Cell-Attachment and Extracellular Matrix on Bone Formation In Vivo in Collagen-Hydroxyapatite Scaffolds  

PubMed Central

Cell-based tissue engineering can be used to replace missing or damaged bone, but the optimal methods for delivering therapeutic cells to a bony defect have not yet been established. Using transgenic reporter cells as a donor source, two different collagen-hydroxyapatite (HA) scaffolds, and a critical-size calvarial defect model, we investigated the effect of a cell-attachment period prior to implantation, with or without an extracellular matrix-based seeding suspension, on cell engraftment and osteogenesis. When quantitatively compared, the in-house scaffold implanted immediately had a higher mean radiopacity than in-house scaffolds incubated overnight. Both scaffold types implanted immediately had significantly higher area fractions of donor cells, while the in-house collagen-HA scaffolds implanted immediately had higher area fractions of the mineralization label compared with groups incubated overnight. When the cell loading was compared in vitro for each delivery method using the in-house scaffold, immediate loading led to higher numbers of delivered cells. Immediate loading may be preferable in order to ensure robust bone formation in vivo. The use of a secondary ECM carrier improved the distribution of donor cells only when a pre-attachment period was applied. These results have improved our understanding of cell delivery to bony defects in the context of in vivo outcomes. PMID:25329879

Villa, Max M.; Wang, Liping; Rowe, David W.; Wei, Mei

2014-01-01

329

Human histologic evaluation of the use of the dental putty for bone formation in the maxillary sinus: case series.  

PubMed

A proof-of-principle study was conducted to assess the safety and efficacy of dental putty as an alternative sinus augmentation biomaterial. Six healthy patients requiring a total of 10 sinus augmentations received sinus augmentations. All patients volunteered and signed an informed consent based on the Helsinki declaration of 1975, as revised in 2000. The sinus augmentation was performed under local anesthesia with a mucoperiosteal flap elevated to expose the buccal wall of the maxillary sinus. The space was then filled with the dental putty in several increments, and the window was covered with an absorbable collagen membrane. Biopsies were harvested from all 10 treated sinuses using a 3-mm trephine bur at the time of implant placement at either 6 or at 9 months after sinus augmentation. All patients completed the study without complications, except for 1 patient who reported fistulas at 1 and 2 months after the surgery. Clinical reentry revealed that regenerated bone on the osteotomy site was soft and immature. The ground sections of the biopsied cores revealed minimum amounts of trabeculation surrounded by an abundant array of irregular-shaped residual alloplastic particles embedded in loose connective tissue. The present study's findings revealed inadequate bone formation, although the material appears to be bioinert as there is no elicitation of inflammatory response. PMID:21767203

Kim, David M; Nevins, Myron; Camelo, Marcelo; Nevins, Marc L; Schupbach, Peter; Rodrigues, Vinicius S; Fiorellini, Joseph P

2012-08-01

330

Effects of Palm Vitamin E on Bone-Formation-Related Gene Expression in Nicotine-Treated Rats  

PubMed Central

The study determines the effects of palm vitamin E on the gene expression of bone-formation-related genes in nicotine-treated rats. Male rats were divided into three groups: normal saline olive oil (NSO), nicotine olive oil (NO), and nicotine palm vitamin E (NE). The treatment was carried out in 2 phases. During the first 2 months, the NSO group received normal saline while the NO and NE groups received nicotine 7?mg/kg, 6 days a week, intraperitoneally. The following 2 months, normal saline and nicotine administration was stopped and was replaced with oral supplementation of olive oil for the NSO and NO groups and oral supplementation of palm vitamin E (60?mg/kg) for the NE group. Both femurs were harvested to determine the gene expression of bone morphogenetic protein-2 (BMP-2), Osterix (OSX), and Runt-related transcription factor 2 (RUNX2). Nicotine significantly downregulated the gene expression. This effect was reversed by palm vitamin E treatment. In conclusion, palm vitamin E may play a role in osteoblast differentiation and can be considered as an anabolic agent to treat nicotine-induced osteoporosis. PMID:23049610

Abukhadir, Seham Salem Ahmed; Mohamed, Norazlina; Makpol, Suzana; Muhammad, Norliza

2012-01-01

331

Local mechanical properties of a hyperswollen lyotropic lamellar phase  

NASA Astrophysics Data System (ADS)

The local and slow dynamics of a colloidal particle dispersed in a hyperswollen lyotropic lamellar phase was studied by passive and active microrheological methods. According to observation by a particle-tracking video microscopy, the motion of a particle follows a normal diffusion process in a lamellar phase with a large interlayer distance. However, trap-diffusion motion was also observed for a small interlayer distance. This characteristic motion was discussed by consideration of the time evolution of mean square displacement, the van Hove self-correlation function and the non-Gaussian parameter. These indicate that the dynamics of a particle becomes spatially heterogeneous in a lamellar phase whose interlayer distance is close to the size of the particle. By the measurement of local viscosity using optical tweezers, Newtonian behavior was observed at a high shear rate. In a lamellar phase with a small interlayer distance, non-Newtonian behavior was also observed at a low shear rate. The dependences of effective viscosity on the interlayer distance obtained by both methods are in agreement. The effective viscosity in the lamellar phase was found to be four to five times larger than that of water even for a large interlayer distance. Possible reasons for the increase in effective viscosity are discussed quantitatively.

Yamamoto, Naoki; Ichikawa, Masatoshi; Kimura, Yasuyuki

2010-08-01

332

Vitamin D antagonist, TEI-9647, inhibits osteoclast formation induced by 1alpha,25-dihydroxyvitamin D3 from pagetic bone marrow cells.  

PubMed

(23S)-25-Dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone (TEI-9647) functions an antagonist of the 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) nuclear receptor (VDR)-mediated differentiation of human leukemia (HL-60) cells [J. Biol. Chem. 274 (1999) 16392]. We examined the effect of vitamin D antagonist, TEI-9647, on osteoclast formation induced by 1alpha,25-(OH)(2)D(3) from bone marrow cells of patients with Paget's disease. TEI-9647 itself never induced osteoclast formation even at 10(-6)M, but dose-dependently (10(-10) to 10(-6)M) inhibited osteoclast formation induced by physiologic concentrations of 1alpha,25-(OH)(2)D(3) (41 pg/ml, 10(-10)M) from bone marrow cells of patients with Paget's disease. At the same time, 10(-8)M of TEI-9647 alone did not cause 1alpha,25-(OH)(2)D(3) dependent gene expression, but almost completely suppressed TAF(II)-17, a potential coactivator of VDR and 25-hydroxyvitamin D(3)-24-hydroxylase (25-OH-D(3)-24-hydroxylase) gene expression induced by 10(-10)M 1alpha,25-(OH)(2)D(3) in bone marrow cells of patients with Paget's disease. Moreover, TEI-9647 dose-dependently inhibited bone resorption induced by 10(-9)M 1alpha,25-(OH)(2)D(3) by osteoclasts produced by RANKL and M-CSF treatment of measles virus nucleocapsid gene transduced bone marrow cells. These results suggest that TEI-9647 acts directly on osteoclast precursors and osteoclasts, and that TEI-9647 may be a novel agent to suppress the excessive bone resorption and osteoclast formation in patients with Paget's disease. PMID:15225795

Ishizuka, Seiichi; Kurihara, Noriyoshi; Miura, Daishiro; Takenouchi, Kazuya; Cornish, Jillian; Cundy, Tim; Reddy, Sakamuri V; Roodman, G David

2004-05-01

333

Fluctuations and Defects in Lamellar Stacks of Amphiphilic Bilayers  

E-print Network

We review recent molecular dynamics simulations of thermally activated undulations and defects in the lamellar $L_\\alpha$ phase of a binary amphiphile-solvent mixture, using an idealized molecular coarse-grained model: Solvent particles are represented by beads, and amphiphiles by bead-and-spring tetramers. We find that our results are in excellent agreement with the predictions of simple mesoscopic theories: An effective interface model for the undulations, and a line tension model for the (pore) defects. We calculate the binding rigidity and the compressibility modulus of the lamellar stack as well as the line tension of the pore rim. Finally, we discuss implications for polymer-membrane systems.

Claire Loison; Michel Mareschal; Friederike Schmid

2005-01-05

334

Damaging effects of chronic low-dose methotrexate usage on primary bone formation in young rats and potential protective effects of folinic acid supplementary treatment.  

PubMed

Methotrexate (MTX) is a most commonly used anti-metabolite in cancer treatment and as an anti-rheumatic drug. While MTX chemotherapy at a high dose is known to cause bone growth defects in growing bones, effects of its chronic use at a low dose on growing skeleton remain less clear. Here, we examined effects on bone growth of long-term MTX chemotherapy at a low dose in young rats, and potential protective effects of supplementary treatment with antidote folinic acid (given ip at 1 mg/kg 6 h after MTX). After two cycles of 5 once-daily MTX injections (at 0.75 mg/kg, 5 days on/9 days off/5 days on), histological analysis showed that MTX at this dose caused significant reduction in heights of growth plate and primary spongiosa bone on day 22 compared to controls (P<0.05). In contrast, a similar dosing regimen but at a lower dose (0.4 mg/kg) caused only slight or no reduction in heights of both regions. However, after the induction phase at this 0.4 mg/kg dosing, continued use of MTX at a low dose (once weekly at 0.2 mg/kg) caused a reduction in primary spongiosa height and bone volume on weeks 9 and 14, which was associated with an increased osteoclast formation and their bone surface density as well as a decreased osteoblast bone surface density in the primary spongiosa. Folinic acid supplementation was shown able to prevent the MTX effects in the primary spongiosa. These results suggest that acute use of MTX can damage growth plate and primary bone at a high dose, but not at a low dose. However, long-term use of MTX at a low dose can reduce primary bone formation probably due to decreased osteoblastic function but increased osteoclastic formation and function, and supplementary treatment with folinic acid may be potentially useful in protecting bone growth during long-term low-dose MTX chemotherapy. PMID:18976724

Fan, Chiaming; Cool, Johanna C; Scherer, Michaela A; Foster, Bruce K; Shandala, Tetyana; Tapp, Heather; Xian, Cory J

2009-01-01

335

Comparison of the structure and mechanical properties of bovine femur bone and antler of the North American elk ( Cervus elaphus canadensis)  

Microsoft Academic Search

Antler and limb bone have a similar microstructure and chemical composition. Both are primarily composed of type I collagen and a mineral phase (carbonated apatite), arranged in osteons in compact (cortical bone) sections and a lamellar structure in the cancellous (spongy or trabecular bone) sections. The mineral content is lower in antler bone and it has a core of cancellous

P.-Y. Chen; A. G. Stokes; J. McKittrick

2009-01-01

336

Transplanted xenogenic bone marrow stem cells survive and generate new bone formation in the posterolateral lumbar spine of non-immunosuppressed rabbits  

Microsoft Academic Search

Bone marrow stem cells (BMSCs) are pluripotent cells that have been used to facilitate bone repair because of their capability\\u000a of differentiating into osteoblasts. However, it is well known that the number of BMSCs with osteogenic potential decreases\\u000a in patients with old age, osteoporosis, and metabolic diseases. In such conditions, xenogenic BMSCs may provide an alternative\\u000a to autologous BMSCs. In

Hyung-Jun Kim; Jong-Beom Park; Jin Kyung Lee; Eun-Young Park; K. Daniel Riew; Seung-Koo Rhee

2008-01-01

337

Signaling by Bone Morphogenetic Proteins directs formation of an ectodermal signaling center that regulates craniofacial development  

PubMed Central

We previously described a signaling center, the Frontonasal Ectodermal Zone (FEZ) that regulates growth and patterning of the frontonasal process (FNP). The FEZ is comprised of FNP ectoderm flanking a boundary between Sonic hedgehog (Shh) and Fibroblast growth factor 8 (Fgf8) expression domains. Our objective was to examine BMP signaling during formation of the FEZ. We blocked BMP signaling throughout the FNP prior to FEZ formation by infecting chick embryos at stage 10 (HH10) with a replication competent avian retrovirus encoding the BMP antagonist Noggin. We assessed gene expression patterns in the FNP 72 hours after infection (~HH22) and observed that Shh expression was reduced or absent. In the mesenchyme we observed that Bmp2 transcripts were absent while the Bmp4 expression domain was expanded proximally. In addition to the molecular changes, infected embryos also exhibited facial malformations at 72 and 96 hours after infection suggesting that the FEZ did not form. Our data indicate that reduced cell proliferation, but not apoptosis, in the mesenchyme contributed to the phenotype that we observed. Additionally, adding exogenous SHH into the mesenchyme of RCAS-Noggin infected embryos did not restore Bmp2 and Bmp4 to a normal pattern of expression. These data indicate that BMP signaling mediates interactions between tissues in the FNP that regulate FEZ formation; and that the correct pattern of Bmp2 and Bmp4, but not Bmp7, expression in the FNP mesenchyme requires signaling by the BMP pathway. PMID:18028903

Foppiano, Silvia; Hu, Diane; Marcucio, Ralph S.

2008-01-01

338

Sclerostin Is an Osteocyte-expressed Negative Regulator of Bone Formation, But Not a Classical BMP Antagonist  

Microsoft Academic Search

Sclerosteosis, a skeletal disorder characterized by high bone mass due to increased osteoblast activity, is caused by loss of the SOST gene product, sclerostin. The localization in bone and the mechanism of action of sclerostin are not yet known, but it has been hypothesized that it may act as a bone morphogenetic protein (BMP) antagonist. We show here that SOST

Rutger L. van Bezooijen; Bernard A. J. Roelen; Annemieke Visser; Lianne van der Wee-Pals; Edwin de Wilt; Marcel Karperien; Herman Hamersma; Socrates E. Papapoulos; Clemens W. G. M. Löwik

2004-01-01

339

Eco-mechanics of lamellar autotomy in larval damselflies.  

PubMed

In larval damselflies, the self-amputation (autotomy) of the caudal lamellae permits escape from predatory larval dragonflies. Lamellar joint size declines among populations with increasing risk of dragonfly predation, but the breaking force required for autotomy and the biomechanical factors that influence breaking force are unknown. If autotomy enhances survival in larval damselflies, then predation by larval dragonflies should select for joints that require less force to break. We test this adaptive hypothesis by evaluating whether breaking force is negatively related to local predation risk from larval dragonflies. We also test a cuticle structure hypothesis, which predicts that breaking force is positively related to joint size and to joint cuticle thickness because of a structural support relationship between joint and lamella. The peak force necessary for lamellar autotomy was assessed on individual larval Enallagma damselflies collected from populations that varied in risk of predation. Easier lamellar autotomy occurred in larvae from sites with higher predation risk because damselflies from fishless ponds (where predatory larval dragonflies are likely more abundant) had lower breaking forces than those from ponds with fish (where larval dragonfly predation is likely reduced). Furthermore, breaking force was a positive function of joint size and also of total cuticle cross-sectional area after controlling for joint size. This suggests that autotomy may evolve in larval damselflies under selection from small grasping predators such as larval dragonflies by favouring smaller joint size or reduced cuticle area of lamellar joints. PMID:24431142

Gleason, Jennifer E; Fudge, Douglas S; Robinson, Beren W

2014-01-15

340

A Modal Analysis of Lamellar Diffraction Gratings in Conical Mountings  

Microsoft Academic Search

A rigorous modal analysis of lamellar gratings, i.e. gratings having rectangular grooves, in conical mountings is presented. It is an extension of the analysis of Botten et al. which considered non-conical mountings. A key step in the extension is a decomposition of the electromagnetic field in the grating region into two orthogonal components. A computer program implementing this extended modal

Lifeng Li

1993-01-01

341

Synthesis and characterization of lamellar aragonite with hydrophobic property  

Microsoft Academic Search

A novel and simple synthetic method for the preparation of hydrophobic lamellar aragonite has been developed. The crystallization of aragonite was conducted by the reaction of sodium carbonate with calcium chloride in the presence of sodium stearate. The resulting products were characterized by powder X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and the contact angle.

Chengyu Wang; Yang Xu; Yalan Liu; Jian Li

2009-01-01

342

Cataract progression and treatment following posterior lamellar keratoplasty  

Microsoft Academic Search

Purpose: To describe the development and treatment of cataracts following posterior lamellar keratoplasty (PLK) in phakic eyes with Fuchs' endothelial dystrophy.Setting: Price Vision Group, Indianapolis, Indiana, USA.Methods: A retrospective chart review was performed on 47 PLK cases performed by a single surgeon between June 2001 and December 2002 in a tertiary care setting. Four of the eyes were phakic at

Marianne O Price; Francis W Price

2004-01-01

343

Intrauterine growth restriction may not suppress bone formation at term, as indicated by circulating concentrations of undercarboxylated osteocalcin and Dickkopf-1.  

PubMed

The objective was to investigate circulating concentrations of bone formation markers (undercarboxylated osteocalcin [Glu-OC], an established marker of bone formation during fetal and early postnatal life], and Dickkopf-1 [DKK-1], a natural inhibitor of osteoblastogenesis during fetal development]) in intrauterine-growth-restricted (IUGR; associated with impaired fetal skeletal development) and appropriate-for-gestational-age (AGA) pregnancies. Circulating concentrations of Glu-OC and DKK-1 were determined by enzyme immunoassay in 40 mothers and their 20 asymmetric IUGR and 20 AGA singleton full-term fetuses and neonates on postnatal day 1 (N1) and 4 (N4). Parametric tests were applied in the statistical analysis. No significant differences in Glu-OC concentrations were observed between IUGR and AGA groups, whereas fetal DKK-1 concentrations were lower in the IUGR group (P = .028). In both groups, maternal Glu-OC and DKK-1 concentrations were lower than fetal, N1, and N4 concentrations (P ? .012 in all cases), whereas fetal Glu-OC concentrations were higher than N1 and N4 ones (P ? .037 in all cases). In addition, N1 Glu-OC concentrations were higher than N4 concentrations (P = .047). Finally, maternal Glu-OC and DKK-1 concentrations positively correlated with fetal, N1, and N4 ones (r ? 0.404, P ? .01 in all cases). Fetal/neonatal bone formation may not be impaired in full-term asymmetric IUGR infants, as indicated by the similar Glu-OC concentrations in both groups. Fetal DDK-1 concentrations are lower in the IUGR group, representing probably a compensatory mechanism, favoring the formation of mineralized bone. Fetal/neonatal bone turnover is markedly enhanced compared with maternal one and seems to be associated with the latter in both late pregnancy and early postpartum. PMID:21944272

Briana, Despina D; Gourgiotis, Dimitrios; Georgiadis, Anestis; Boutsikou, Maria; Baka, Stavroula; Marmarinos, Antonios; Hassiakos, Dimitrios; Malamitsi-Puchner, Ariadne

2012-03-01

344

[Bone and androgens].  

PubMed

Sexual steroids are major determinants of skeletal maturation and steady state. Estrogens are mandatory in both sexes. They induce endochondral bone formation and growth plate knitting. Androgens are mainly active in male. They increase length and radial bone growth. These differences explain the duality of biomechanics in both sexes. Deep androgen deficiency induces rapid bone loss and increases bone fracture risk. The androgen treatment of andropause has weak rationale. Androgens interact with bone metabolism within the medulla-bone unit. They activate the whole osteoblastic lineage and interact with preosteoclastic regulation. Androgens found their place in bone metabolism regulation through RANK/osteoprotegerin and Wnt/sclerostin pathways. PMID:24332181

Weryha, Georges; Angelousi, Anna; Diehdiou, Demba; Cuny, Thomas

2014-02-01

345

Evolutionary Patterns of Bone Histology and Bone Compactness in Xenarthran Mammal Long Bones  

PubMed Central

Bone microstructure reflects physiological characteristics and has been shown to contain phylogenetic and ecological signals. Although mammalian long bone histology is receiving increasing attention, systematic examination of the main clades has not yet been performed. Here we describe the long bone microstructure of Xenarthra based on thin sections representing twenty-two species. Additionally, patterns in bone compactness of humeri and femora are investigated. The primary bone tissue of xenarthran long bones is composed of a mixture of woven, parallel-fibered and lamellar bone. The vascular canals have a longitudinal, reticular or radial orientation and are mostly arranged in an irregular manner. Concentric rows of vascular canals and laminar organization of the tissue are only found in anteater bones. The long bones of adult specimens are marked by dense Haversian bone, a feature that has been noted for most groups of mammals. In the long bones of armadillos, secondary osteons have an oblique orientation within the three-dimensional bone tissue, thus resulting in their irregular shape when the bones are sectioned transversely. Secondary remodeling is generally more extensive in large taxa than in small taxa, and this could be caused by increased loading. Lines of arrested growth are assumed to be present in all specimens, but they are restricted to the outermost layer in bones of armadillos and are often masked by secondary remodeling in large taxa. Parameters of bone compactness show a pattern in the femur that separates Cingulata and Pilosa (Folivora and Vermilingua), with cingulates having a lower compactness than pilosans. In addition, cingulates show an allometric relationship between humeral and femoral bone compactness. PMID:23874932

Straehl, Fiona R.; Scheyer, Torsten M.; Forasiepi, Analia M.; MacPhee, Ross D.; Sanchez-Villagra, Marcelo R.

2013-01-01

346

Nrf2 in bone marrow-derived cells positively contributes to the advanced stage of atherosclerotic plaque formation.  

PubMed

Atherosclerosis is the major etiology underlying myocardial infarction and stroke, and strategies for preventing atherosclerosis are urgently needed. In the context of atherosclerosis, the deletion of the Nrf2 gene, which encodes a master regulator of the oxidative stress response in mammals, reportedly attenuates atherosclerosis formation. However, the precise mechanisms of protection against atherosclerosis are largely unknown. To further clarify the role of Nrf2 in atherosclerosis in vivo, we performed a time course analysis of atherosclerosis development utilizing an ApoE knockout (KO) mouse model. The results demonstrate that oil red O-stainable lesions were similar in size 5 weeks after the initiation of an HFC (high fat and high cholesterol) diet, but the lesions were markedly attenuated in the Nrf2 and ApoE double KO mice (A0N0 mice) compared with the lesions in the ApoE KO mice (A0N2 mice) at 12 weeks. Consistent with these results, the immunohistochemical analysis revealed that Nrf2 activation is observed in late-stage atherosclerotic plaques but not in earlier lesions. The RT-qPCR analysis of 12-week atherosclerotic plaques revealed that Nrf2 target genes, such as Ho-1 and SLPI, are expressed at significantly lower levels in the A0N0 mice compared with the A0N2 mice, and this change was associated with a decreased expression of macrophage M1-subtype genes Arginase II and inducible NO synthase in the A0N0 mice. Furthermore, the bone marrow (BM) transplantation (BMT) analysis revealed that the Nrf2 activity in the BM-derived cells contributed to lesion formation. Therefore, our study has characterized the positive role of Nrf2 in the BM-derived cells during the development of atherosclerosis, which suggests that Nrf2 may influence the inflammatory reactions in the plaques. PMID:23051009

Harada, Nobuhiko; Ito, Koichi; Hosoya, Tomonori; Mimura, Junsei; Maruyama, Atsushi; Noguchi, Noriko; Yagami, Ken-ichi; Morito, Naoki; Takahashi, Satoru; Maher, Jon M; Yamamoto, Masayuki; Itoh, Ken

2012-12-15

347

The role of middle ear effusions and epidermal growth factor in cholesteatoma formation in the gerbilline temporal bone.  

PubMed

To study the process of aural cholesteatoma formation, we used gerbilline temporal bones to examine histologically the early stages of spontaneous cholesteatomas associated with experimentally induced otitis media with effusion (OME) following electric cauterizations of the eustachian tube. Epidermal growth factor (EGF) was then localized immunohistochemically in the pars flaccida of normal ears and the forming spontaneous cholesteatomas. Findings in the ears with the early spontaneous cholesteatomas were effusion inside the pars flaccida and hypertrophy and hyperkeratosis of the pars flaccida. Findings in the ears with experimental OME involved an effusion in the whole middle ear cavity as well as hypertrophy and hyperkeratosis in both the pars flaccida and pars tensa. The incidence of ear drum changes was higher in the experimental OME group than in control animals without cauterization. EGF was localized in the mucous layer of normal drums, the mucous layer and lamina propria of drums with hypertrophy alone, and all layers in drums with hypertrophy and hyperkeratosis. EGF was especially positive in the cytoplasms of transformed cuboidal cells. These findings suggest that EGF within the transformed mucous layer may play an important role as a biochemical factor in developing cholesteatomas. PMID:8562039

Omura, F; Makino, K; Amatsu, M; Itoh, H

1995-01-01

348

Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding.  

PubMed

Secreted noggin protein regulates bone morphogenetic protein activity during development. In mice, a complete loss of noggin protein leads to multiple malformations including joint fusion, whereas mice heterozygous for Nog loss-of-function mutations are normal. In humans, heterozygous NOG missense mutations have been found in patients with two autosomal dominant disorders of joint development, multiple synostosis syndrome (SYNS1) and a milder disorder proximal symphalangism (SYM1). This study investigated the effect of one SYNS1 and two SYM1 disease-causing missense mutations on the structure and function of noggin. The SYNS1 mutation abolished, and the SYM1 mutations reduced, the secretion of functional noggin dimers in transiently transfected COS-7 cells. Coexpression of mutant noggin with wild-type noggin, to resemble the heterozygous state, did not interfere with wild-type noggin secretion. These data indicate that the human disease-causing mutations are hypomorphic alleles that reduce secretion of functional dimeric noggin. Therefore, we conclude that noggin has both species-specific and joint-specific dosage-dependent roles during joint formation. Surprisingly, in contrast to the COS-7 cell studies, the SYNS1 mutant was able to form dimers in Xenopus laevis oocytes. This finding indicates that there also exist species-specific differences in the ability to process mutant noggin polypeptides. PMID:11562478

Marcelino, J; Sciortino, C M; Romero, M F; Ulatowski, L M; Ballock, R T; Economides, A N; Eimon, P M; Harland, R M; Warman, M L

2001-09-25

349

Calcified Rheumatic Valve Neoangiogenesis Is Associated With Vascular Endothelial Growth Factor Expression and Osteoblast-Like Bone Formation  

PubMed Central

Background Rheumatic heart disease is the most common cause of valvular disease in developing countries. Despite the high prevalence of this disease, the cellular mechanisms are not well known. We hypothesized that rheumatic valve calcification is associated with an osteoblast bone formation and neoangiogenesis. Methods and Results To test this hypothesis, we examined human rheumatic valves replaced at surgery (n=23), normal human valves (n=20) removed at cardiac transplantation, and degenerative mitral valve leaflets removed during surgical valve repair (n=15). Microcomputed tomography was used to assess mineralization fronts to reconstruct the extents of mineralization. Immunohistochemistry was used to localize osteopontin protein, ?-actin, osteocalcin, vascular endothelial growth factor, von Willebrand factor, and CD68 (human macrophage). Microcomputed tomography demonstrated complex calcification developing within the heavily calcified rheumatic valves, not in the degenerative mitral valves and control valves. Immunohistochemistry localized osteopontin and osteocalcin to areas of smooth muscle cells within microvessels and proliferating myofibroblasts. Vascular endothelial growth factor was present in areas of inflammation and colocalized with the CD68 stain primarily in the calcified rheumatic valves. Alizarin red, osteopontin, and osteocalcin protein expression was upregulated in the calcified rheumatic valves and was present at low levels in the degenerative mitral valves. Conclusions These findings support the concept that rheumatic valve calcification is not a random passive process but a regulated, inflammatory cellular process associated with the expression of osteoblast markers and neoangiogenesis. PMID:15956138

Rajamannan, Nalini M.; Nealis, Thomas B.; Subramaniam, Malayannan; Pandya, Sanjay; Stock, Stuart R.; Ignatiev, Constatine I.; Sebo, Thomas J.; Rosengart, Todd K.; Edwards, William D.; McCarthy, Patrick M.; Bonow, Robert O.; Spelsberg, Thomas C.

2014-01-01

350

Histological assessment of tissue from large human bone defects repaired with ?-tricalcium phosphate.  

PubMed

This report describes the histological characteristics of large human bone defects that were implanted with ?-tricalcium phosphate (?-TCP). Samples were obtained longer after the primary operation than in the earlier studies. We assessed a total of nine biopsies taken 33-208 weeks after implantation. The tissue sections were stained with hematoxylin-eosin for general observation, with Gomori stain to visualize the reticulin fibers, and with an antibody against tartrate-resistant alkaline phosphatase (TRAP) to characterize the cells. Ongoing bone remodeling was observed even 208 weeks after implantation as determined by the presence of osteoclasts and active osteoblasts and new woven and lamellar bone. We observed multinuclear giant cells phagocytosing the biomaterial and the attachment of osteoclasts to the ?-TCP. The osteoclasts showed intense TRAP positivity, while the giant cells showed variable TRAP positivity. There was a zonal pattern in the original defects: The central regions showed granules and fibrous septa, while peripheral areas showed a layer of new bone formation. These data demonstrate ongoing bone remodeling long after implantation in the peripheral regions of the original defects as well as fibrous changes in the central regions and phagocytosis of biomaterial by multinuclear giant cells. PMID:24091824

Kucera, Tomas; Sponer, Pavel; Urban, Karel; Kohout, Ales

2014-12-01

351

[Suppressive effect of xenogenic bone marrow cells on antibody formation in a spleen cell culture in vitro].  

PubMed

Bone marrow cells from syngenetic and xenogeneic donors of different species were added to splenocyte culture to induce the primary immune response to sheep red blood cells. It has been shown that both xenogeneic and syngeneic bone marrow cells suppress the primary immune response in vitro. A conclusion is made that the suppressant effect exerted by bone marrow cells on the immune response of splenocytes is not liable to xenogenic restriction. PMID:7407376

Vlasov, A A; Sidorovich, I G; Khaitov, R M

1980-07-01

352

Prostaglandin E2, Interleukin 1 , and Tumor Necrosis Factor  Increase Human Osteoclast Formation and Bone Resorption in Vitro  

Microsoft Academic Search

Prostaglandin E2 (PGE2) and the cytokines interleukin (IL) 1a and tumor necrosis factor (TNF)a increase bone resorption in vivo, but the effect of these agents on osteoclastic bone resorption has never been studied in an in vitro human system. Our recently described human bone marrow culture system, in which osteoclasts are generated (vi- tronectin and calcitonin receptor-positive cells which resorb

C. S. Lader; A. M. FLANAGAN

1998-01-01

353

Cyclooxygenase2 Inhibition Delays the Attainment of Peak Woven Bone Formation following Four-Point Bending in the Rat  

Microsoft Academic Search

Fracture healing is retarded in the presence of cyclooxygenase-2 (COX-2) inhibitors, demonstrating an important role of COX-2\\u000a in trauma-induced woven bone adaptation. The aim of this experiment was to determine the influence of COX-2 inhibition on\\u000a the remodeling and consolidation of nontraumatic woven bone produced by mechanical loading. A periosteal woven bone callus\\u000a was initiated in the right tibia of

L. S. Gregory; M. R. Forwood

2007-01-01

354

Carboxyl-modified single-wall carbon nanotubes improve bone tissue formation in vitro and repair in an in vivo rat model  

PubMed Central

The clinical management of bone defects caused by trauma or nonunion fractures remains a challenge in orthopedic practice due to the poor integration and biocompatibility properties of the scaffold or implant material. In the current work, the osteogenic properties of carboxyl-modified single-walled carbon nanotubes (COOH–SWCNTs) were investigated in vivo and in vitro. When human preosteoblasts and murine embryonic stem cells were cultured on coverslips sprayed with COOH–SWCNTs, accelerated osteogenic differentiation was manifested by increased expression of classical bone marker genes and an increase in the secretion of osteocalcin, in addition to prior mineralization of the extracellular matrix. These results predicated COOH–SWCNTs’ use to further promote osteogenic differentiation in vivo. In contrast, both cell lines had difficulties adhering to multi-walled carbon nanotube-based scaffolds, as shown by scanning electron microscopy. While a suspension of SWCNTs caused cytotoxicity in both cell lines at levels >20 ?g/mL, these levels were never achieved by release from sprayed SWCNTs, warranting the approach taken. In vivo, human allografts formed by the combination of demineralized bone matrix or cartilage particles with SWCNTs were implanted into nude rats, and ectopic bone formation was analyzed. Histological analysis of both types of implants showed high permeability and pore connectivity of the carbon nanotube-soaked implants. Numerous vascularization channels appeared in the formed tissue, additional progenitor cells were recruited, and areas of de novo ossification were found 4 weeks post-implantation. Induction of the expression of bone-related genes and the presence of secreted osteopontin protein were also confirmed by quantitative polymerase chain reaction analysis and immunofluorescence, respectively. In summary, these results are in line with prior contributions that highlight the suitability of SWCNTs as scaffolds with high bone-inducing capabilities both in vitro and in vivo, confirming them as alternatives to current bone-repair therapies.

Barrientos-Duran, Antonio; Carpenter, Ellen M; zur Nieden, Nicole I; Malinin, Theodore I; Rodriguez-Manzaneque, Juan Carlos; Zanello, Laura P

2014-01-01

355

Enhanced MC3T3-E1 preosteoblast response and bone formation on the addition of nano-needle and nano-porous features to microtopographical titanium surfaces.  

PubMed

Micro/nanotopographical modifications on titanium surfaces constitute a new process to increase osteoblast response to enhance bone formation. In this study, we utilized alkali heat treatment at high (SB-AH1) and low temperatures (SB-AH2) to nano-modify sandblasted titanium with microtopographical surfaces. Then, we evaluated the surface properties, biocompatibility and osteogenic capability of SB-AH1 and SB-AH2 in vitro and in vivo, and compared these with conventional sandblast-acid etching (SLA) and Ti control surfaces. SB-AH1 and SB-AH2 surfaces exhibited micro/nanotopographical modifications of nano-needle structures and nano-porous network layers, respectively, compared with the sole microtopographical surface of macro and micro pits on the SLA surface and the relatively smooth surface on the Ti control. SB-AH1 and SB-AH2 showed different roughness and elemental components, but similar wettability. MC3T3-E1 preosteoblasts anchored closely on the nanostructures of SB-AH1 and SB-AH2 surfaces, and these two surfaces more significantly enhanced cell proliferation and alkaline phosphatase (ALP) activity than others, while the SB-AH2 surface exhibited better cell proliferation and higher ALP activity than SB-AH1. All four groups of titanium domes with self-tapping screws were implanted in rabbit calvarial bone models, and these indicated that SB-AH1 and SB-AH2 surfaces achieved better peri-implant bone formation and implant stability, while the SB-AH2 surface achieved the best percentage of bone-implant contact (BIC%). Our study demonstrated that the micro/nanotopographical surface generated by sandblasting and alkali heat treatment significantly enhanced preosteoblast proliferation, ALP activity and bone formation in vitro and in vivo, and nano-porous network topography may further induce better preosteoblast proliferation, ALP activity and BIC%. PMID:24945708

Zhuang, X-M; Zhou, B; Ouyang, J-L; Sun, H-P; Wu, Y-L; Liu, Q; Deng, F-L

2014-08-01

356

Deletion of EP4 on bone marrow-derived cells enhances inflammation and angiotensin II-induced abdominal aortic aneurysm formation  

PubMed Central

Objective To examine whether a lack of prostaglandin E receptor 4 (EP4) on bone marrow-derived cells would increase local inflammation and enhance the formation of abdominal aortic aneurysm (AAA) in vivo. Methods and Results Prostaglandin E2 (PGE2), through activation of its receptor EP4, can mute inflammation. Hypercholesterolemic low-density lipoprotein receptor knockout (LDLR?/?) mice transplanted with either EP4+/+ [EP4+/+/LDLR?/?] or EP4?/? [EP4?/?/LDLR?/?] bone marrow received infusions of angiotensin II to induce AAA. Deficiency of EP4 on bone marrow–derived cells increased the incidence (50% of male EP4+/+/LDLR?/? vs. 88.9% male EP4?/?/LDLR?/? developed AAA; and 22% of female EP4+/+/LDLR?/? vs. 83.3% female EP4?/?/LDLR?/? developed AAA) and severity of AAA, increased monocyte chemoattractant protein-1 (2.72-fold in males and 1.64-fold in females), and enhanced infiltration of macrophages (3.8-fold in males and 2.44-fold in females) and T cells (1.88-fold in males and 1.66-fold in females) into AAA lesions. Lack of EP4 on bone marrow–derived cells augmented elastin fragmentation, increased apoptotic markers, and decreased smooth-muscle cell accumulation within AAA lesions. Conclusions Deficiency of EP4 on bone marrow–derived cells boosted inflammation and AAA formation induced by angiotensin II in hyperlipidemic mice. This study affirms the pathophysiologic importance of PGE2 signaling through EP4 as an endogenous anti-inflammatory pathway involved in experimental aneurysm formation. PMID:21088251

Tang, Eva HC; Shvartz, Eugenia; Shimizu, Koichi; Rocha, Viviane Z; Zheng, Chunyu; Fukuda, Daiju; Shi, Guo-Ping; Sukhova, Galina; Libby, Peter

2010-01-01

357

A ?-Arrestin-Biased Agonist of the Parathyroid Hormone Receptor (PTH1R) Promotes Bone Formation Independent of G Protein Activation  

PubMed Central

About 40% of the therapeutic agents in use today exert their effects through seven-transmembrane receptors (7TMRs). When activated by ligands, these receptors trigger two pathways that independently transduce signals to the cell: one through heterotrimeric GTP-binding proteins (G proteins) and one through ?-arrestins; so-called biased agonists can selectively activate these distinct pathways. Here, we investigate selective activation of these pathways through the use of a biased agonist for the type 1 parathyroid hormone (PTH)–PTH-related protein receptor (PTH1R), (D-Trp12, Tyr34)-PTH(7–34) (PTH-?arr), which activates ?-arrestin but not classic G protein signaling. In mice, PTH-?arr induces anabolic bone formation, as does the nonselective agonist PTH (1–34), which activates both mechanisms. In ?-arrestin2–null mice, the increase in bone mineral density evoked by PTH(1–34) is attenuated and that stimulated by PTH-?arr is ablated. The ?-arrestin2–dependent pathway contributes primarily to trabecular bone formation and does not stimulate bone resorption. These results show that a biased agonist selective for the ?-arrestin pathway can elicit a response in vivo distinct from that elicited by nonselective agonists. Ligands with these properties may form the basis for improved 7TMR-directed pharmacologic agents with enhanced therapeutic specificity. PMID:20368153

Gesty-Palmer, Diane; Flannery, Pat; Yuan, Ling; Corsino, Leonor; Spurney, Robert; Lefkowitz, Robert J.; Luttrell, Louis M.

2010-01-01

358

Stress response and structural transitions in sheared gyroidal and lamellar amphiphilic mesophases: lattice-Boltzmann simulations  

E-print Network

We report on the stress response of gyroidal and lamellar amphiphilic mesophases to steady shear simulated using a bottom-up lattice-Boltzmann model for amphiphilic fluids and sliding periodic (Lees-Edwards) boundary conditions. We study the gyroid per se (above the sponge-gyroid transition, of high crystallinity) and the molten gyroid (within such a transition, of shorter-range order). We find that both mesophases exhibit shear-thinning, more pronounced and at lower strain rates for the molten gyroid. At late times after the onset of shear, the skeleton of the crystalline gyroid becomes a structure of interconnected irregular tubes and toroidal rings, mostly oriented along the velocity ramp imposed by the shear, in contradistinction with free-energy Langevin-diffusion studies which yield a much simpler structure of disentangled tubes. We also compare the shear stress and deformation of lamellar mesophases with and without amphiphile when subjected to the same shear flow applied normal to the lamellae. We find that the presence of amphiphile allows (a) the shear stress at late times to be higher than in the case without amphiphile, and (b) the formation of rich patterns on the sheared interface, characterised by alternating regions of high and low curvature.

Nelido Gonzalez-Segredo; Jens Harting; Giovanni Giupponi; Peter V. Coveney

2006-01-20

359

Ephrin B2/EphB4 mediates the actions of IGF-I signaling in regulating endochondral bone formation.  

PubMed

Ephrin B2/EphB4 mediates interactions among osteoblasts (OBs), osteoclasts (OCLs), and chondrocytes to regulate their differentiation. We investigated the role of ephrin B2/EphB4 signaling in mediating the anabolic effects of insulin-like growth factor-I (IGF-I) and parathyroid hormone (PTH) on those cells and overall endochondral bone formation. Immunohistochemistry demonstrated that the expression of ephrin B2 in OBs, OCLs, and osteocytes, and the expression of EphB4 in OBs and osteocytes was dramatically decreased in global IGF-I knockout mice. Inactivation of EphB4 by EphB4 small, interfering RNA (siRNA) in cultured bone marrow stromal cells significantly decreased the mRNA levels of OB differentiation markers and abolished the stimulatory effects of IGF-I on these markers. Blocking the interaction of EphB4 and ephrin B2 in the OB-OCL cocultures with the EphB4 specific peptide TNYL-RAW or deletion of ephrin B2 in OCL prior to coculture led to fewer and smaller tartrate-resistant acid phosphatase (TRAP)-positive cells, decreased expression of OB differentiation markers, and blunted response to IGF-I for both OCL and OB differentiation. In the growth plate, both ephrin B2 and EphB4 are expressed in late stage proliferating and prehypertrophic chondrocytes, and their expression was decreased in mice lacking the IGF-I receptor specifically in chondrocytes. In vitro, blocking the interaction of EphB4 and ephrin B2 in chondrogenic ATDC5 cells with TNYL-RAW significantly decreased both basal and IGF1-induced expression of type II and type X collagen. In the cocultures of ATDC5 cells and spleen cells (osteoclast precursors), TNYL-RAW decreased the numbers of TRAP-positive cells and the expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) and receptor activator of NF-?B (RANK), and blocked their stimulation by IGF-I. Our data indicate that IGF-I/IGF-IR signaling promotes OB, OCL, and chondrocyte differentiation via ephrin B2/EphB4 mediated cell-cell communication. PMID:24677183

Wang, Yongmei; Menendez, Alicia; Fong, Chak; ElAlieh, Hashem Z; Chang, Wenhan; Bikle, Daniel D

2014-08-01

360

Novel porous Al2O3-SiO2-TiO2 bone grafting materials: formation and characterization.  

PubMed

The present article deals with the development of 3D porous scaffolds for bone grafting. They were prepared based on rapid fluid infiltration of Al2O3-SiO2 sol into a polyethylene non-woven fabric template structure. Titanium dioxide in concentration equal to 5 wt% was added to the Al2O3-SiO2 mixture to produce Al2O3-SiO2-TiO2 composite scaffolds. The prepared scaffolds are characterized by means of X-ray diffraction, scanning electron microscopy and three-point bending test techniques. The bioactivity of the produced bodies is discussed, including the in vitro and in vivo assessments. The produced scaffolds exhibit mean total porosity of 66.0% and three-point bending strength of 7.1?MPa. In vitro studies showed that MG-63 osteoblast-like cells attach and spread on the scaffolds surfaces. Furthermore, cells grew through the scaffolds and start to produce extra-cellular matrix. Additionally, in vivo studies revealed the ability of the porous scaffolds to regenerate bone tissue in femur defects of albino rats 5 months post surgery. Histological analysis showed that the defect is almost entirely filled with new bone. The formed bone is characterized as a mature bone. The produced bone grafts are intended to be used as bone substitute or bone filler as their degradation products caused no inflammatory effects. PMID:23594680

Naga, Salma M; El-Kady, Abeer M; El-Maghraby, Hesham F; Awaad, Mohamed; Detsch, Rainer; Boccaccini, Aldo R

2014-02-01

361

Dual-delivery of vancomycin and icariin from an injectable calcium phosphate cement-release system for controlling infection and improving bone healing.  

PubMed

Infectious bone diseases following severely contaminated open fractures are frequently encountered in clinical practice. It