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Bone corticalization requires local SOCS3 activity and is promoted by androgen action via interleukin-6.
Cho DC, Brennan HJ, Johnson RW, Poulton IJ, Gooi JH, Tonkin BA, McGregor NE, Walker EC, Handelsman DJ, Martin TJ, Sims NA
(2017) Nat Commun 8: 806
MeSH Terms: Androgens, Animals, Cancellous Bone, Chondrocytes, Dihydrotestosterone, Estradiol, Female, Interleukin-6, Male, Mice, Inbred C57BL, Osteogenesis, Ovariectomy, Suppressor of Cytokine Signaling 3 Protein
Show Abstract · Added March 26, 2019
Long bone strength is determined by its outer shell (cortical bone), which forms by coalescence of thin trabeculae at the metaphysis (corticalization), but the factors that control this process are unknown. Here we show that SOCS3-dependent cytokine expression regulates bone corticalization. Young male and female Dmp1Cre.Socs3 mice, in which SOCS3 has been ablated in osteocytes, have high trabecular bone volume and poorly defined metaphyseal cortices. After puberty, male mice recover, but female corticalization is still impaired, leading to a lasting defect in bone strength. The phenotype depends on sex-steroid hormones: dihydrotestosterone treatment of gonadectomized female Dmp1Cre.Socs3 mice restores normal cortical morphology, whereas in males, estradiol treatment, or IL-6 deletion, recapitulates the female phenotype. This suggests that androgen action promotes metaphyseal corticalization, at least in part, via IL-6 signaling.The strength of long bones is determined by coalescence of trabeculae during corticalization. Here the authors show that this process is regulated by SOCS3 via a mechanism dependent on IL-6 and expression of sex hormones.
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Fabrication of Trabecular Bone-Templated Tissue-Engineered Constructs by 3D Inkjet Printing.
Vanderburgh JP, Fernando SJ, Merkel AR, Sterling JA, Guelcher SA
(2017) Adv Healthc Mater 6:
MeSH Terms: Biocompatible Materials, Bone Regeneration, Cancellous Bone, Cartilage, Cell Differentiation, Cells, Cultured, Humans, Materials Testing, Mesenchymal Stem Cells, Osteogenesis, Printing, Three-Dimensional, Tissue Engineering, Tissue Scaffolds
Show Abstract · Added March 21, 2018
3D printing enables the creation of scaffolds with precisely controlled morphometric properties for multiple tissue types, including musculoskeletal tissues such as cartilage and bone. Computed tomography (CT) imaging has been combined with 3D printing to fabricate anatomically scaled patient-specific scaffolds for bone regeneration. However, anatomically scaled scaffolds typically lack sufficient resolution to recapitulate the <100 micrometer-scale trabecular architecture essential for investigating the cellular response to the morphometric properties of bone. In this study, it is hypothesized that the architecture of trabecular bone regulates osteoblast differentiation and mineralization. To test this hypothesis, human bone-templated 3D constructs are fabricated via a new micro-CT/3D inkjet printing process. It is shown that this process reproducibly fabricates bone-templated constructs that recapitulate the anatomic site-specific morphometric properties of trabecular bone. A significant correlation is observed between the structure model index (a morphometric parameter related to surface curvature) and the degree of mineralization of human mesenchymal stem cells, with more concave surfaces promoting more extensive osteoblast differentiation and mineralization compared to predominately convex surfaces. These findings highlight the significant effects of trabecular architecture on osteoblast function.
© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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13 MeSH Terms
Hypoxia and Reactive Oxygen Species Homeostasis in Mesenchymal Progenitor Cells Define a Molecular Mechanism for Fracture Nonunion.
Muinos-López E, Ripalda-Cemboráin P, López-Martínez T, González-Gil AB, Lamo-Espinosa JM, Valentí A, Mortlock DP, Valentí JR, Prósper F, Granero-Moltó F
(2016) Stem Cells 34: 2342-53
MeSH Terms: Animals, Bone Morphogenetic Protein 2, Cell Hypoxia, Cell Separation, Disulfides, Fracture Healing, Fractures, Ununited, Homeostasis, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Imidazoles, Male, Mesenchymal Stem Cells, Mice, Inbred C57BL, Osteogenesis, Oxidative Stress, Periosteum, Reactive Oxygen Species
Show Abstract · Added February 3, 2017
Fracture nonunion is a major complication of bone fracture regeneration and repair. The molecular mechanisms that result in fracture nonunion appearance are not fully determined. We hypothesized that fracture nonunion results from the failure of hypoxia and hematoma, the primary signals in response to bone injury, to trigger Bmp2 expression by mesenchymal progenitor cells (MSCs). Using a model of nonstabilized fracture healing in transgenic 5'Bmp2BAC mice we determined that Bmp2 expression appears in close association with hypoxic tissue and hematoma during the early phases of fracture healing. In addition, BMP2 expression is induced when human periosteum explants are exposed to hypoxia ex vivo. Transient interference of hypoxia signaling in vivo with PX-12, a thioredoxin inhibitor, results in reduced Bmp2 expression, impaired fracture callus formation and atrophic-like nonunion by a HIF-1α independent mechanism. In isolated human periosteum-derived MSCs, BMP2 expression could be induced with the addition of platelets concentrate lysate but not with hypoxia treatment, confirming HIF-1α-independent BMP2 expression. Interestingly, in isolated human periosteum-derived mesenchymal progenitor cells, inhibition of BMP2 expression by PX-12 is accomplished only under hypoxic conditions seemingly through dis-regulation of reactive oxygen species (ROS) levels. In conclusion, we provide evidence of a molecular mechanism of hypoxia-dependent BMP2 expression in MSCs where interference with ROS homeostasis specifies fracture nonunion-like appearance in vivo through inhibition of Bmp2 expression. Stem Cells 2016;34:2342-2353.
© 2016 AlphaMed Press.
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Effects of Recombinant Human Bone Morphogenetic Protein-2 Dose and Ceramic Composition on New Bone Formation and Space Maintenance in a Canine Mandibular Ridge Saddle Defect Model.
Talley AD, Kalpakci KN, Shimko DA, Zienkiewicz KJ, Cochran DL, Guelcher SA
(2016) Tissue Eng Part A 22: 469-79
MeSH Terms: Alveolar Process, Animals, Bone Morphogenetic Protein 2, Ceramics, Disease Models, Animal, Dogs, Dose-Response Relationship, Drug, Humans, Mandible, Osteogenesis, Recombinant Proteins, Space Maintenance, Orthodontic, Transforming Growth Factor beta, X-Ray Microtomography
Show Abstract · Added February 23, 2016
Treatment of mandibular osseous defects is a significant clinical challenge. Maintenance of the height and width of the mandibular ridge is essential for placement of dental implants and restoration of normal dentition. While guided bone regeneration using protective membranes is an effective strategy for maintaining the anatomic contour of the ridge and promoting new bone formation, complications have been reported, including wound failure, seroma, and graft exposure leading to infection. In this study, we investigated injectable low-viscosity (LV) polyurethane/ceramic composites augmented with 100 μg/mL (low) or 400 μg/mL (high) recombinant human bone morphogenetic protein-2 (rhBMP-2) as space-maintaining bone grafts in a canine mandibular ridge saddle defect model. LV grafts were injected as a reactive paste that set in 5-10 min to form a solid porous composite with bulk modulus exceeding 1 MPa. We hypothesized that compression-resistant LV grafts would enhance new bone formation and maintain the anatomic contour of the mandibular ridge without the use of protective membranes. At the rhBMP-2 dose recommended for the absorbable collagen sponge carrier in dogs (400 μg/mL), LV grafts maintained the width and height of the host mandibular ridge and supported new bone formation, while at suboptimal (100 μg/mL) doses, the anatomic contour of the ridge was not maintained. These findings indicate that compression-resistant bone grafts with bulk moduli exceeding 1 MPa and rhBMP-2 doses comparable to that recommended for the collagen sponge carrier support new bone formation and maintain ridge height and width in mandibular ridge defects without protective membranes.
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14 MeSH Terms
Glycoprotein130 (Gp130)/interleukin-6 (IL-6) signalling in osteoclasts promotes bone formation in periosteal and trabecular bone.
Johnson RW, McGregor NE, Brennan HJ, Crimeen-Irwin B, Poulton IJ, Martin TJ, Sims NA
(2015) Bone 81: 343-351
MeSH Terms: Animals, Bone Marrow, Bone Marrow Cells, Bone and Bones, Cartilage, Cathepsin K, Cytokine Receptor gp130, Female, Femur, Gene Deletion, Interleukin-6, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Osteoclasts, Osteogenesis, Real-Time Polymerase Chain Reaction, Receptors, Interleukin-11, Receptors, Interleukin-6, Sex Factors, Signal Transduction, X-Ray Microtomography
Show Abstract · Added March 26, 2019
Interleukin-6 (IL-6) and interleukin-11 (IL-11) receptors (IL-6R and IL-11R, respectively) are both expressed in osteoclasts and transduce signal via the glycoprotein130 (gp130) co-receptor, but the physiological role of this pathway is unclear. To determine the critical roles of gp130 signalling in the osteoclast, we generated mice using cathepsin K Cre (CtskCre) to disrupt gp130 signalling in osteoclasts. Bone marrow macrophages from CtskCre.gp130(f/f) mice generated more osteoclasts in vitro than cells from CtskCre.gp130(w/w) mice; these osteoclasts were also larger and had more nuclei than controls. While no increase in osteoclast numbers was observed in vivo, osteoclasts on trabecular bone surfaces of CtskCre.gp130(f/f) mice were more spread out than in control mice, but had no functional defect detectable by serum CTX1 levels or trabecular bone cartilage remnants. However, trabecular osteoblast number and mineralising surfaces were significantly lower in male CtskCre.gp130(f/f) mice compared to controls, and this was associated with a significantly lower trabecular bone volume at 12 weeks of age. Furthermore, CtskCre.gp130(f/f) mice exhibited greatly suppressed periosteal bone formation at this age, indicated by significant reductions in both double-labelled surface and mineral apposition rate. By 26 weeks of age, CtskCre.gp130(f/f) mice exhibited narrower femora, with lower periosteal and endocortical perimeters than CtskCre.gp130(w/w) controls. Since IL-6 and IL-11R global knockout mice exhibited a similar reduction in femoral width, we also assessed periosteal bone formation in those strains, and found bone forming surfaces were also reduced in male IL-6 null mice. These data suggest that IL-6/gp130 signalling in the osteoclast is not essential for normal bone resorption in vivo, but maintains both trabecular and periosteal bone formation in male mice by promoting osteoblast activity through the stimulation of osteoclast-derived "coupling factors" and "osteotransmitters", respectively.
Copyright © 2015 Elsevier Inc. All rights reserved.
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D-amino acid inhibits biofilm but not new bone formation in an ovine model.
Harmata AJ, Ma Y, Sanchez CJ, Zienkiewicz KJ, Elefteriou F, Wenke JC, Guelcher SA
(2015) Clin Orthop Relat Res 473: 3951-61
MeSH Terms: Amino Acids, Animals, Anti-Bacterial Agents, Biofilms, Biomarkers, Bone Transplantation, Cell Differentiation, Cell Proliferation, Cells, Cultured, Dose-Response Relationship, Drug, Female, Femur, Mesenchymal Stem Cells, Methicillin-Resistant Staphylococcus aureus, Methionine, Mice, Models, Animal, Osseointegration, Osteoblasts, Osteoclasts, Osteogenesis, Phenylalanine, Proline, Sheep, Domestic, Time Factors, X-Ray Microtomography
Show Abstract · Added May 16, 2017
BACKGROUND - Infectious complications of musculoskeletal trauma are an important factor contributing to patient morbidity. Biofilm-dispersive bone grafts augmented with D-amino acids (D-AAs) prevent biofilm formation in vitro and in vivo, but the effects of D-AAs on osteocompatibility and new bone formation have not been investigated.
QUESTIONS/PURPOSES - We asked: (1) Do D-AAs hinder osteoblast and osteoclast differentiation in vitro? (2) Does local delivery of D-AAs from low-viscosity bone grafts inhibit new bone formation in a large-animal model?
METHODS - Methicillin-sensitive Staphylococcus aureus and methicillin-resistant S aureus clinical isolates, mouse bone marrow stromal cells, and osteoclast precursor cells were treated with an equal mass (1:1:1) mixture of D-Pro:D-Met:D-Phe. The effects of the D-AA dose on biofilm inhibition (n = 4), biofilm dispersion (n = 4), and bone marrow stromal cell proliferation (n = 3) were quantitatively measured by crystal violet staining. Osteoblast differentiation was quantitatively assessed by alkaline phosphatase staining, von Kossa staining, and quantitative reverse transcription for the osteogenic factors a1Col1 and Ocn (n = 3). Osteoclast differentiation was quantitatively measured by tartrate-resistant acid phosphatase staining (n = 3). Bone grafts augmented with 0 or 200 mmol/L D-AAs were injected in ovine femoral condyle defects in four sheep. New bone formation was evaluated by μCT and histology 4 months later. An a priori power analysis indicated that a sample size of four would detect a 7.5% difference of bone volume/total volume between groups assuming a mean and SD of 30% and 5%, respectively, with a power of 80% and an alpha level of 0.05 using a two-tailed t-test between the means of two independent samples.
RESULTS - Bone marrow stromal cell proliferation, osteoblast differentiation, and osteoclast differentiation were inhibited at D-AAs concentrations of 27 mmol/L or greater in a dose-responsive manner in vitro (p < 0.05). In methicillin-sensitive and methicillin-resistant S aureus clinical isolates, D-AAs inhibited biofilm formation at concentrations of 13.5 mmol/L or greater in vitro (p < 0.05). Local delivery of D-AAs from low-viscosity grafts did not inhibit new bone formation in a large-animal model pilot study (0 mmol/L D-AAs: bone volume/total volume = 26.9% ± 4.1%; 200 mmol/L D-AAs: bone volume/total volume = 28.3% ± 15.4%; mean difference with 95% CI = -1.4; p = 0.13).
CONCLUSIONS - D-AAs inhibit biofilm formation, bone marrow stromal cell proliferation, osteoblast differentiation, and osteoclast differentiation in vitro in a dose-responsive manner. Local delivery of D-AAs from bone grafts did not inhibit new bone formation in vivo at clinically relevant doses.
CLINICAL RELEVANCE - Local delivery of D-AAs is an effective antibiofilm strategy that does not appear to inhibit bone repair. Longitudinal studies investigating bacterial burden, bone formation, and bone remodeling in contaminated defects as a function of D-AA dose are required to further support the use of D-AAs in the clinical management of infected open fractures.
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26 MeSH Terms
Fabrication of 3D Scaffolds with Precisely Controlled Substrate Modulus and Pore Size by Templated-Fused Deposition Modeling to Direct Osteogenic Differentiation.
Guo R, Lu S, Page JM, Merkel AR, Basu S, Sterling JA, Guelcher SA
(2015) Adv Healthc Mater 4: 1826-32
MeSH Terms: Animals, Cell Differentiation, Cell Movement, Cell Proliferation, Cells, Cultured, Mesenchymal Stem Cells, Osteogenesis, Rats, Rats, Sprague-Dawley, Tissue Scaffolds
Show Abstract · Added February 23, 2016
Scaffolds with tunable mechanical and topological properties fabricated by templated-fused deposition modeling promote increased osteogenic differentiation of bone marrow stem cells with increasing substrate modulus and decreasing pore size. These findings guide the rational design of cell-responsive scaffolds that recapitulate the bone microenvironment for repair of bone damaged by trauma or disease.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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10 MeSH Terms
Recessive osteogenesis imperfecta caused by missense mutations in SPARC.
Mendoza-Londono R, Fahiminiya S, Majewski J, Care4Rare Canada Consortium, Tétreault M, Nadaf J, Kannu P, Sochett E, Howard A, Stimec J, Dupuis L, Roschger P, Klaushofer K, Palomo T, Ouellet J, Al-Jallad H, Mort JS, Moffatt P, Boudko S, Bächinger HP, Rauch F
(2015) Am J Hum Genet 96: 979-85
MeSH Terms: Amino Acid Sequence, Base Sequence, Collagen Type I, Electrophoresis, Polyacrylamide Gel, Exome, Female, Genes, Recessive, Humans, Immunoblotting, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutation, Missense, Osteogenesis Imperfecta, Osteonectin, Pedigree, Protein Conformation, Sequence Alignment, Sequence Analysis, DNA
Show Abstract · Added November 2, 2017
Secreted protein, acidic, cysteine-rich (SPARC) is a glycoprotein that binds to collagen type I and other proteins in the extracellular matrix. Using whole-exome sequencing to identify the molecular defect in two unrelated girls with severe bone fragility and a clinical diagnosis of osteogenesis imperfecta type IV, we identified two homozygous variants in SPARC (GenBank: NM_003118.3; c.497G>A [p.Arg166His] in individual 1; c.787G>A [p.Glu263Lys] in individual 2). Published modeling and site-directed mutagenesis studies had previously shown that the residues substituted by these mutations form an intramolecular salt bridge in SPARC and are essential for the binding of SPARC to collagen type I. The amount of SPARC secreted by skin fibroblasts was reduced in individual 1 but appeared normal in individual 2. The migration of collagen type I alpha chains produced by these fibroblasts was mildly delayed on SDS-PAGE gel, suggesting some overmodification of collagen during triple helical formation. Pulse-chase experiments showed that collagen type I secretion was mildly delayed in skin fibroblasts from both individuals. Analysis of an iliac bone sample from individual 2 showed that trabecular bone was hypermineralized on the material level. In conclusion, these observations show that homozygous mutations in SPARC can give rise to severe bone fragility in humans.
Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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19 MeSH Terms
Local application of a proteasome inhibitor enhances fracture healing in rats.
Yoshii T, Nyman JS, Yuasa M, Esparza JM, Okawa A, Gutierrez GE
(2015) J Orthop Res 33: 1197-204
MeSH Terms: Animals, Biomechanical Phenomena, Bone Morphogenetic Protein 2, Cell Differentiation, Femoral Fractures, Fracture Healing, Male, Osteogenesis, Proteasome Inhibitors, Rats, Rats, Sprague-Dawley, Stem Cells, Tomography, X-Ray Computed
Show Abstract · Added March 16, 2015
The ubiquitin/proteasome system plays an important role in regulating the activity of osteoblast precursor cells. Proteasome inhibitors (PSIs) have been shown to stimulate the differentiation of osteoblast precursor cells and to promote bone formation. This raises the possibility that PSIs might be useful for enhancing fracture healing. In this study, we examined the effect of the local administration of PSI on fracture repair in rats. The effects of treatment on the healing of a fractured femur were assessed based on radiographs, micro-computed tomography (μCT) analysis, biomechanical testing, and histological analysis. PSI enhanced osteogenic differentiation in bone marrow- and periosteum-derived mesenchymal progenitor cells in vitro. Moreover, the local administration of PSI in vivo promoted fracture healing in rats, as demonstrated by an increased fracture callus volume in radiographs at 2 weeks post-fracture, and improved radiographic scores. By week 4, PSI treatment had enhanced biomechanical strength and mineral density in the callus as assessed using bending tests, and μCT, respectively. Histological sections demonstrated that PSI treatment accelerated endochondral ossification during the early stages of fracture repair. Although further investigations are necessary to assess its clinical use, the local administration of PSIs might be a novel, and effective therapeutic approach for fracture repair.
© 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.
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13 MeSH Terms
Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB.
Rauch F, Fahiminiya S, Majewski J, Carrot-Zhang J, Boudko S, Glorieux F, Mort JS, Bächinger HP, Moffatt P
(2015) Am J Hum Genet 96: 425-31
MeSH Terms: Child, Preschool, Craniosynostoses, Eye Abnormalities, Female, Gene Frequency, Heterozygote, Humans, Hydrocephalus, Infant, Male, Mutation, Missense, Osteogenesis Imperfecta, Pedigree, Procollagen-Proline Dioxygenase, Protein Conformation, Protein Disulfide-Isomerases, Protein Folding, Sequence Analysis, DNA
Show Abstract · Added November 2, 2017
Cole-Carpenter syndrome is a severe bone fragility disorder that is characterized by frequent fractures, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features. To identify the cause of Cole-Carpenter syndrome in the two individuals whose clinical results were presented in the original description of this disorder, we performed whole-exome sequencing of genomic DNA samples from both individuals. The two unrelated individuals had the same heterozygous missense mutation in exon 9 of P4HB (NM_000918.3: c.1178A>G [p.Tyr393Cys]), the gene that encodes protein disulfide isomerase (PDI). In one individual, the P4HB mutation had arisen de novo, whereas in the other the mutation was transmitted from the clinically unaffected father who was a mosaic carrier of the variant. The mutation was located in the C-terminal disulfide isomerase domain of PDI, sterically close to the enzymatic center, and affected disulfide isomerase activity in vitro. Skin fibroblasts showed signs of increased endoplasmic reticulum stress, but despite the reported importance of PDI for collagen type I production, the rate of collagen type I secretion appeared normal. In conclusion, Cole-Carpenter syndrome is caused by a specific de novo mutation in P4HB that impairs the disulfide isomerase activity of PDI.
Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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18 MeSH Terms