Sample records for early bone formation

  1. Biphasic electrical current stimulator for early bone formation in dental implant

    Microsoft Academic Search

    Jong Keun Song; Sung June Kim

    Since the discovery of piezoelectric properties of natural bone, electrical stimulation has been widely used in the clinical treatment of orthopedic fracture. Nevertheless, in dental implant technologies, it is the methods of surface modification that has been recently developed to enhance early osteointegration between implant's surface and surrounding tissue. In this paper, in order to accelerate bone formation, we developed

  2. Light-emitting diode photobiomodulation: effect on bone formation in orthopedically expanded suture in rats--early bone changes.

    PubMed

    Ekizer, Abdullah; Uysal, Tancan; Güray, Enis; Yüksel, Yasemin

    2013-09-01

    The aim of this experimental study was to evaluate histomorphometrically the effects of light-emitting diode (LED) photobiomodulation therapy (LPT) on bone formation in response to expansion of the interpremaxillary suture in rats. Twenty male, 50- to 60-day-old Wistar rats were divided into two equal groups (control and experimental). Both groups were subjected to expansion for 5 days, and 50 cN of force was applied to the maxillary incisors with helical spring. An OsseoPulse® LED device, 618-nm wavelength and 20-mW/cm(2) output power irradiation, was applied to the interpremaxillary suture for 10 days. Bone formation in the sutural area was histomorphometrically evaluated, including the amount of new bone formation (in square micrometers), number of osteoblasts, number of osteoclasts, and number of vessels. Mann-Whitney U test was used for statistical evaluation at p?bone formation area (p?=?0.024, 1.48-fold), number of osteoblasts (p?Bone histomorphometric measurements revealed that bone architecture in the LPT group was improved. The application of LPT can stimulate bone formation in the orthopedically expanded interpremaxillary suture during expansion and the early phase of the retention periods. PMID:23139069

  3. Early bone formation adjacent to oxidized and machined implant surfaces: a histologic study.

    PubMed

    Simion, Massimo; Benigni, Marco; Al-Hezaimi, Khalid; Kim, David M

    2015-01-01

    Various designs of dental implants representing different geometries and surface technologies are commercially available for patient treatment. However, data with regard to the biologic events that occur immediately after implant placement, regardless of the surface characteristic, are scarce. It has become a common procedure to perform immediate/early prosthetic loading rather than delayed loading. The goal of this study was to observe the early biologic events of peri-implant healing to understand the role of surface modifications in relation to the early phases of bone integration. The secondary goal was to observe the possible differences in the healing pattern at two oral implant surfaces differing in morphology and roughness (Ra, with Ra values ranging from 0.5 ?m (machined surface; MS) to 1.5 ?m (oxidized surface; OS). A total of 36 implants were placed in six foxhound dogs, equally divided between machined and oxidized surfaces. Three implants were positioned per hemimandible following a randomization scheme. Each animal was euthanized at a specific time point for histologic observation and histomorphometry: immediately after implant insertion and after 24 hours, 7 days, 15 days, 30 days, and 90 days. The study demonstrated an extremely low bone-implant contact (BIC) for both OS and MS implant surfaces during the first 15 days after implant placement (ranging from 12.9% to 26.9% independent of the implant surface). Increased BIC values were observed only in the 30- and 90-day specimens. The presence and the degradation of residual bone particles acted as centers for new bone formation, with osteoblasts lining osteoid tissue and subsequently woven bone independent of the implant surface characteristics. The bone-forming activity appeared strongly reduced after 30 days of healing and seemed to be complete only in the 90-day specimens, where abundant lamellar bone was evident. There is a continuing effort to develop improved titanium surfaces to achieve more rapid osseointegration and improve BIC, with the ultimate goal of applying occlusal load as early as possible. Since immediate or early implant loading is applied during and not after the first 15 days, the findings in the present study of an extremely low BIC and limited mineralized bone formation for both implant surfaces during the first 15 days after implant placement suggest that the surface roughness may not be a key factor for successful osseointegration of immediately or early loaded implants. Within the limits of this study, it can be stated that osseointegration follows a similar healing pattern with machined and oxidized implant surfaces. PMID:25734702

  4. Early stages of bone fracture healing: formation of a fibrin-collagen scaffold in the fracture hematoma.

    PubMed

    Echeverri, L F; Herrero, M A; Lopez, J M; Oleaga, G

    2015-01-01

    This work is concerned with the sequence of events taking place during the first stages of bone fracture healing, from bone breakup until the formation of early fibrous callus (EFC). The latter provides a scaffold over which subsequent remodeling processes will eventually result in successful bone repair. Specifically, some mathematical models are proposed to estimate the time required for (1) the formation immediately after fracture of a fibrin clot, described in terms of a phase transition in a polymerization process, and (2) the onset of EFC which is produced when fibroblasts arising from differentiation of chemotactically recruited mesenchymal stem cells remodel a previous fibrin clot by releasing a collagen matrix over it. An attempt has been made to keep models as simple as possible, so that a explicit dependence of the estimates obtained on relevant biochemical parameters involved is obtained. PMID:25537828

  5. Incorporation of raloxifene-impregnated allograft around orthopedic titanium implants impairs early fixation but improves new bone formation

    PubMed Central

    Hermansen, Lars L; Sørensen, Mette; Barckman, Jeppe; Bechtold, Joan E; Søballe, Kjeld; Baas, Jørgen

    2015-01-01

    Background The anti-osteoporotic drug raloxifene reduces the risk of vertebral fractures by increasing bone mass density. We investigated whether raloxifene offers any benefits in augmenting early fixation of orthopedic implants in the setting of impaction bone grafting. Methods 24 non-weight-bearing grafted gap implants were inserted bilaterally into the tibia of 12 dogs. The 2.5-mm peri-implant gap was filled with either raloxifene-impregnated or untreated bone allograft. Implants were harvested after 28 days. Implant fixation was assessed by mechanical testing and histomorphometric evaluation. Results Raloxifene-treated allograft reduced early implant fixation compared to untreated allograft, as measured by inferior maximum shear strength (p < 0.001) and apparent shear stiffness (p = 0.001). We found that the raloxifene group had more newly formed bone in the gap around the implant (p = 0.02), but also less allograft (p = 0.03). Interpretation The accelerated allograft resorption in the raloxifene group explained the impaired early fixation, despite its stimulation of new bone formation. Our results with local and possible high-dose treatment are not consistent with current theory regarding the mechanism of how systemic raloxifene administration counteracts the decrease in BMD in postmenopausal women. Instead of being solely anti-resorptive as generally held, our results indicate a possible anabolic side of raloxifene. PMID:25175661

  6. A Novel Chitosan-?PGA Polyelectrolyte Complex Hydrogel Promotes Early New Bone Formation in the Alveolar Socket Following Tooth Extraction

    PubMed Central

    Chang, Hao-Hueng; Wang, Yin-Lin; Chiang, Yu-Chih; Chen, Yen-Liang; Chuang, Yu-Horng; Tsai, Shang-Jye; Heish, Kuo-Huang; Lin, Feng-Huei; Lin, Chun-Pin

    2014-01-01

    A novel chitosan-?PGA polyelectrolyte complex hydrogel (C-PGA) has been developed and proven to be an effective dressing for wound healing. The purpose of this study was to evaluate if C-PGA could promote new bone formation in the alveolar socket following tooth extraction. An animal model was proposed using radiography and histomorphology simultaneously to analyze the symmetrical sections of Wistar rats. The upper incisors of Wistar rats were extracted and the extraction sockets were randomly treated with gelatin sponge, neat chitosan, C-PGA, or received no treatment. The extraction sockets of selected rats from each group were evaluated at 1, 2, 4, or 6 wk post-extraction. The results of radiography and histopathology indicated that the extraction sockets treated with C-PGA exhibited lamellar bone formation (6.5%) as early as 2 wk after the extraction was performed. Moreover, the degree of new bone formation was significantly higher (P < 0.05) in the extraction sockets treated with C-PGA at 6 wk post-extraction than that in the other study groups. In this study, we demonstrated that the proposed animal model involving symmetrical sections and simultaneous radiography and histomorphology evaluation is feasible. We also conclude that the novel C-PGA has great potential for new bone formation in the alveolar socket following tooth extraction. PMID:24658174

  7. ?CT-based, in vivo dynamic bone histomorphometry allows 3D evaluation of the early responses of bone resorption and formation to PTH and alendronate combination therapy.

    PubMed

    de Bakker, Chantal M J; Altman, Allison R; Tseng, Wei-Ju; Tribble, Mary Beth; Li, Connie; Chandra, Abhishek; Qin, Ling; Liu, X Sherry

    2015-04-01

    Current osteoporosis treatments improve bone mass by increasing net bone formation: anti-resorptive drugs such as bisphosphonates block osteoclast activity, while anabolic agents such as parathyroid hormone (PTH) increase bone remodeling, with a greater effect on formation. Although these drugs are widely used, their role in modulating formation and resorption is not fully understood, due in part to technical limitations in the ability to longitudinally assess bone remodeling. Importantly, it is not known whether or not PTH-induced bone formation is independent of resorption, resulting in controversy over the effectiveness of combination therapies that use both PTH and an anti-resorptive. In this study, we developed a ?CT-based, in vivo dynamic bone histomorphometry technique for rat tibiae, and applied this method to longitudinally track changes in bone resorption and formation as a result of treatment with alendronate (ALN), PTH, or combination therapy of both PTH and ALN (PTH+ALN). Correlations between our ?CT-based measures of bone formation and measures of bone formation based on calcein-labeled histology (r=0.72-0.83) confirm the accuracy of this method. Bone remodeling parameters measured through ?CT-based in vivo dynamic bone histomorphometry indicate an increased rate of bone formation in rats treated with PTH and PTH+ALN, together with a decrease in bone resorption measures in rats treated with ALN and PTH+ALN. These results were further supported by traditional histology-based measurements, suggesting that PTH was able to induce bone formation while bone resorption was suppressed. PMID:25554598

  8. Peripheral Leptin Regulates Bone Formation

    PubMed Central

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

    2012-01-01

    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

  9. Inhibition of bone formation during space flight

    NASA Technical Reports Server (NTRS)

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

    1978-01-01

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

  10. Recombinant Human Bone Morphogenetic Protein Induces Bone Formation

    Microsoft Academic Search

    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

    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

  11. Mechanisms of osteoclast-dependent bone formation

    PubMed Central

    Teti, Anna

    2013-01-01

    Should we believe that osteoclasts are only involved in bone resorption? What about their contribution to bone formation? In this article I will review evidence that bone formation can be regulated by osteoclasts. Why is this? Likely because in the physiologic condition of bone remodeling, bone resorption and formation are balanced, and there is no better way to control this equilibrium than through a concerted action between the two cell types. Although the influence of osteoblasts on osteoclastic bone resorption is well documented and consolidated over time, what osteoclasts do to regulate osteoblast activity is still matter of intense investigation. The original hypothesis that all is in the osteoblast-seeking factors stored in the bone matrix, released and activated during bone resorption, is now being challenged by several studies, suggesting that osteoclasts are also capable of producing ‘clastokines' that regulate osteoblast performance. Indeed, several of them have been demonstrated to orchestrate osteoclast–osteoblast activities. However, we are probably still at the dawn of a new era, and future work will tell us whether any of these clastokines can be exploited to stimulate bone formation and rebalance bone remodeling in skeletal diseases. PMID:24422142

  12. Early radiographic changes in radiation bone injury

    SciTech Connect

    Fujita, M.; Tanimoto, K.; Wada, T.

    1986-06-01

    A chronologic series of periapical radiographs was evaluated for the purpose of detecting damage to bone and tooth-supporting tissues in a patient receiving radiation therapy for a basal cell carcinoma of the mandibular gingiva. Widening of the periodontal space was one of the early radiographic changes observed. It is suggested, from the sequence of radiographic changes, that radiation-induced changed in the circulatory system of the bone might be primarily responsible for the resulting changes.

  13. Space flight and bone formation

    NASA Technical Reports Server (NTRS)

    Doty, St B.

    2004-01-01

    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.

  14. Space flight and bone formation.

    PubMed

    Doty, St B

    2004-12-01

    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. PMID:15895501

  15. Inherited human diseases of heterotopic bone formation

    Microsoft Academic Search

    Frederick S. Kaplan; Eileen M. Shore

    2010-01-01

    Human disorders of hereditary and nonhereditary heterotopic ossification are conditions in which osteogenesis occurs outside of the skeleton, within soft tissues of the body. The resulting extraskeletal bone is normal. The aberration lies within the mechanisms that regulate cell-fate determination, directing the inappropriate formation of cartilage or bone, or both, in tissues such as skeletal muscle and adipose tissue. Specific

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

    SciTech Connect

    Evans, H.B.; Brown, S.; Hurst, L.N. (Division of Plastic and Reconstructive Surgery, University of Western Ontario, London (Canada))

    1991-06-01

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

  17. Metallic materials stimulating bone formation.

    PubMed

    Kokubo, T

    2004-05-01

    Metallic materials implanted into bone defects are generally encapsulated by a fibrous tissue. Some metallic materials such as titanium and tantalum, however, have been revealed to bond to the living bone without forming the fibrous tissue, when they were subjected to NaOH solution and heat treatments. Thus treated metals form bone tissue around them even in muscle, when they take a porous form. This kind of osteoconductive and osteoinductive properties are attributed to sodium titanate or tantalate layer on their surfaces formed by the NaOH and heat treatments. These layers induce the deposition of bonelike apatite on the surface of the metals in the living body. This kind of bioactive metals are useful as bone substitutes even highly loaded portions, such as hip joint, spine and tooth root. PMID:15468833

  18. Destructive bone disease in early syphilis.

    PubMed

    Dismukes, W E; Delgado, D G; Mallernee, S V; Myers, T C

    1976-12-01

    Although destructive bone disease is a well-known complication of tertiary syphilis, osteitis or osteomyelitis are not commonly recognized as complications of early (primary or secondary) syphillis. A patient with secondary syphilis characterized by generalized lymphadenopathy, perianal condyloma lata, and positive rapid plasma reagin (RPR) and fluorescent treponemal antibody-absorption (FTA-ABS) tests also complained of headache, right should pain, and right anterior chest pain and swelling. Roentgenograms showed mottled osteolytic lesions consistent with previously described luetic bone disease. Biopsy confirmed the diagnosis of syphilitic osteomyelitis, and treatment with penicillin resulted in prompt resolution of symptoms. PMID:1036540

  19. Pregnane X receptor knockout mice display osteopenia with reduced bone formation and enhanced bone resorption

    E-print Network

    Blumberg, Bruce

    of femoral trabecular bones revealed that the three-dimensional bone volume fraction of PXRKO mice was markedly reduced compared with that of WT mice. Histomorphometrical analysis of the trabecular bones of the trabecular bones, bone formation is reduced, whereas bone resorption is enhanced in PXRKO mice. Histomorphome

  20. Dissociation of bone formation markers in bone metastasis of prostate cancer

    Microsoft Academic Search

    M Koizumi; H Maeda; K Yoshimura; T Yamauchi; T Kawai; E Ogata

    1997-01-01

    To clarify the meaning and clinical value of bone formation markers in bone metastasis from prostate cancer, we investigated the bone formation markers carboxy-terminal propeptide of type I procollagen (PICP), bone-specific alkaline phosphatase (BA1-p) and osteocalcin, so-called bone gla protein (BGP) in 43 prostate cancer patients with and 46 patients without overt bone metastasis. Patients with bone metastasis were evaluated

  1. Direct bone formation on alumina bead composite.

    PubMed

    Kobayashi, M; Kikutani, T; Kokubo, T; Nakamura, T

    1997-12-15

    We have developed a composite (designated ABC), consisting of alumina bead powder as an inorganic filler and bisphenol-alpha-glycidyl methacrylate (Bis-GMA)-based resin as an organic matrix, which allows direct bone formation on its surface in vivo. Alumina bead powder was manufactured by fusing crushed alpha-alumina powder and quenching it. The beads took spherical form 3 microns in average size. According to powder X-ray diffraction and Fourier transform infrared spectroscopy, the alumina bead powder was composed of amorphous and delta-crystal phases of alumina in its main crystal structure. Fused-quenched silica glass-filled composite (SGC) was used as a control. The proportion of filler added to the composites was 70% w/w. Mechanical testing of the ABC indicated that it would be strong enough for use under weight-bearing conditions. No apatite formation was detected on the surfaces of either composite after soaking in simulated body fluid for 28 days in vitro. Histological examination of rat tibiae for up to 8 weeks revealed that ABC bonded to bone directly via a layer of calcium, phosphorus, and alumina with no interposed soft-tissue layer. Moreover, the amount of bone directly apposed to the ABC surface increased with time, whereas with SGC there was poor direct bone formation even at 8 weeks. The precise mechanism of direct bone formation on ABC is as yet unknown but it is possible that changes in the crystallinity of alumina, which is known to be highly biocompatible, contribute to its excellent osteoconductivity in vivo. Although bioactive materials such as Bioglass or apatite and wollastonite-containing glass-ceramic have previously been reported to form bone-like apatite on their surfaces under acellular conditions via simple chemical reactions, ABC does not have such characteristics, and presenting favorable conditions for osteoconduction and tissue calcification may lead to direct bone formation on its surface in vivo. PMID:9407305

  2. Early implant bone loss: preventable or inevitable?

    PubMed

    Tatarakis, Nikolaos; Bashutski, Jill; Wang, Hom-Lay; Oh, Tae-Ju

    2012-10-01

    Early implant bone loss (EIBL) is defined as the periimplant crestal bone loss occurring from fixture installation to 1 year after loading. This phenomenon has been suggested to be associated with biologic and biomechanical factors. Minimizing EIBL at every treatment step is preferable because this may improve implant health, aesthetics, and overall success. This review presents the host-related factors, implant design characteristics, and the surgical and restorative protocol modifiers that should be evaluated during therapy. Host-related factors may involve the healing capacity, periodontal status, and occlusal function. Implant design features to be considered include the control of biologic width, microgap, and crestal stress distribution. Finally, surgical and restorative factors to be considered are implant site development, minimally invasive surgical approach, implant positioning, and the restorative design and occlusal scheme. Rationale and strategies to control the modifiable factors are also proposed. PMID:22983314

  3. Bone Formation and Inflammation in Cardiac Valves

    Microsoft Academic Search

    Emile R. Mohler III; Francis Gannon; Carol Reynolds; Robert Zimmerman; Martin G. Keane; Frederick S. Kaplan

    2010-01-01

    Background—For nearly a century, the mechanical failure of calcified heart valves was attributed to a passive degenerative process. Recently, several case reports described bone formation in surgically excised heart valves and suggested an unexpected process of tissue repair. Methods and Results—We studied the prevalence and pathology of heterotopic ossification in 347 surgically excised heart valves (256 aortic, 91 mitral) in

  4. Directing mesenchymal stem cells to bone to augment bone formation and increase bone mass

    PubMed Central

    Guan, Min; Yao, Wei; Liu, Ruiwu; Lam, Kit S.; Nolta, Jan; Jia, Junjing; Panganiban, Brian; Meng, Liping; Zhou, Ping; Shahnazari, Mohammad; Ritchie, Robert O.; Lane, Nancy E.

    2013-01-01

    Aging reduces the number of mesenchymal stem cells (MSCs) in the bone marrow which leads to impairment of osteogenesis. However, if MSCs could be directed toward osteogenic differentiation, they could be a viable therapeutic option for bone regeneration. We have developed a method to direct the MSCs to the bone surface by attaching a synthetic high affinity and specific peptidomimetic ligand (LLP2A) against integrin ?4?1 on the MSC surface, to a bisphosphonate (alendronate, Ale) that has high affinity for bone. LLP2A-Ale increased MSCs migration and osteogenic differentiation in vitro. A single intravenous injection of LLP2A-Ale increased trabecular bone formation and bone mass in both xenotransplantation and immune competent mice. Additionally, LLP2A-Ale prevented trabecular bone loss after peak bone acquisition was achieved or following estrogen deficiency. These results provide a proof of principle that LLP2A-Ale can direct MSCs to the bone to form new bone and increase bone strength. PMID:22306732

  5. Rescuing loading induced bone formation at senescence.

    PubMed

    Srinivasan, Sundar; Ausk, Brandon J; Prasad, Jitendra; Threet, Dewayne; Bain, Steven D; Richardson, Thomas S; Gross, Ted S

    2010-01-01

    The increasing incidence of osteoporosis worldwide requires anabolic treatments that are safe, effective, and, critically, inexpensive given the prevailing overburdened health care systems. While vigorous skeletal loading is anabolic and holds promise, deficits in mechanotransduction accrued with age markedly diminish the efficacy of readily complied, exercise-based strategies to combat osteoporosis in the elderly. Our approach to explore and counteract these age-related deficits was guided by cellular signaling patterns across hierarchical scales and by the insight that cell responses initiated during transient, rare events hold potential to exert high-fidelity control over temporally and spatially distant tissue adaptation. Here, we present an agent-based model of real-time Ca(2+)/NFAT signaling amongst bone cells that fully described periosteal bone formation induced by a wide variety of loading stimuli in young and aged animals. The model predicted age-related pathway alterations underlying the diminished bone formation at senescence, and hence identified critical deficits that were promising targets for therapy. Based upon model predictions, we implemented an in vivo intervention and show for the first time that supplementing mechanical stimuli with low-dose Cyclosporin A can completely rescue loading induced bone formation in the senescent skeleton. These pre-clinical data provide the rationale to consider this approved pharmaceutical alongside mild physical exercise as an inexpensive, yet potent therapy to augment bone mass in the elderly. Our analyses suggested that real-time cellular signaling strongly influences downstream bone adaptation to mechanical stimuli, and quantification of these otherwise inaccessible, transient events in silico yielded a novel intervention with clinical potential. PMID:20838577

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

    E-print Network

    Simmons, Craig A.

    INTRODUCTION The clinical success of bone-interfacing implants for orthopedic and dental applicationsMechanical regulation of localized and appositional bone formation around bone-interfacing implants: The local mechanical environment around bone- interfacing implants determines, in large part, whether bone

  7. Early tissue responses to zoledronate, locally delivered by bone screw, into a compromised cancellous bone site: a pilot study

    PubMed Central

    2014-01-01

    Background In fracture treatment, adequate fixation of implants is crucial to long-term clinical performance. Bisphosphonates (BP), potent inhibitors of osteoclastic bone resorption, are known to increase peri-implant bone mass and accelerate primary fixation. However, adverse effects are associated with systemic use of BPs. Thus, Zoledronic acid (ZOL) a potent BP was loaded on bone screws and evaluated in a local delivery model. Whilst mid- to long-term effects are already reported, early cellular events occurring at the implant/bone interface are not well described. The present study investigated early tissue responses to ZOL locally delivered, by bone screw, into a compromised cancellous bone site. Methods ZOL was immobilized on fibrinogen coated titanium screws. Using a bilateral approach, ZOL loaded test and non-loaded control screws were implanted into femoral condyle bone defects, created by an overdrilling technique. Histological analyses of the local tissue effects such as new bone formation and osteointegration were performed at days 1, 5 and 10. Results Histological evaluation of the five day ZOL group, demonstrated a higher osseous differentiation trend. At ten days an early influx of mesenchymal and osteoprogenitor cells was seen and a higher level of cellular proliferation and differentiation (p?bone-to-screw contact and bone volume values within the defect tended to increase. Local drug release did not induce any adverse cellular effects. Conclusion This study indicates that local ZOL delivery into a compromised cancellous bone site actively supports peri-implant osteogenesis, positively affecting mesenchymal cells, at earlier time points than previously reported in the literature. PMID:24656151

  8. 885. VEGF Enhances Bone Formation and Bone Healing Elicited by Transduced Muscle-Derived Stem Cells Expressing Human BMP2

    Microsoft Academic Search

    Hairong Peng; Arvydas Usas; Brian Gearhart; Johnny Huard

    2004-01-01

    Introduction: Bone formation and bone healing require concerted interactions among many different pathways, including osteogenesis and angiogenesis. Previous studies have shown that the angiogenic factor VEGF is important for both normal bone development and BMP4-induced bone formation. More importantly, VEGF can synergistically enhance the bone formation and bone healing elicited by BMP4. The aim of this study was to determine

  9. Control of bone mass by sclerostin: Inhibiting BMP and WNT-induced bone formation

    Microsoft Academic Search

    David J. J. Gorter; Carola Krause; Peter Dijke; Clemens W. G. M. Löwik; Rutger L. Bezooijen

    Bone is continuously replacing itself by the actions of bone-resorbing osteoclasts and bone-forming osteoblasts, a process\\u000a called bone remodeling. Because both cell types control each other’s activity, there is a tight balance between bone resorption\\u000a and bone formation. However, when this delicate balance is disturbed by increased osteoclast or decreased osteoblast activity,\\u000a it can lead to diseases characterized by low

  10. A new approach to enhancement of bone formation by electrically polarized hydroxyapatite.

    PubMed

    Teng, N C; Nakamura, S; Takagi, Y; Yamashita, Y; Ohgaki, M; Yamashita, K

    2001-10-01

    An electrical field may affect osteogenesis. Since we found that hydroxyapatite (HA) ceramics may be polarizable, we hypothesized that electrically polarized HA may foster production of new bone in vivo. Both polarized and non-polarized HA ceramics were inserted into the subperiosteum spaces at the parietal bone area of rats. After 2, 4, and 8 weeks, the implant sites were examined histologically. Morphometric analysis revealed that new bone formation was accelerated on the negatively charged surface of the polarized HA (N-surface) at 2 weeks. The newly formed bone approached maturation at 4 weeks and was thicker on the N-surface than in the controls. By 8 weeks, newly formed bone in the controls was almost the same as that on the N-surface. These findings suggest that polarized HA is biocompatible and that bone formation on the N-surface is enhanced in the early stage of bone healing. PMID:11706953

  11. Effects of acute intoxication with uranyl nitrate on bone formation

    Microsoft Academic Search

    M. B. Guglielmotti; A. M. Ubios; B. M. de Rey; R. L. Cabrini

    1984-01-01

    Summary The alteration of bone formation by an acute intoxication with uranyl nitrate is demonstrated by histologic and histometric methods. When compared with the controls, intoxicated animals showed a markedly lower density in healing sockets, while bone formation was reduced in healing sockets as well as in metaphyseal bone.

  12. Effects of acute intoxication with uranyl nitrate on bone formation.

    PubMed

    Guglielmotti, M B; Ubios, A M; de Rey, B M; Cabrini, R L

    1984-05-15

    The alteration of bone formation by an acute intoxication with uranyl nitrate is demonstrated by histologic and histometric methods. When compared with the controls, intoxicated animals showed a markedly lower density in healing sockets, while bone formation was reduced in healing sockets as well as in metaphyseal bone. PMID:6723911

  13. Tooth loss early in life accelerates age-related bone deterioration in mice.

    PubMed

    Kurahashi, Minori; Kondo, Hiroko; Iinuma, Mitsuo; Tamura, Yasuo; Chen, Huayue; Kubo, Kin-Ya

    2015-01-01

    Both osteoporosis and tooth loss are health concerns that affect many older people. Osteoporosis is a common skeletal disease of the elderly, characterized by low bone mass and microstructural deterioration of bone tissue. Chronic mild stress is a risk factor for osteoporosis. Many studies showed that tooth loss induced neurological alterations through activation of a stress hormone, corticosterone, in mice. In this study, we tested the hypothesis that tooth loss early in life may accelerate age-related bone deterioration using a mouse model. Male senescence-accelerated mouse strain P8 (SAMP8) mice were randomly divided into control and toothless groups. Removal of the upper molar teeth was performed at one month of age. Bone response was evaluated at 2, 5 and 9 months of age. Tooth loss early in life caused a significant increase in circulating corticosterone level with age. Osteoblast bone formation was suppressed and osteoclast bone resorption was activated in the toothless mice. Trabecular bone volume fraction of the vertebra and femur was decreased in the toothless mice with age. The bone quality was reduced in the toothless mice at 5 and 9 months of age, compared with the age-matched control mice. These findings indicate that tooth loss early in life impairs the dynamic homeostasis of the bone formation and bone resorption, leading to reduced bone strength with age. Long-term tooth loss may have a cumulative detrimental effect on bone health. It is important to take appropriate measures to treat tooth loss in older people for preventing and/or treating senile osteoporosis. PMID:25744201

  14. Mechanical stimulation of bone marrow in situ induces bone formation in trabecular explants.

    PubMed

    Birmingham, E; Kreipke, T C; Dolan, E B; Coughlin, T R; Owens, P; McNamara, L M; Niebur, G L; McHugh, P E

    2015-04-01

    Low magnitude high frequency (LMHF) loading has been shown to have an anabolic effect on trabecular bone in vivo. However, the precise mechanical signal imposed on the bone marrow cells by LMHF loading, which induces a cellular response, remains unclear. This study investigates the influence of LMHF loading, applied using a custom designed bioreactor, on bone adaptation in an explanted trabecular bone model, which isolated the bone and marrow. Bone adaptation was investigated by performing micro CT scans pre and post experimental LMHF loading, using image registration techniques. Computational fluids dynamic models were generated using the pre-experiment scans to characterise the mechanical stimuli imposed by the loading regime prior to adaptation. Results here demonstrate a significant increase in bone formation in the LMHF loaded group compared to static controls and media flow groups. The calculated shear stress in the marrow was between 0.575 and 0.7 Pa, which is within the range of stimuli known to induce osteogenesis by bone marrow mesenchymal stem cells in vitro. Interestingly, a correlation was found between the bone formation balance (bone formation/resorption), trabecular number, trabecular spacing, mineral resorption rate, bone resorption rate and mean shear stresses. The results of this study suggest that the magnitude of the shear stresses generated due to LMHF loading in the explanted bone cores has a contributory role in the formation of trabecular bone and improvement in bone architecture parameters. PMID:25281407

  15. Effect of spaceflight on periosteal bone formation in rats

    NASA Technical Reports Server (NTRS)

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

    1983-01-01

    Male Wistar rats were placed in orbit for 18.5 days aboard the Soviet COSMOS 1129 biological satellite. Tetracycline was administered before and after spaceflight to label areas of bone formation. An inhibition of periosteal bone formation occurred during spaceflight in the tibial and humeral diaphyses, but this defect was corrected during the postflight period. The increased extent of arrest lines at these skeletal sites suggested that periosteal bone formation may have even ceased during spaceflight. The rib exhibited a small but nonsignificant decrease in periosteal bone formation. Endosteal bone resorption was not affected markedly by spaceflight conditions. The observed inhibition of periosteal bone formation may be a result of mechanical unloading, but endocrine factors cannot be ruled out.

  16. Bioactive ceramics: the effect of surface reactivity on bone formation and bone cell function

    Microsoft Academic Search

    P Ducheyne; Q Qiu

    1999-01-01

    Surface reactivity is one of the common characteristics of bone bioactive ceramics. It contributes to their bone bonding ability and their enhancing effect on bone tissue formation. During implantation, reactions occur at the material–tissue interface that lead to time-dependent changes in the surface characteristics of the implant material and the tissues at the interface. This review describes some of the

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

    PubMed Central

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

    2011-01-01

    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

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

    NASA Technical Reports Server (NTRS)

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

    1983-01-01

    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.

  19. Early expression of bone matrix proteins in osteogenic cell cultures.

    PubMed

    de Oliveira, Paulo Tambasco; Zalzal, Sylvia Francis; Irie, Kazuharu; Nanci, Antonio

    2003-05-01

    Osteogenic cells express some matrix proteins at early culture intervals. The aim of this study was to determine if, and in what proportion, cells used for plating contain bone sialoprotein (BSP) and osteopontin (OPN), two matrix proteins associated with initial events in bone formation. Their pattern of expression, as well as that of fibronectin (FN) and type I pro-collagen, was also examined at 6 hr and at 1 and 3 days. The cells were obtained by enzymatic digestion of newborn rat calvariae, and grown on glass coverslips. Cytocentrifuge preparations of isolated cells and coverslips were processed for single or dual immunolabeling with monoclonal and/or polyclonal primary antibodies, followed by fluorochrome-conjugated antibodies. The cell labeling was mainly associated with perinuclear elements. OPN was also distinctively found at peripheral cytoplasmic sites. About 31% of isolated cells were OPN-positive and 18% were BSP-positive. After 1 day, almost 50% of cells were immunoreactive for OPN and for type I pro-collagen, and still less than 20% reacted for BSP. Approximately 7% exhibited peripheral staining for OPN. Almost all cells were associated with extracellular FN. However, only 15% showed intracellular labeling. These results indicate that an important proportion of cells used for plating contain BSP and OPN, a situation that should be taken into consideration in experimental analyses of osteoblast activity in vitro. PMID:12704211

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

    Microsoft Academic Search

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

    2003-01-01

    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

  1. The impact of skeletal unloading on bone formation

    NASA Technical Reports Server (NTRS)

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

    2003-01-01

    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.

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

    PubMed

    Fumoto, Toshio; Ito, Masako; Ikeda, Kyoji

    2014-09-01

    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

  3. Bone sialoprotein plays a functional role in bone formation and osteoclastogenesis

    PubMed Central

    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

    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

  4. Brief Review of Models of Ectopic Bone Formation

    PubMed Central

    Scott, Michelle A.; Levi, Benjamin; Askarinam, Asal; Nguyen, Alan; Rackohn, Todd; Ting, Kang; Soo, Chia

    2012-01-01

    Ectopic bone formation is a unique biologic entity—distinct from other areas of skeletal biology. Animal research models of ectopic bone formation most often employ rodent models and have unique advantages over orthotopic (bone) environments, including a relative lack of bone cytokine stimulation and cell-to-cell interaction with endogenous (host) bone-forming cells. This allows for relatively controlled in vivo experimental bone formation. A wide variety of ectopic locations have been used for experimentation, including subcutaneous, intramuscular, and kidney capsule transplantation. The method, benefits and detractions of each method are summarized in the following review. Briefly, subcutaneous implantation is the simplest method. However, the most pertinent concern is the relative paucity of bone formation in comparison to other models. Intramuscular implantation is also widely used and relatively simple, however intramuscular implants are exposed to skeletal muscle satellite progenitor cells. Thus, distinguishing host from donor osteogenesis becomes challenging without cell-tracking studies. The kidney capsule (perirenal or renal capsule) method is less widely used and more technically challenging. It allows for supraphysiologic blood and nutrient resource, promoting robust bone growth. In summary, ectopic bone models are extremely useful in the evaluation of bone-forming stem cells, new osteoinductive biomaterials, and growth factors; an appropriate choice of model, however, will greatly increase experimental success. PMID:22085228

  5. Brief review of models of ectopic bone formation.

    PubMed

    Scott, Michelle A; Levi, Benjamin; Askarinam, Asal; Nguyen, Alan; Rackohn, Todd; Ting, Kang; Soo, Chia; James, Aaron W

    2012-03-20

    Ectopic bone formation is a unique biologic entity--distinct from other areas of skeletal biology. Animal research models of ectopic bone formation most often employ rodent models and have unique advantages over orthotopic (bone) environments, including a relative lack of bone cytokine stimulation and cell-to-cell interaction with endogenous (host) bone-forming cells. This allows for relatively controlled in vivo experimental bone formation. A wide variety of ectopic locations have been used for experimentation, including subcutaneous, intramuscular, and kidney capsule transplantation. The method, benefits and detractions of each method are summarized in the following review. Briefly, subcutaneous implantation is the simplest method. However, the most pertinent concern is the relative paucity of bone formation in comparison to other models. Intramuscular implantation is also widely used and relatively simple, however intramuscular implants are exposed to skeletal muscle satellite progenitor cells. Thus, distinguishing host from donor osteogenesis becomes challenging without cell-tracking studies. The kidney capsule (perirenal or renal capsule) method is less widely used and more technically challenging. It allows for supraphysiologic blood and nutrient resource, promoting robust bone growth. In summary, ectopic bone models are extremely useful in the evaluation of bone-forming stem cells, new osteoinductive biomaterials, and growth factors; an appropriate choice of model, however, will greatly increase experimental success. PMID:22085228

  6. Leptin regulates bone formation via the sympathetic nervous system

    NASA Technical Reports Server (NTRS)

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

    2002-01-01

    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.

  7. Stratigraphy and depositional history, Bone Spring Formation, Lea County, New Mexico

    SciTech Connect

    Mazzullo, L.J. (Nearburg Producing Co., Dallas, TX (USA))

    1987-02-01

    The Bone Spring formation of the northern Delaware basin in southeastern New Mexico produces oil in Lea County from foreshelf detrital carbonate facies, such as in Scharb field. Production there comes from several intervals. Stratigraphic correlations between the various Bone Springs units and equivalent Leonardian facies of the Northwest shelf in Lea County suggest that the Bone Spring is correlative to the Yeso Formation of the Northwest shelf. The shelf facies there are divided into lower, middle, and upper Yeso. The upper part of what has generally been considered to be Wolfcamp in some areas, beneath the lowermost Bone Spring sandstone, is inferred to be lower Leonardian (lower Yeso) throughout the area studied. A model is proposed for the sedimentologic and reservoir evolution of the Bone Spring Formation in Lea County. Permian-Pennsylvanian tectonic activity provided the initial substrate for the development of a high-energy shelf edge in early Yeso time. In early middle Yeso time, the basin filled with sediments of the 3rd and 2nd Bone Spring units, and the shelf to basin transition was more subtle. As the basin subsided with infilling, a high-energy shelf edge again developed in late middle Yeso time. With continued basin infilling by 1st Bone Springs facies, the shelf to basin transition again evolved into a more subtle feature. Continued basin subsidence caused infilling by a thick sequence of upper Yeso carbonate, which was capped by progradational shelf carbonates of the upper Yeso.

  8. HIF-1? regulates bone formation after osteogenic mechanical loading.

    PubMed

    Tomlinson, Ryan E; Silva, Matthew J

    2015-04-01

    HIF-1 is a transcription factor typically associated with angiogenic gene transcription under hypoxic conditions. In this study, mice with HIF-1? deleted in the osteoblast lineage (?HIF-1?) were subjected to damaging or non-damaging mechanical loading known to produce woven or lamellar bone, respectively, at the ulnar diaphysis. By microCT, ?HIF-1? mice produced significantly less woven bone than wild type (WT) mice 7days after damaging loading. This decrease in woven bone volume and extent was accompanied by a significant decrease in vascularity measured by immunohistochemistry against vWF. Additionally, osteocytes, rather than osteoblasts, appear to be the main bone cell expressing HIF-1? following damaging loading. In contrast, 10days after non-damaging mechanical loading, dynamic histomorphometry measurements demonstrated no impairment in loading-induced lamellar bone formation in ?HIF-1? mice. In fact, both non-loaded and loaded ulnae from ?HIF-1? mice had increased bone formation compared with WT ulnae. When comparing the relative increase in periosteal bone formation in loaded vs. non-loaded ulnae, it was not different between ?HIF-1? mice and controls. There were no significant differences observed between WT and ?HIF-1? mice in endosteal bone formation parameters. The increases in periosteal lamellar bone formation in ?HIF-1? mice are attributed to non-angiogenic effects of the knockout. In conclusion, these results demonstrate that HIF-1? is a pro-osteogenic factor for woven bone formation after damaging loading, but an anti-osteogenic factor for lamellar bone formation under basal conditions and after non-damaging loading. PMID:25541207

  9. Early chronic kidney disease-mineral bone disorder stimulates vascular calcification

    PubMed Central

    Fang, Yifu; Ginsberg, Charles; Sugatani, Toshifumi; Monier-Faugere, Marie-Claude; Malluche, Hartmut; Hruska, Keith A

    2013-01-01

    The chronic kidney disease-mineral and bone disorder (CKD-MBD) syndrome is an extremely important complication of kidney diseases. Here we tested whether CKD-MBD causes vascular calcification in early kidney failure by developing a mouse model of early CKD in a background of atherosclerosis stimulated arterial calcification. CKD equivalent in glomerular filtration reduction to human CKD stage 2 stimulated early vascular calcification and inhibited the tissue expression of ?-klotho (klotho) in the aorta. In addition, osteoblast transition in the aorta was stimulated by early CKD as shown by the expression of the critical transcription factor, RUNX2. The ligand associated with the klotho-fibroblast growth factor receptor complex, FGF23, was found to be expressed in the vascular media of sham operated mice. Its expression was decreased in early CKD. Increased circulating levels of the osteocyte secreted proteins, FGF23, and sclerostin may have been related to increased circulating klotho levels. Finally, we observed low turnover bone disease with a reduction in bone formation rates more than bone resorption. Thus, the CKD-MBD, characterized by cardiovascular risk factors, vascular calcification, increased circulating klotho, FGF23 and sclerostin levels, and low turnover renal osteodystrophy, was established in early CKD. Early CKD caused a reduction of vascular klotho, stimulated vascular osteoblastic transition, increased osteocytic secreted proteins, and inhibited skeletal modeling producing the CKD-MBD. PMID:23884339

  10. Impaired Bone Formation in Pdia3 Deficient Mice

    PubMed Central

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

    2014-01-01

    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

  11. Regulation of bone morphogenetic proteins in early embryonic development

    NASA Astrophysics Data System (ADS)

    Yamamoto, Yukiyo; Oelgeschläger, Michael

    2004-11-01

    Bone morphogenetic proteins (BMPs), a large subgroup of the TGF-? family of secreted growth factors, control fundamental events in early embryonic development, organogenesis and adult tissue homeostasis. The plethora of dose-dependent cellular processes regulated by BMP signalling demand a tight regulation of BMP activity. Over the last decade, a number of proteins have been identified that bind BMPs in the extracellular space and regulate the interaction of BMPs with their cognate receptors, including the secreted BMP antagonist Chordin. In the early vertebrate embryo, the localized secretion of BMP antagonists from the dorsal blastopore lip establishes a functional BMP signalling gradient that is required for the determination of the dorsoventral or back to belly body axis. In particular, inhibition of BMP activity is essential for the formation of neural tissue in the development of vertebrate and invertebrate embryos. Here we review recent studies that have provided new insight into the regulation of BMP signalling in the extracellular space. In particular, we discuss the recently identified Twisted gastrulation protein that modulates, in concert with metalloproteinases of the Tolloid family, the interaction of Chordin with BMP and a family of proteins that share structural similarities with Chordin in the respective BMP binding domains. In addition, genetic and functional studies in zebrafish and frog provide compelling evidence that the secreted protein Sizzled functionally interacts with the Chd BMP pathway, despite being expressed ventrally in the early gastrula-stage embryo. These intriguing discoveries may have important implications, not only for our current concept of early embryonic patterning, but also for the regulation of BMP activity at later developmental stages and tissue homeostasis in the adult.

  12. Sim1 inhibits bone formation by enhancing the sympathetic tone in male mice.

    PubMed

    Wang, Xunde; Wei, Wei; Zinn, Andrew R; Wan, Yihong

    2015-04-01

    Single-minded 1 (Sim1) is a basic helix-loop-helix Per-Arnt-Sim transcription factor that is important for neuronal development in the hypothalamus. Loss-of-function mutation of Sim1 causes early-onset obesity. However, it is unknown whether and how Sim1 regulates bone remodeling. In this study, we found that adult-onset Sim1 deletion increases bone formation, leading to high bone mass. In contrast, Sim1-overexpressing transgenic mice exhibit decreased bone formation and low bone mass. Sim1 does not directly regulate osteoblastogenesis, because bone marrow mesenchymal stem cells from Sim1 mutant mice display a normal capacity for osteoblast differentiation. Instead, Sim1 inhibits bone formation via stimulating the sympathetic nervous system, because sympathetic tone is decreased by Sim1 deletion but increased by Sim1 overexpression. Treatment with the ?-adrenergic agonist isoproterenol effectively reverses the high bone mass in Sim1-knockout mice. These findings reveal Sim1 as a critical yet previously unrecognized modulator of skeletal homeostasis that functions through a central relay. PMID:25607894

  13. The circadian modulation of leptin-controlled bone formation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mice with circadian gene Period and Cryptochrome mutations develop high bone mass early in life. Such a phenotype is accompanied by an increase in osteoblast numbers in mutant bone and cannot be corrected by leptin intracerebroventricular infusion. Thus, the molecular clock plays a key role in lepti...

  14. Osteogenic Matrix Cell Sheet Transplantation Enhances Early Tendon Graft to Bone Tunnel Healing in Rabbits

    PubMed Central

    Uematsu, Kota; Akahane, Manabu; Morita, Yusuke; Ogawa, Munehiro; Ueha, Tomoyuki; Shimizu, Takamasa; Kura, Tomohiko; Kawate, Kenji; Tanaka, Yasuhito

    2013-01-01

    The objective of this study was to determine whether osteogenic matrix cell sheets (OMCS) could induce bone formation around grafted tendons, thereby enhancing early stage tendon to bone tunnel healing in skeletally mature male Japanese white rabbits. First, the osteogenic potential of rabbit OMCS was evaluated. Then, the OMCS were transplanted into the interface between the grafted tendon and the bone tunnel created at the tibia. Histological assessments and biomechanical tensile testing were performed after 3 weeks. The rabbit OMCS showed high alkaline phosphatase (ALP) activity, positive staining of ALP, and osteogenic potential when transplanted subcutaneously with beta tricalcium phosphate disks. Newly formed bony walls and positive collagen type I staining were seen around the grafted tendon with OMCS transplantation, whereas such bony walls were thinner or less frequent without OMCS transplantation. Micro-computed tomography images showed significantly higher bone volume in the OMCS transplantation group. The pullout strength was significantly higher with OMCS (0.74 ± 0.23?N/mm2) than without OMCS (0.58 ± 0.15?N/mm2). These results show that OMCS enhance early tendon to bone tunnel healing. This method can be applied to cases requiring early tendon to bone tunnel healing after ligament reconstruction surgery. PMID:24106718

  15. Formation of blood clot on biomaterial implants influences bone healing.

    PubMed

    Shiu, Hoi Ting; Goss, Ben; Lutton, Cameron; Crawford, Ross; Xiao, Yin

    2014-12-01

    The first step in bone healing is forming a blood clot at injured bones. During bone implantation, biomaterials unavoidably come into direct contact with blood, leading to a blood clot formation on its surface prior to bone regeneration. Despite both situations being similar in forming a blood clot at the defect site, most research in bone tissue engineering virtually ignores the important role of a blood clot in supporting healing. Dental implantology has long demonstrated that the fibrin structure and cellular content of a peri-implant clot can greatly affect osteoconduction and de novo bone formation on implant surfaces. This article reviews the formation of a blood clot during bone healing in relation to the use of platelet-rich plasma (PRP) gels. It is implicated that PRP gels are dramatically altered from a normal clot in healing, resulting in conflicting effect on bone regeneration. These results indicate that the effect of clots on bone regeneration depends on how the clots are formed. Factors that influence blood clot structure and properties in relation to bone healing are also highlighted. Such knowledge is essential for developing strategies to optimally control blood clot formation, which ultimately alter the healing microenvironment of bone. Of particular interest are modification of surface chemistry of biomaterials, which displays functional groups at varied composition for the purpose of tailoring blood coagulation activation, resultant clot fibrin architecture, rigidity, susceptibility to lysis, and growth factor release. This opens new scope of in situ blood clot modification as a promising approach in accelerating and controlling bone regeneration. PMID:24906469

  16. Controlled Delivery of Zoledronate Improved Bone Formation Locally In Vivo

    PubMed Central

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

    2014-01-01

    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

  17. Effect of Buguzhi (Psoralea corylifolia fruit) extract on bone formation.

    PubMed

    Wong, R W K; Rabie, A B M

    2010-06-01

    The objective of the study is to compare the amount of new bone produced by Buguzhi (Psoralea corylifolia fruit) extract in collagen matrix to that produced and collagen matrix in vivo. Eighteen bone defects, 5 mm by 10 mm, were created in the parietal bone of 9 New Zealand white rabbits. Six defects were grafted with Buguzhi extract mixed with collagen matrix. Six defects were grafted with collagen matrix alone (positive control) and 6 were left empty (negative control). Animals were sacrificed on day 14 and the defects were dissected and prepared for histological assessment. Quantitative analysis of new bone formation and bone cells was made on 100 sections (50 sections for each group) using image analysis. A total of 275% more new bone was present in defects grafted with Buguzhi extract in collagen matrix than those grafted with collagen matrix. No bone was formed in the negative control group. The amount of bone cells was also significantly greater in the Buguzhi group than in the positive control group. To conclude, Buguzhi extract in collagen matrix has the effect of increasing new bone formation locally in vivo. Buguzhi extract in collagen matrix can be used as a bone graft material. PMID:19953524

  18. The progress of early phase bone healing using porous granules produced from calcium phosphate cement

    PubMed Central

    2010-01-01

    Objective Bone grafting is a vital component in many surgical procedures to facilitate the repair of bone defects or fusions. Autologous bone has been the gold standard to date in spite of associated donor-site morbidity and the limited amount of available donor bone. The aim of this study was to investigate the progress of bone regeneration and material degradation of calcium phosphate granules (CPG) produced from a calcium phosphate self-setting cement powder compared to the use of autologous bone grafting in the treatment of "critical size defects" on load-bearing long bones of minipigs. Methods A critical size defect in the tibial metaphysis of 16 mini-pigs was filled either with autologous cancellous graft or with micro- and macroporous carbonated, apatic calcium phosphate granules (CPG) produced from a calcium phosphate self-setting cement powder. After 6 weeks, the specimens were assessed by X-ray and histological evaluation. The amount of new bone formation was analysed histomorphometrically. Results The semi-quantitative analysis of the radiological results showed a complete osseous bridging of the defect in three cases for the autograft group. In the same group five animals showed a beginning, but still incomplete bridging of the defect, whereas in the CPG group just two animals developed this. All other animals of the CPG group showed only a still discontinuous new bone formation. Altogether, radiologically a better osseous bridging was observed in the autograft group compared to the CPG group. Histomorphometrical analysis after six weeks of healing revealed that the area of new bone was significantly greater in the autograft group concerning the central area of the defect zone (p < 0.001) as well as the cortical defect zone (p < 0.002). All defects showed new bone formation, but only in the autograft group defects regenerated entirely Conclusions Within the limits of the present study it could be demonstrated that autologous cancellous grafts lead to a significantly better bone regeneration compared to the application of calcium phosphate granules (CPG) produced from a calcium phosphate self-setting cement powder after 6 weeks. In the early phase of bone-healing, the sole application of CPG appears to be inferior to the autologous cancellous grafts in an in vivo critical size defect on load-bearing long bones of mini-pigs. PMID:20562058

  19. Dual growth factor delivery and controlled scaffold degradation enhance in vivo bone formation by transplanted bone marrow stromal cells

    E-print Network

    Simmons, Craig A.

    . Individual delivery of BMP2 or TGF-h3 resulted in negligible bone tissue formation up to 22 weeks, regardless of exogenous growth factors are typically required to obtain bone regeneration, and it is unclear why lower to be used for therapeutic bone regeneration. We tested this hypothesis by measuring bone formation by rat

  20. Influence of short-term aluminum exposure on demineralized bone matrix induced bone formation

    Microsoft Academic Search

    Arlen R. Severson; Craig F. Haut; Conrad E. Firling; Thomas E. Huntley

    1992-01-01

    The effects of aluminum exposure on bone formation employing the demineralized bone matrix (DBM) induced bone development model were studied using 4-week-old Sprague-Dawley rats injected with a saline (control) or an aluminum chloride (experimental) solution. After 2 weeks of aluminum treatment, 20-mg portions of rat DBM were implanted subcutaneously on each side in the thoracic region of the control and

  1. Bone Formation Rate in Experimental Disuse Osteoporosis in Monkeys

    NASA Technical Reports Server (NTRS)

    Cann, Christopher; Young, Donald R.

    1976-01-01

    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.

  2. Rethinking the nature of fibrolamellar bone: an integrative biological revision of sauropod plexiform bone formation.

    PubMed

    Stein, Koen; Prondvai, Edina

    2014-02-01

    We present novel findings on sauropod bone histology that cast doubt on general palaeohistological concepts concerning the true nature of woven bone in primary cortical bone and its role in the rapid growth and giant body sizes of sauropod dinosaurs. By preparing and investigating longitudinal thin sections of sauropod long bones, of which transverse thin sections were published previously, we found that the amount of woven bone in the primary complex has been largely overestimated. Using comparative cellular and light-extinction characteristics in the two section planes, we revealed that the majority of the bony lamina consists of longitudinally organized primary bone, whereas woven bone is usually represented only by a layer a few cells thin in the laminae. Previous arguments on sauropod biology, which have been based on the overestimated amount, misinterpreted formation process and misjudged role of woven bone in the plexiform bone formation of sauropod dinosaurs, are thereby rejected. To explain the observed pattern in fossil bones, we review the most recent advances in bone biology concerning bone formation processes at the cellular and tissue levels. Differentiation between static and dynamic osteogenesis (SO and DO) and the revealed characteristics of SO- versus DO-derived bone tissues shed light on several questions raised by our palaeohistological results and permit identification of these bone tissues in fossils with high confidence. By presenting the methods generally used for investigating fossil bones, we show that the major cause of overestimation of the amount of woven bone in previous palaeohistological studies is the almost exclusive usage of transverse sections. In these sections, cells and crystallites of the longitudinally organized primary bone are cut transversely, thus cells appear rounded and crystallites remain dark under crossed plane polarizers, thereby giving the false impression of woven bone. In order to avoid further confusion in palaeohistological studies, we introduce new osteohistological terms as well as revise widely used but incorrect terminology. To infer the role of woven bone in the bone formation of fast-growing tetrapods, we review some aspects of the interrelationships between the vascularity of bone tissues, basal metabolic rate, body size and growth rate. By putting our findings into the context of osteogenesis, we provide a new model for the diametrical limb bone growth of sauropods and present new implications for the evolution of fast growth in vertebrates. Since biomechanical studies of bone tissues suggest that predominant collagen fibre orientation (CFO) is controlled by endogenous, functional and perhaps phylogenetic factors, the relationship between CFO and bone growth rate as defined by Amprino's rule, which has been the basis for the biological interpretation of several osteohistological features, must be revised. Our findings draw attention to the urgent need for revising widely accepted basic concepts of palaeohistological studies, and for a more integrative approach to bone formation, biomechanics and bone microstructural features of extant and extinct vertebrates to infer life history traits of long extinct, iconic animals like dinosaurs. PMID:23647662

  3. ANA Deficiency Enhances Bone Morphogenetic Protein-induced Ectopic Bone Formation via Transcriptional Events*

    PubMed Central

    Miyai, Kentaro; Yoneda, Mitsuhiro; Hasegawa, Urara; Toita, Sayaka; Izu, Yayoi; Hemmi, Hiroaki; Hayata, Tadayoshi; Ezura, Yoichi; Mizutani, Shuki; Miyazono, Kohei; Akiyoshi, Kazunari; Yamamoto, Tadashi; Noda, Masaki

    2009-01-01

    Ectopic bone formation after joint replacement or brain injury in humans is a serious complication that causes immobility of joints and severe pain. However, mechanisms underlying such ectopic bone formation are not fully understood. Bone morphogenetic protein (BMPs) are defined as inducers of ectopic bone formation, and they are regulated by several types of inhibitors. ANA is an antiproliferative molecule that belongs to Tob/BTG family, but its activity in bone metabolism has not been known. Here, we examined the role of ANA on ectopic bone formation activity of BMP. In ANA-deficient and wild-type mice, BMP2 was implanted to induce ectopic bone formation in muscle. ANA deficiency increased mass of newly formed bone in vivo compared with wild-type based on 3D-?CT analyses. ANA mRNA was expressed in bone in vivo as well as in osteoblastic cells in vitro. Such ANA mRNA levels were increased by BMP2 treatment in MC3T3-E1 osteoblastic cells. Overexpression of ANA suppressed BMP-induced expression of luciferase reporter gene linked to BMP response elements in these cells. Conversely, ANA mRNA knockdown by small interference RNA enhanced the BMP-dependent BMP response element reporter expression. It also enhanced BMP-induced osteoblastic differentiation in muscle-derived C2C12 cells. Immunoprecipitation assay indicated that ANA interacts with Smad8. Thus, ANA is a suppressor of ectopic bone formation induced by BMP, and this inhibitory ANA activity is a part of the negative feedback regulation of BMP function. PMID:19234306

  4. NGF blockade at early times during bone cancer development attenuates bone destruction and increases limb use.

    PubMed

    McCaffrey, Gwen; Thompson, Michelle L; Majuta, Lisa; Fealk, Michelle N; Chartier, Stephane; Longo, Geraldine; Mantyh, Patrick W

    2014-12-01

    Studies in animals and humans show that blockade of nerve growth factor (NGF) attenuates both malignant and nonmalignant skeletal pain. While reduction of pain is important, a largely unanswered question is what other benefits NGF blockade might confer in patients with bone cancer. Using a mouse graft model of bone sarcoma, we demonstrate that early treatment with an NGF antibody reduced tumor-induced bone destruction, delayed time to bone fracture, and increased the use of the tumor-bearing limb. Consistent with animal studies in osteoarthritis and head and neck cancer, early blockade of NGF reduced weight loss in mice with bone sarcoma. In terms of the extent and time course of pain relief, NGF blockade also reduced pain 40% to 70%, depending on the metric assessed. Importantly, this analgesic effect was maintained even in animals with late-stage disease. Our results suggest that NGF blockade immediately upon detection of tumor metastasis to bone may help preserve the integrity and use, delay the time to tumor-induced bone fracture, and maintain body weight. PMID:25287160

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

    PubMed Central

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

    2014-01-01

    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

  6. Biomimetic matrices self-initiating the induction of bone formation.

    PubMed

    Ripamonti, Ugo; Roden, Laura C; Ferretti, Carlo; Klar, Roland M

    2011-09-01

    The new strategy of tissue engineering, and regenerative medicine at large, is to construct biomimetic matrices to mimic nature's hierarchical structural assemblages and mechanisms of simplicity and elegance that are conserved throughout genera and species. There is a direct spatial and temporal relationship of morphologic and molecular events that emphasize the biomimetism of the remodeling cycles of the osteonic corticocancellous bone versus the "geometric induction of bone formation," that is, the induction of bone by "smart" concavities assembled in biomimetic matrices of macroporous calcium phosphate-based constructs. The basic multicellular unit of the corticocancellous bone excavates a trench across the bone surface, leaving in its wake a hemiosteon rather than an osteon, that is, a trench with cross-sectional geometric cues of concavities after cyclic episodes of osteoclastogenesis, eventually leading to osteogenesis. The concavities per se are geometric regulators of growth-inducing angiogenesis and osteogenesis as in the remodeling processes of the corticocancellous bone. The concavities act as a powerful geometric attractant for myoblastic/myoendothelial and/or endothelial/pericytic stem cells, which differentiate into bone-forming cells. The lacunae, pits, and concavities cut by osteoclastogenesis within the biomimetic matrices are the driving morphogenetic cues that induce bone formation in a continuum of sequential phases of resorption/dissolution and formation. To induce the cascade of bone differentiation, the soluble osteogenic molecular signals of the transforming growth factor ? supergene family must be reconstituted with an insoluble signal or substratum that triggers the bone differentiation cascade. By carving a series of repetitive concavities into solid and/or macroporous biomimetic matrices of highly crystalline hydroxyapatite or biphasic hydroxyapatite/?-tricalcium phosphate, we were able to embed smart biologic functions within intelligent scaffolds for tissue engineering of bone. The concavities assembled in the bioceramic constructs biomimetize the remodeling cycle of the corticocancellous bone and are endowed with multifunctional pleiotropic self-assembly capacities, initiating angiogenesis and bone formation by induction without the exogenous applications of the osteogenic-soluble molecular signals of the transforming growth factor ? supergene family. The incorporation of specific biologic activities into biomimetic matrices by manipulating the geometry of the substratum, defined as geometric induction of bone formation, is now helping to engineer therapeutic osteogenesis in clinical contexts. PMID:21959451

  7. Dissolution behavior and early bone apposition of calcium phosphate-coated machined implants

    PubMed Central

    Hwang, Ji-Wan; Lee, Eun-Ung; Lee, Jung-Seok; Jung, Ui-Won; Lee, In-Seop

    2013-01-01

    Purpose Calcium phosphate (CaP)-coated implants promote osseointegration and survival rate. The aim of this study was to (1) analyze the dissolution behavior of the residual CaP particles of removed implants and (2) evaluate bone apposition of CaP-coated machined surface implants at the early healing phase. Methods Mandibular premolars were extracted from five dogs. After eight weeks, the implants were placed according to drilling protocols: a nonmobile implant (NI) group and rotational implant (RI) group. For CaP dissolution behavior analysis, 8 implants were removed after 0, 1, 2, and 4 weeks. The surface morphology and deposition of the coatings were observed. For bone apposition analysis, block sections were obtained after 1-, 2-, and 4-week healing periods and the specimens were analyzed. Results Calcium and phosphorus were detected in the implants that were removed immediately after insertion, and the other implants were composed mainly of titanium. There were no notable differences between the NI and RI groups in terms of the healing process. The bone-to-implant contact and bone density in the RI group showed a remarkable increase after 2 weeks of healing. Conclusions It can be speculated that the CaP coating dissolves early in the healing phase and chemically induces early bone formation regardless of the primary stability. PMID:24455442

  8. Functional Diversity of Fibroblast Growth Factors in Bone Formation

    PubMed Central

    Minamizaki, Tomoko; Yoshiko, Yuji

    2015-01-01

    The functional significance of fibroblast growth factor (FGF) signaling in bone formation has been demonstrated through genetic loss-of-function and gain-of-function approaches. FGFs, comprising 22 family members, are classified into three subfamilies: canonical, hormone-like, and intracellular. The former two subfamilies activate their signaling pathways through FGF receptors (FGFRs). Currently, intracellular FGFs appear to be primarily involved in the nervous system. Canonical FGFs such as FGF2 play significant roles in bone formation, and precise spatiotemporal control of FGFs and FGFRs at the transcriptional and posttranscriptional levels may allow for the functional diversity of FGFs during bone formation. Recently, several research groups, including ours, have shown that FGF23, a member of the hormone-like FGF subfamily, is primarily expressed in osteocytes/osteoblasts. This polypeptide decreases serum phosphate levels by inhibiting renal phosphate reabsorption and vitamin D3 activation, resulting in mineralization defects in the bone. Thus, FGFs are involved in the positive and negative regulation of bone formation. In this review, we focus on the reciprocal roles of FGFs in bone formation in relation to their local versus systemic effects. PMID:25873956

  9. Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption.

    PubMed

    Xiong, Lei; Jung, Ji-Ung; Wu, Haitao; Xia, Wen-Fang; Pan, Jin-Xiu; Shen, Chengyong; Mei, Lin; Xiong, Wen-Cheng

    2015-03-17

    Bone mass is maintained by balanced activity of osteoblasts and osteoclasts. Lrp4 (low-density lipoprotein receptor related protein 4) is a member of the LDL receptor family, whose mutations have been identified in patients with high-bone-mass disorders, such as sclerosteosis and van Buchem diseases. However, it remains unknown whether and how Lrp4 regulates bone-mass homeostasis in vivo. Here we provide evidence that Lrp4-null mutation or specific mutation in osteoblast-lineage cells increased cortical and trabecular bone mass, which was associated with elevated bone formation and impaired bone resorption. This phenotype was not observed in osteoclast-selective Lrp4 knockout mice. Mechanistic studies indicate that loss of Lrp4 function in osteoblast-lineage cells increased serum levels of sclerostin, a key factor for bone-mass homeostasis that interacts with Lrp4, but abolished the inhibition of Wnt/?-catenin signaling and osteoblastic differentiation by sclerostin. Concomitantly, sclerostin induction of RANKL (receptor activator of nuclear kappa B ligand) was impaired, leading to a lower ratio of RANKL over OPG (osteoprotegerin) (a key factor for osteoclastogenesis). Taken together, these results support the view for Lrp4 as a receptor of sclerostin to inhibit Wnt/?-catenin signaling and bone formation and identify Lrp4 as a critical player in bone-mass homeostasis. PMID:25733894

  10. Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption

    PubMed Central

    Xiong, Lei; Jung, Ji-Ung; Wu, Haitao; Xia, Wen-Fang; Pan, Jin-Xiu; Shen, Chengyong; Mei, Lin; Xiong, Wen-Cheng

    2015-01-01

    Bone mass is maintained by balanced activity of osteoblasts and osteoclasts. Lrp4 (low-density lipoprotein receptor related protein 4) is a member of the LDL receptor family, whose mutations have been identified in patients with high–bone-mass disorders, such as sclerosteosis and van Buchem diseases. However, it remains unknown whether and how Lrp4 regulates bone-mass homeostasis in vivo. Here we provide evidence that Lrp4-null mutation or specific mutation in osteoblast-lineage cells increased cortical and trabecular bone mass, which was associated with elevated bone formation and impaired bone resorption. This phenotype was not observed in osteoclast-selective Lrp4 knockout mice. Mechanistic studies indicate that loss of Lrp4 function in osteoblast-lineage cells increased serum levels of sclerostin, a key factor for bone-mass homeostasis that interacts with Lrp4, but abolished the inhibition of Wnt/?-catenin signaling and osteoblastic differentiation by sclerostin. Concomitantly, sclerostin induction of RANKL (receptor activator of nuclear kappa B ligand) was impaired, leading to a lower ratio of RANKL over OPG (osteoprotegerin) (a key factor for osteoclastogenesis). Taken together, these results support the view for Lrp4 as a receptor of sclerostin to inhibit Wnt/?-catenin signaling and bone formation and identify Lrp4 as a critical player in bone-mass homeostasis. PMID:25733894

  11. FOXOs attenuate bone formation by suppressing Wnt signaling

    PubMed Central

    Iyer, Srividhya; Ambrogini, Elena; Bartell, Shoshana M.; Han, Li; Roberson, Paula K.; de Cabo, Rafael; Jilka, Robert L.; Weinstein, Robert S.; O’Brien, Charles A.; Manolagas, Stavros C.; Almeida, Maria

    2013-01-01

    Wnt/?-catenin/TCF signaling stimulates bone formation and suppresses adipogenesis. The hallmarks of skeletal involution with age, on the other hand, are decreased bone formation and increased bone marrow adiposity. These changes are associated with increased oxidative stress and decreased growth factor production, which activate members of the FOXO family of transcription factors. FOXOs in turn attenuate Wnt/?-catenin signaling by diverting ?-catenin from TCF- to FOXO-mediated transcription. We show herein that mice lacking Foxo1, -3, and -4 in bipotential progenitors of osteoblast and adipocytes (expressing Osterix1) exhibited increased osteoblast number and high bone mass that was maintained in old age as well as decreased adiposity in the aged bone marrow. The increased bone mass in the Foxo-deficient mice was accounted for by increased proliferation of osteoprogenitor cells and bone formation resulting from upregulation of Wnt/?-catenin signaling and cyclin D1 expression, but not changes in redox balance. Consistent with this mechanism, ?-catenin deletion in Foxo null cells abrogated both the increased cyclin D1 expression and proliferation. The elucidation of a restraining effect of FOXOs on Wnt signaling in bipotential progenitors suggests that FOXO activation by accumulation of age-associated cellular stressors may be a seminal pathogenetic mechanism in the development of involutional osteoporosis. PMID:23867625

  12. Measurement of spinal or peripheral bone mass to estimate early postmenopausal bone loss

    SciTech Connect

    Riis, B.J.; Christiansen, C.

    1988-04-01

    This report presents data from 153 healthy, early postmenopausal women who were randomly allocated to two years of treatment with estrogen or placebo. Bone mineral content in the forearms was measured by single-photon absorptiometry, and bone mineral density of the lumbar spine and total-body bone mineral by dual-photon absorptiometry, before and after one and two years of treatment. At the end of the two years, there were highly significant differences of 6 to 7 percent between the estrogen and the placebo groups at all sites measured. The range of the changes of the spine measurement was twice that of the forearm and total-body measurements. It is concluded that measurement of the forearm by single-photon absorptiometry is superior to measurement of the spine by dual-photon absorptiometry both in clinical studies and in the individual patient for detecting estrogen-dependent bone loss and its treatment by estrogen replacement.

  13. Early complete bone union after condylar fracture in a child.

    PubMed

    Kim, Youn Hwan; Youn, Seungki; Kim, Jeong Tae

    2011-07-01

    A 3-year-old boy had unilateral intracapsular condylar fracture due to a fall. Short duration of immobilization using a facial band was performed for 5 days without any surgical intervention. The patient had full recovery in mouth opening with no deviation or asymmetry of the mandible. Posttraumatic 6 weeks later, the patient's computed tomogram revealed complete reduction of fracture, and bone union had occurred. In condylar fractures of children, treatment protocols with short duration of immobilization and early active exercise can obtain complete bone union, contrary to the previously described deformity or remodeling process. PMID:21778852

  14. Early structure formation from cosmic string loops

    SciTech Connect

    Shlaer, Benjamin; Vilenkin, Alexander [Institute of Cosmology, Department of Physics and Astronomy, Tufts University, 212 College Avenue, Medford, MA 02155 (United States); Loeb, Abraham, E-mail: shlaer@cosmos.phy.tufts.edu, E-mail: vilenkin@cosmos.phy.tufts.edu, E-mail: aloeb@cfa.harvard.edu [Institute for Theory and Computation, Harvard-Smithsonian Center for Astrophysics, 60 Garden Street, Cambridge, MA, 02138 (United States)

    2012-05-01

    We examine the effects of cosmic strings on structure formation and on the ionization history of the universe. While Gaussian perturbations from inflation are known to provide the dominant contribution to the large scale structure of the universe, density perturbations due to strings are highly non-Gaussian and can produce nonlinear structures at very early times. This could lead to early star formation and reionization of the universe. We improve on earlier studies of these effects by accounting for high loop velocities and for the filamentary shape of the resulting halos. We find that for string energy scales G??>10{sup ?7}, the effect of strings on the CMB temperature and polarization power spectra can be significant and is likely to be detectable by the Planck satellite. We mention shortcomings of the standard cosmological model of galaxy formation which may be remedied with the addition of cosmic strings, and comment on other possible observational implications of early structure formation by strings.

  15. Infant formula increases bone turnover favoring bone formation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In the first year of life, the major infant food choices have traditionally been breast milk (BM), cow's milk formula (MF), or soy formula (SF). Studies examining the effects of infant formula on early life skeletal development are extremely limited. We have enrolled 120 healthy 6-month-old infants ...

  16. Arthroscopic assisted bone grafting for early stages of Kienböck's disease.

    PubMed

    Pegoli, L; Ghezzi, A; Cavalli, E; Luchetti, R; Pajardi, G

    2011-01-01

    Kienböck's disease is known for its difficulty in being diagnosed and treated at early stages; option treatments are few and most of them quite aggressive. The author describes his experience with arthroscopic assisted lunate bone grafting. Three patients with diagnosis of stage I avascular necrosis of the lunate (average age: 45 years), were treated. Before surgical procedure, the patients underwent to a conservative treatment. After harvesting the bone graft from the volar surface of the radius, arthroscopic bone grafting was performed. At an average follow-up of 13.5 months (9-15), all the patients show a normal density of the lunate and no arthritic changes in radiographs. The MRI confirmed the lunate vascularity. The number of patients is definitely small, due also to the rarity of the disease and the difficulty in diagnosis, but, despite the very high learning curve, could be the proper first choice of treatment. PMID:21548146

  17. Title: Patterning Bone Regeneration In Silico Modeling of Bone Morphogenetic Protein (BMP) Driven bone formation

    E-print Network

    Wolper, Pierre

    Title: Patterning Bone Regeneration ­ In Silico Modeling of Bone Morphogenetic Protein (BMP) Driven as BMP-2 and BMP-7) are produced, Food and Drug Administration (FDA)-approved, and thus are being used this phenomenon so that novel tissue engineering strategys can be developed to pattern bone regeneration in a pre

  18. Directing mesenchymal stem cells to bone to augment bone formation and increase bone mass

    Microsoft Academic Search

    Min Guan; Ruiwu Liu; Kit S Lam; Jan Nolta; Junjing Jia; Brian Panganiban; Liping Meng; Ping Zhou; Mohammad Shahnazari; Robert O Ritchie; Wei Yao

    2012-01-01

    Aging reduces the number of mesenchymal stem cells (MSCs) that can differentiate into osteoblasts in the bone marrow, which leads to impairment of osteogenesis. However, if MSCs could be directed toward osteogenic differentiation, they could be a viable therapeutic option for bone regeneration. We have developed a method to direct MSCs to the bone surface by attaching a synthetic high-affinity

  19. Early reconstitution of haematopoiesis after allogeneic bone marrow transplantation: a prospective histopathological study of bone marrow biopsy specimens

    Microsoft Academic Search

    H van den Berg; P M Kluin; J M Vossen

    1990-01-01

    To study early haematopoietic reconstitution after bone marrow transplantation bone marrow biopsy specimens taken in the third week after transplantation were evaluated. Cellularity was highly variable; localisation of the various cell lineages and the ratios of myeloid cells to erythroid cells were abnormal. Clustering of cells of the same lineage in the same stage of maturation was prominent. The bone

  20. Soluble silica inhibits osteoclast formation and bone resorption in vitro.

    PubMed

    Mladenovi?, Živko; Johansson, Anders; Willman, Britta; Shahabi, Kaveh; Björn, Erik; Ransjö, Maria

    2014-01-01

    Several studies have suggested that silicon (Si) may be essential for the normal development of connective tissue and the skeleton. Positive effects of Si from the diet as well as from Si-containing biomaterials, such as bioactive glass 45S5 (BG), have been demonstrated. Studies have reported that Si stimulates osteoblast proliferation and differentiation. However, the effects of Si on osteoclasts have not been directly addressed. The purpose of the present in vitro study was to clarify if Si has regulatory effects on osteoclast formation and bone resorption. The effects of BG, BG dissolution extracts and Si containing cell culture medium were investigated in a mouse calvarial bone resorption assay and osteoclast formation assays (mouse bone marrow cultures and RAW264.7 cell cultures). We conclude from our results that Si causes significant inhibition of osteoclast phenotypic gene expressions, osteoclast formation and bone resorption in vitro. In conclusion, the present study suggests that Si has a dual nature in bone metabolism with stimulatory effects on osteoblasts and inhibitory effects on osteoclasts. This suggested property of Si might be interesting to further explore in future biomaterials for treatments of bone defects in patients. PMID:24016843

  1. Re-evaluating the induction of bone formation in primates.

    PubMed

    Ripamonti, Ugo; Duarte, Raquel; Ferretti, Carlo

    2014-11-01

    The molecular cloning of the osteogenic proteins of the transforming growth factor-? (TGF-?) supergene family and the results of numerous pre-clinical studies in several mammalian species including non-human primates, have prematurely convinced molecular biologists, tissue engineers and skeletal reconstructionists alike to believe that single recombinant human bone morphogenetic/osteogenic proteins (hBMPs/OPs) would result in tissue induction when translated in clinical contexts. This theoretical potential has not been translated to acceptable clinical results. Clinical trials in craniofacial and orthopedic applications such as mandibular reconstruction and sinus-lift operations have indicated that supra physiological doses of a single recombinant human protein are needed to induce unacceptable tissue regeneration whilst incurring significant costs without achieving equivalence to autogenous bone grafts. The acid test for clinically relevant bone tissue engineering should now become the concept of clinically significant osteoinduction, whereby the regenerated bone is readily identifiable on radiographic examination by virtue of its opacity and trabecular architecture. The need for alternatives to the hBMPs/OPs is now felt more acutely following reported complications and performance failure associated with the clinical use of hBMP-2 and hOP-1 (BMP-7). Because of the often substandard regeneration of clinical defects implanted with hBMPs/OPs, we now need to finally deal with the provocative question: are the hBMPs/OPs the only initiators of the induction of bone formation in pre-clinical and clinical contexts? The rapid induction of bone formation by the hTGF-?? isoform in heteropic intramuscular sites of the Chacma baboon Papio ursinus together with TGF-??, TGF-??, BMP-2, BMP-3, OP-1, RUNX-2 and Osteocalcin up-regulation and expression, hyper cellular osteoblastic activity, osteoid synthesis, angiogenesis and capillary sprouting are the molecular and morphological foundation for the induction of bone formation in clinical contexts. The induction of bone as initiated by hTGF-?3 when implanted in the rectus abdominis muscle of P. ursinus is via the BMPs/OPs pathway with hTGF-?? controlling the induction of bone formation by regulating the expression of BMPs/OPs via Noggin expression, eliciting the induction of bone formation by up-regulating endogenous BMPs/OPs and it is blocked by hNoggin, providing insights into performance failure of hBMPs/OPs in clinical contexts. Physiological expression of BMPs/OPs genes upon implantation of hTGF-?? may escape the antagonist expression of Noggin and other inhibitors, whereas direct application of hBMPs/OPs, representing a later by-product step of the bone induction cascade as set by the TGF-?? master gene in primates, sets into motion Noggin' antagonist action, as shown by the limited effectiveness of hBMPs/OPs in clinical contexts. The unprecedented induction of bone formation by 250 ?g hTGF-?? when combined with coral-derived macroporous constructs is the novel molecular and morphological frontier for the induction of bone formation in man. The induction of bone by hTGF-?? has been thus translated in clinical contexts to treat a large mandibular defect in a pediatric patient; 30 months after implantation of 250 ?g hTGF-?? per gram of human demineralized bone matrix, radiographic analyses show the reconstruction of the avulsed large mandibular segment including the induction of the avulsed coronoid process. PMID:25155544

  2. The divalent strontium salt S12911 enhances bone cell replication and bone formation in vitro

    Microsoft Academic Search

    E. Canalis; M. Hott; P. Deloffre; Y. Tsouderos; P. J. Marie

    1996-01-01

    In this study, we have determined the effect of the divalent strontium salt S12911 on bone cell replication and bone formation in two culture systems. In the first series of experiments, half-calvariae of newborn rats were cultured with S12911 from 24 to 96 h and labeled with 3H-thymidine for the last 6 h of culture or treated with S12911 for

  3. Non-Linear Pattern Formation in Bone Growth and Architecture

    PubMed Central

    Salmon, Phil

    2014-01-01

    The three-dimensional morphology of bone arises through adaptation to its required engineering performance. Genetically and adaptively bone travels along a complex spatiotemporal trajectory to acquire optimal architecture. On a cellular, micro-anatomical scale, what mechanisms coordinate the activity of osteoblasts and osteoclasts to produce complex and efficient bone architectures? One mechanism is examined here – chaotic non-linear pattern formation (NPF) – which underlies in a unifying way natural structures as disparate as trabecular bone, swarms of birds flying, island formation, fluid turbulence, and others. At the heart of NPF is the fact that simple rules operating between interacting elements, and Turing-like interaction between global and local signals, lead to complex and structured patterns. The study of “group intelligence” exhibited by swarming birds or shoaling fish has led to an embodiment of NPF called “particle swarm optimization” (PSO). This theoretical model could be applicable to the behavior of osteoblasts, osteoclasts, and osteocytes, seeing them operating “socially” in response simultaneously to both global and local signals (endocrine, cytokine, mechanical), resulting in their clustered activity at formation and resorption sites. This represents problem-solving by social intelligence, and could potentially add further realism to in silico computer simulation of bone modeling. What insights has NPF provided to bone biology? One example concerns the genetic disorder juvenile Pagets disease or idiopathic hyperphosphatasia, where the anomalous parallel trabecular architecture characteristic of this pathology is consistent with an NPF paradigm by analogy with known experimental NPF systems. Here, coupling or “feedback” between osteoblasts and osteoclasts is the critical element. This NPF paradigm implies a profound link between bone regulation and its architecture: in bone the architecture is the regulation. The former is the emergent consequence of the latter. PMID:25653638

  4. DYSAPOPTOSIS OF OSTEOBLASTS AND OSTEOCYTES INCREASES CANCELLOUS BONE FORMATION BUT EXAGGERATES BONE POROSITY WITH AGE

    PubMed Central

    Jilka, Robert L.; O’Brien, Charles A.; Roberson, Paula K.; Bonewald, Lynda F.; Weinstein, Robert S.; Manolagas, Stavros C.

    2013-01-01

    Skeletal aging is accompanied by decreased cancellous bone mass and increased formation of pores within cortical bone. The latter accounts for a large portion of the increase in non-vertebral fractures after age 65 in humans. We selectively deleted Bak and Bax, two genes essential for apoptosis, in two types of terminally differentiated bone cells: the short-lived osteoblasts that elaborate the bone matrix, and the long-lived osteocytes that are immured within the mineralized matrix and choreograph the regeneration of bone. Attenuation of apoptosis in osteoblasts increased their working lifespan and thereby cancellous bone mass in the femur. In long-lived osteocytes, however, it caused dysfunction with advancing age and greatly magnified intracortical femoral porosity associated with increased production of receptor activator of nuclear factor-?B ligand and vascular endothelial growth factor. Increasing bone mass by artificial prolongation of the inherent lifespan of short-lived osteoblasts, while exaggerating the adverse effects of aging on long-lived osteocytes, highlights the seminal role of cell age in bone homeostasis. In addition, our findings suggest that distress signals produced by old and/or dysfunctional osteocytes are the culprits of the increased intracortical porosity in old age. PMID:23761243

  5. MicroRNA control of bone formation and homeostasis

    PubMed Central

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

    2013-01-01

    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 pathways, osteoblast growth and differentiation, osteoclast-mediated bone resorption activity and bone homeostasis in the adult skeleton. miRNAs control multiple layers of gene regulation for bone development and postnatal functions, from the initial response of stem/progenitor cells to the structural and metabolic activity of the mature tissue. This Review brings into focus an emerging concept of bone-regulating miRNAs, the evidence for which has been gathered largely from in vivo mouse models and in vitro studies in human and mouse skeletal cell populations. Characterization of miRNAs that operate through tissue-specific transcription factors in osteoblast and osteoclast lineage cells, as well as intricate feedforward and reverse loops, has provided novel insights into the supervision of signaling pathways and regulatory networks controlling normal bone formation and turnover. The current knowledge of miRNAs characteristic of human pathologic disorders of the skeleton is presented with a future goal towards translational studies. PMID:22290358

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

    Microsoft Academic Search

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

    2008-01-01

    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

  7. Labeling studies on cortical bone formation in the antlers of red deer (Cervus elaphus).

    PubMed

    Gomez, S; Garcia, A J; Luna, S; Kierdorf, U; Kierdorf, H; Gallego, L; Landete-Castillejos, T

    2013-01-01

    The formation and mineralization process of antlers, which constitute the fastest growing bones in vertebrates, is still not fully understood. We used oxytetracycline injections to label different stages of bone formation in antlers of 14 red deer between days 28 and 156 of antler growth. Results show that initially a trabecular scaffold of woven bone is formed which largely replaces a pre-existing scaffold of mineralized cartilage. Lamellar bone is then deposited and from about day 70 onwards, primary osteons fill in the longitudinal tubes lined by the scaffold in a proximal to distal sequence. Mineral apposition rate (MAR) in early stages of primary osteon formation is very high (average 2.15 ?m/d). Lower MARs were recorded for later stages of primary osteon formation (1.56 ?m/d) and for the smaller secondary osteons (0.89 ?m/d). Results suggest a peak in mineral demand around day 100 when the extent of mineralizing surfaces is maximal. A few secondary osteons were formed in a process of antler modeling rather than remodeling, as it occurred simultaneously with formation of primary osteons. The degree of cortical porosity reflects a reduction in MAR during later stages of osteonal growth, whereas cortical thickness is determined earlier. Injections given when the antlers were largely or completely clean from velvet produced no labels in antler bone, strongly suggesting that antlers are dead after velvet shedding. The rapidity of antler mineralization and the short lifespan of antlers make them an extraordinary model to assess the effects of chemicals impairing or promoting bone mineralization. PMID:23000508

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

    Microsoft Academic Search

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

    2005-01-01

    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

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

    SciTech Connect

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

    1986-12-01

    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.

  10. Shell Formation and Bone Strength Laying Hens

    E-print Network

    -related decline of shell quality. Since the majority of eggshell calcium is absorbed in the duodenum, the dramatic. In the shell gland CA is considered a key enzyme in the supply of the carbonate ions needed for shell formation , plasma membrane calcium ATP-ase. Author's address: Anna Wistedt, Department of Anatomy, Physiology

  11. Surface microcracks signal osteoblasts to regulate alignment and bone formation.

    PubMed

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

    2014-11-01

    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 21 days 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

  12. Fresh-frozen allografts combined with bovine bone mineral enhance bone formation in sinus augmentation.

    PubMed

    Sehn, Felipe Perraro; Dias, Rafael Rodrigues; de Santana Santos, Thiago; Silva, Erick Ricardo; Salata, Luiz Antonio; Chaushu, Gavriel; Xavier, Samuel Porfírio

    2015-02-01

    We evaluated histologically, histomorphometrically, and tomographically the effects of the association of fresh-frozen bone allograft (FFB) with bovine bone mineral (BBM) in maxillary sinus floor augmentation. In total, 34 maxillary sinuses from 29 patients, with a mean age of 51.32 (±6.44) years, underwent sinus augmentation. Patients were divided into control and test groups (17 sinuses each). The controls were grafted with allograft bone, and the test group received a combination of FFB and BBM at a 2:1 ratio. After 6 months, bone samples were collected for histological and histomorphometric examinations. The implant survival rates were 93.02% (control group) and 100% (test group) at 6 months after functional loading. Median volumetric reductions of 28.32% (17.05-44.05) and 12.62% (5.65-16.87) were observed for the control and test groups, respectively. Statistically significant histomorphometric differences were found between the control and test groups regarding newly formed bone 12.54% (10.50-13.33) vs. 24.42% (17.62-35.92), p?bone 48.34% (39.03-54.42) vs. 61.32% (50.61-64.96), p?=?0.007, and connective tissue 51.66% (45.57-60.97) vs. 39.30% (35.03-49.37), p?=?0.007. The addition of BBM to allograft bone in maxillary sinus augmentation resulted in higher percentages of new bone formation and total bone, and permitted implant placement with a low rate of osseointegration failure at the 6-month follow-up. PMID:25245781

  13. Transgenic overexpression of bone morphogenetic protein 11 propeptide in skeleton enhances bone formation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bone morphogenetic protein 11 (BMP11) is a key regulatory protein in skeletal development. BMP11 propeptide has been shown to antagonize GDF11 activity in vitro. To explore the role of BMP11 propeptide in skeletal formation in vivo, we generated transgenic mice with skeleton-specific overexpression...

  14. The Biermann Battery and Early Structure Formation

    NASA Astrophysics Data System (ADS)

    Zhao, Fen; Alvarez, Marcelo; Abel, Tom

    2008-03-01

    Using ENZO, a 3D adaptive mesh cosmological simulation code, we look at the characteristics of magnetic fields generated in early structure formation by the Biermann battery process. Tracking six species (H, H+, He, He+, He++ and e-), we follow the formation of structure from multiple independent realizations of cosmological initial conditions to better understand how magnetic fields are generated by non aligned pressure and density gradients. These efforts aim at adding ideal MHD to the ENZO framework which will enable the study of the build up and evolution of cosmic magnetic fields.

  15. Quantitative assessment of early healing of intramembranous and endochondral autogenous bone grafts using micro-computed tomography and Q-win image analyzer.

    PubMed

    Lu, M; Rabie, A B M

    2004-06-01

    Micro-computed tomography (microCT) is a new tool to image and quantify trabecular bone. The aim of this study is to compare the two measurement methods when evaluating the early healing of intramembranous (IM) and endochondral (EC) autogenous bone grafts using micro-computed tomography and Q-win computer image analyzer. Twelve critical size (15 mm x 10 mm) defects were created in rabbit mandibles bilaterally. Six defects were grafted with autogenous EC bone; six defects were grafted with autogenous IM bone. Three weeks post-surgery, the defects were retrieved for microCT imaging analysis and histological evaluation. Results showed a significant correlation (r = 0.96, P < 0.0001) between microCT and Q-win in measuring the volume of new bone and graft bone in the mandibular defects after 3 weeks of early healing. There were distinct differences between IM bone and EC bone grafts in 2D and 3D features of graft bone maintenance as well as new bone formation. MicroCT imaging is a non-destructive, fast and precise procedure that allows for quantitative evaluation of the early healing of IM and EC autogenous bone grafts in membranous bone defects. PMID:15145040

  16. Lithium inhibition of bone mineralization and osteoid formation.

    PubMed Central

    Baran, D T; Schwartz, M P; Bergfeld, M A; Teitelbaum, S L; Slatopolsky, E; Avioli, L V

    1978-01-01

    Lithium chloride administration to growing rats, which resulted in circulating lithium levels of 1.4 meq/liter, was attended by significant suppression of bone mineralization and organic matrix synthesis as assessed by tetracycline labeling and histological quantitation of osteoid, respectively. These effects of lithium were not associated with changes in animal behavior, nor were there any significant differences in blood levels of calcium, phosphorus, alkaline phosphatase, creatinine, pH, or parathyroid hormone. The data suggest that lithium inhibition of bone mineralization is secondary to suppression of osteoid formation. Images PMID:659622

  17. The collagen component of biological bone graft substitutes promotes ectopic bone formation by human mesenchymal stem cells.

    PubMed

    Wagner-Ecker, Mechthild; Voltz, Pia; Egermann, Marcus; Richter, Wiltrud

    2013-07-01

    Synthetic bone substitutes are attractive materials for repairing a variety of bone defects. They are readily available in unlimited quantities, have a defined composition without batch variability and bear no risk of disease transmission. When combined with mesenchymal stem cells (MSCs), bone healing can be further enhanced due to the osteogenic potential of these cells. However, human MSCs showed considerable donor variability in ectopic bone formation assays on synthetic bone substitutes, which may limit clinical success. This study addresses whether bone formation variability of MSCs is cell-intrinsic or biomaterial-dependent and may be improved using biological bone substitutes with and without collagen. Ectopic bone formation of MSCs from nine donors was tested in immune-deficient mice on biological bone substitutes of bovine and equine origin, containing collagen (bHA-C; eHA-C) or not (bHA; eHA). Synthetic ?-TCP was used for comparison. Histology of 8-week explants demonstrated a significant influence of the bone graft substitute (BGS) on donor variability of ectopic bone formation with best results seen for eHA-C (15/17) and ?-TCP (16/18). Bone was of human origin in all groups according to species-specific in situ hybridization, but MSCs from one donor formed no bone with any bone substitute. According to histomorphometry, most neo-bone was formed on eHA-C with significant differences to bHA, eHA and ?-TCP (p<0.001). Collagen-free biological BGSs were inferior to biological BGSs with collagen (p<0.001), while species-origin was of little influence. In conclusion, BGS composition had a strong influence on ectopic bone formation ability of MSCs, and biological BGSs with a collagen component seem most promising to display the strong osteogenic potential of MSCs. PMID:23542556

  18. In vivo bone formation by human bone marrow stromal cells: Effect of carrier particle size and shape

    Microsoft Academic Search

    Mahesh H. Mankani; Sergei A. Kuznetsov; Bruce Fowler; Albert Kingman; Pamela Gehron Robey

    2001-01-01

    Successful closure of bone defects in patients remains an active area of basic and clinical research. A novel and promising approach is the transplantation of human bone marrow stromal cells (BMSCs), which have been shown to possess a significant osteogenic poten- tial. The extent and quality of bone formation by trans- planted human BMSCs strongly depends on the carrier matrix

  19. Improving bone formation in a rat femur segmental defect by controlling bone morphogenetic protein-2 release.

    PubMed

    Brown, Kate V; Li, Bing; Guda, Teja; Perrien, Daniel S; Guelcher, Scott A; Wenke, Joseph C

    2011-07-01

    Nonunion is a common complication in open fractures and other severe bone injuries. Recombinant human bone morphogenetic protein-2 (rhBMP-2) delivered on a collagen sponge enhances healing of fractures. However, the burst release of rhBMP-2 necessitates supra-physiological doses of rhBMP-2 to achieve a robust osteogenic effect, which introduces risk of ectopic bone formation and severe inflammation and increases the cost. Although the concept that the ideal pharmacokinetics for rhBMP-2 includes both a burst and sustained release is generally accepted, investigations into the effects of the release kinetics on new bone formation are limited. In the present study, biodegradable polyurethane (PUR) and PUR/microsphere [PUR/poly(lactic-co-glycolic acid)] composite scaffolds with varying rhBMP-2 release kinetics were compared to the collagen sponge delivery system in a critical-sized rat segmental defect model. Microcomputed tomography analysis indicated that a burst followed by a sustained release of rhBMP-2 from the PUR scaffolds regenerated 50% more new bone than the collagen sponge loaded with rhBMP-2, whereas a sustained release without the burst did not form significantly more bone than the scaffold without rhBMP-2. This study demonstrated that the putative optimal release profile (i.e., burst followed by sustained release) for rhBMP-2 can be achieved using PUR scaffolds, and that this enhanced pharmacokinetics regenerated more bone than the clinically available standard of care in a critical-sized defect in rat femora. PMID:21338268

  20. Protostar formation in the early universe.

    PubMed

    Yoshida, Naoki; Omukai, Kazuyuki; Hernquist, Lars

    2008-08-01

    The nature of the first generation of stars in the universe remains largely unknown. Observations imply the existence of massive primordial stars early in the history of the universe, and the standard theory for the growth of cosmic structure predicts that structures grow hierarchically through gravitational instability. We have developed an ab initio computer simulation of the formation of primordial stars that follows the relevant atomic and molecular processes in a primordial gas in an expanding universe. The results show that primeval density fluctuations left over from the Big Bang can drive the formation of a tiny protostar with a mass 1% that of the Sun. The protostar is a seed for the subsequent formation of a massive primordial star. PMID:18669856

  1. Decreased C-Src Expression Enhances Osteoblast Differentiation and Bone Formation

    Microsoft Academic Search

    Marilena Marzia; Natalie A. Sims; Susanne Voit; Silvia Migliaccio; Anna Taranta; Silvia Bernardini; Tullio Faraggiana; Toshiyuki Yoneda; Gregory R. Mundy; Brendan F. Boyce; Roland Baron; Anna Teti

    2000-01-01

    c-src deletion in mice leads to osteopetrosis as a result of reduced bone resorption due to an alter- ation of the osteoclast. We report that deletion\\/reduc- tion of Src expression enhances osteoblast differentia- tion and bone formation, contributing to the increase in bone mass. Bone histomorphometry showed that bone formation was increased in Src null compared with wild-type mice. In

  2. BMP-13 Emerges as a Potential Inhibitor of Bone Formation

    PubMed Central

    Shen, Bojiang; Bhargav, Divya; Wei, Aiqun; Williams, Lisa A; Tao, Helen; Ma, David D F; Diwan, Ashish D

    2009-01-01

    Bone morphogenetic protein-13 (BMP-13) plays an important role in skeletal development. In the light of a recent report that mutations in the BMP-13 gene are associated with spine vertebral fusion in Klippel-Feil syndrome, we hypothesized that BMP-13 signaling is crucial for regulating embryonic endochondral ossification. In this study, we found that BMP-13 inhibited the osteogenic differentiation of human bone marrow multipotent mesenchymal stromal cells (BM MSCs) in vitro. The endogenous BMP-13 gene expression in MSCs was examined under expansion conditions. The MSCs were then induced to differentiate into osteoblasts in osteo-inductive medium containing exogenous BMP-13. Gene expression was analysed by real-time PCR. Alkaline phosphatase (ALP) expression and activity, proteoglycan (PG) synthesis and matrix mineralization were assessed by cytological staining or ALP assay. Results showed that endogenous BMP-13 mRNA expression was higher than BMP-2 or -7 during MSC growth. BMP-13 supplementation strongly inhibited matrix mineralization and ALP activity of osteogenic differentiated MSCs, yet increased PG synthesis under the same conditions. In conclusion, BMP-13 inhibited osteogenic differentiation of MSCs, implying that functional mutations or deficiency of BMP-13 may allow excess bone formation. Our finding provides an insight into the molecular mechanisms and the therapeutic potential of BMP-13 in restricting pathological bone formation. PMID:19240811

  3. Biologic properties of nano-hydroxyapatite: An in vivo study of calvarial defects, ectopic bone formation and bone implantation.

    PubMed

    Pang, Kang-Mi; Lee, Jeong-Keun; Seo, Young-Kwon; Kim, Soung-Min; Kim, Myung-Jin; Lee, Jong-Ho

    2015-01-01

    This study investigated the biologic properties of nano-hydroxyapatite (nHAp) using the rat calvarial defect, ectopic bone formation, and rabbit tibia implant installation models. Animals were divided into two groups: those implanted with nHAp, and negative controls (Collagen). Eight weeks after creating an 8 mm calvarial defect, bone regeneration was evaluated radiographically and histologically. To investigate ectopic bone formation, materials were injected into the right thigh muscle and were evaluated after 8 weeks. nHAp coated implant and conventional titanium implant were placed bilaterally in rabbit tibias. After 4 weeks, bone-implant contact (BIC), new bone area inside the thread, and removal torque were measured. In the calvarial defect model, radiographic and histologic analysis showed more bone formation in the nHAp Group; particularly, histologically assessed bone area (p=0.034) and microcomputed tomography assessed bone mineral density (p=0.034). In the ectopic bone formation model, calcification and expression of osteogenic biomarkers were seen in the nHAp-injected samples but in none of the controls. nHAp coated implant resulted in increased BIC, new bone area, and increased removal torque, with statistical significance for BIC (p=0.034). This study suggests that nHAp has potential as a coating material for dental implant surfaces and as a bone graft material. PMID:25585978

  4. [A case of renal cell carcinoma with heterotopic bone formation].

    PubMed

    Moriyama, Hiroshige; Fujii, Leona; Shintani, Yasuyo; Inagaki, Takeshi; Kohjimoto, Yasuo; Suzuki, Atsushi; Hirano, Atsuyuki; Sinka, Toshiaki; Doi, Jun

    2002-10-01

    We report a case of renal cell carcinoma with heterotopic bone formation in a 28-year old woman. The patient was referred to our hospital with a complaint of left lumbargo. Laboratory data were within normal limits. Radiography (KUB) suggested a calcification in the left kidney and abdominal computed tomographic (CT) scan confirmed the presence of a renal mass which contained a calcification. Selective renal angiography revealed a hypervascular (microaneurysm-like change) tumor at the lower part of the kidney. Left nephrectomy was performed. Histopathological diagnosis was renal cell carcinoma with heterotopic bone formation (clear cell carcinoma, G1 > G2, pT1b). There has been neither metastasis nor any recurrence during the 7 months since her operation. PMID:12491612

  5. [Musculoskeletal rehabilitation and bone. Mechanical stress and bone quality : do mechanical stimuli alter collagen cross-link formation in bone? "Yes" ].

    PubMed

    Saito, Mitsuru; Marumo, Keishi

    2010-04-01

    Evidence has accumulated that collagen cross-links also play important roles in bone strength and the proper biological functions of bone. Thus, collagen cross-links may be a factor in determining the material properties of bone. Collagen cross-linking is affected by some growth factors, and tissue age. Collagen cross-links can be roughly divided into two types : lysyl oxidase mediated cross-links (enzymatic immature, divalent and mature, trivalent cross-links) and advanced glycation end-products (AGE ; non-enzymatic, pentosidine cross-links). These two types vary by both the mechanism of formation and by functional differences. Hyper- and micro-gravity, weight-bearing, and low intensity pulsed ultrasound (LIPUS) have distinct biological effects on bone collagen cross-link formation in vitro and in vivo (Saito M, J Bone Miner Res 2003, Bone 2004, Calcif Tissue Int 2004) . We demonstrated in previous studies that physiologic levels of mechanical strain such as hypergravity, weight-bearing, and LIPUS induce the formation of bone-type collagenous matrix into a specific molecular packing arrangement through the formation of characteristic types of cross-links as mineralization begins. Collagen cross-links play important roles in the expression of bone strength and the proper biological function of bone. Thus, collagen cross-links are thought to be a determinant of bone quality. While LIPUS have beneficial effects on collagen enzymatic cross-link formation, mechanical stress may improve bone quality (Saito M, Osteoporos Int, REVIEW, 2010) . PMID:20354325

  6. Evidence for a distinctive pattern of bone formation in enthesophytes

    Microsoft Academic Search

    M Benjamin; H Toumi; D Suzuki; K Hayashi; D McGonagle

    2009-01-01

    Objectives:The mechanism of new bone formation at entheses in spondyloarthritis (SpA) is poorly understood, but it is a key factor contributing to disability in disease. As bony spur development is also an age-related phenomenon, spurs in elderly dissecting room cadavers were studied in order to establish general principles relating to their development.Methods:Spurs of different sizes were studied by routine histology

  7. Black hole formation in the early Universe

    NASA Astrophysics Data System (ADS)

    Latif, M. A.; Schleicher, D. R. G.; Schmidt, W.; Niemeyer, J.

    2013-08-01

    Supermassive black holes with up to a 109 M? dwell in the centres of present-day galaxies, and their presence has been confirmed at z ? 6. Their formation at such early epochs is still an enigma. Different pathways have been suggested to assemble supermassive black holes in the first billion years after the big bang. Direct collapse has emerged as a highly plausible scenario to form black holes as it provides seed masses of 105-106 M?. Gravitational collapse in atomic cooling haloes with virial temperatures Tvir ? 104 K may lead to the formation of massive seed black holes in the presence of an intense background ultraviolet flux. Turbulence plays a central role in regulating accretion and transporting angular momentum. We present here the highest resolution cosmological large eddy simulations to date which track the evolution of high-density regions on scales of 0.25 au beyond the formation of the first peak, and study the impact of subgrid-scale turbulence. The peak density reached in these simulations is 1.2 × 10-8 g cm-3. Our findings show that while fragmentation occasionally occurs, it does not prevent the growth of a central massive object resulting from turbulent accretion and occasional mergers. The central object reaches ˜1000 M? within four free-fall times, and we expect further growth up to 106 M? through accretion in about 1 Myr. The direct collapse model thus provides a viable pathway of forming high-mass black holes at early cosmic times.

  8. Early formation of evolved asteroidal crust.

    PubMed

    Day, James M D; Ash, Richard D; Liu, Yang; Bellucci, Jeremy J; Rumble, Douglas; McDonough, William F; Walker, Richard J; Taylor, Lawrence A

    2009-01-01

    Mechanisms for the formation of crust on planetary bodies remain poorly understood. It is generally accepted that Earth's andesitic continental crust is the product of plate tectonics, whereas the Moon acquired its feldspar-rich crust by way of plagioclase flotation in a magma ocean. Basaltic meteorites provide evidence that, like the terrestrial planets, some asteroids generated crust and underwent large-scale differentiation processes. Until now, however, no evolved felsic asteroidal crust has been sampled or observed. Here we report age and compositional data for the newly discovered, paired and differentiated meteorites Graves Nunatak (GRA) 06128 and GRA 06129. These meteorites are feldspar-rich, with andesite bulk compositions. Their age of 4.52 +/- 0.06 Gyr demonstrates formation early in Solar System history. The isotopic and elemental compositions, degree of metamorphic re-equilibration and sulphide-rich nature of the meteorites are most consistent with an origin as partial melts from a volatile-rich, oxidized asteroid. GRA 06128 and 06129 are the result of a newly recognized style of evolved crust formation, bearing witness to incomplete differentiation of their parent asteroid and to previously unrecognized diversity of early-formed materials in the Solar System. PMID:19129845

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

    PubMed Central

    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

    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

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

    PubMed Central

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

    2011-01-01

    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

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

    Microsoft Academic Search

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

    2006-01-01

    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

  12. OSTEOBLAST DIFFERENTIATION AND BONE FORMATION GENE EXPRESSION IN STRONTIUM-INDUCING BONE MARROW MESENCHYMAL STEM CELL

    Microsoft Academic Search

    Monnipha Sila-asna; Ahnond Bunyaratvej; Sakan Maeda; Hiromichi Kitaguchi; Narong Bunyaratavej

    2007-01-01

    Osteoblastic differentiation from human mesenchymal stem cell (hMSCs) is an important step of bone formation. We studied the in vitro induction of hMSCs by using strontium ranelate, a natural trace amount in water, food and human skeleton. The mRNA synthesis of various osteoblast specific genes was assessed by means of reverse transcription polymerase chain reaction (RT-PCR). In the hMSCs culture,

  13. Effects of etidronate-mediated suppression of bone remodeling on aluminum-induced de novo bone formation.

    PubMed

    Quarles, L D; Drezner, M K

    1992-07-01

    The mechanism by which aluminum chloride stimulates de novo bone formation is unknown. To evaluate the role of bone remodeling and mature osteoblastic function in aluminum-induced neoosteogenesis, we compared the osteogenic effects of aluminum in normal beagles to those in animals with low turnover osteomalacia induced by treatment with etidronate [1-hydroxyethane-1,1-diphosphoric acid (HEBP)]. As assessed by quantitative bone histomorphology, beagles treated with HEBP developed low turnover osteomalacia characterized by a 78% reduction in osteoblast number, a 5.5-fold increase in osteoid volume, complete absence of active mineralization, and diminished resorption surfaces compared to untreated controls. The iv administration of aluminum chloride to normal dogs generated new trabecular structures in the marrow cavity consistent with induction of de novo bone formation. This response consisted of increased trabecular bone volume and number, accumulation of woven osteoid, and increased number of bone-forming cells. The concomitant administration of HEBP failed to prevent induction of de novo bone formation by aluminum. Instead, the neoosteogenic process was superimposed on low turnover osteomalacia in HEBP-treated dogs. Serum aluminum concentrations were increased 2-fold, whereas bone aluminum accumulation was reduced by 58% in HEBP- and aluminum-treated dogs compared to that in aluminum-treated controls. These findings indicate that aluminum stimulation of neoosteogenesis in beagles is independent of mature osteoblast function, normal bone remodeling, and total bone aluminum accumulation. Rather, aluminum-induced de novo bone formation appears to result from stimulation of mesenchymal precursors to form a primitive type of bone which is distinct from coupled bone formation. PMID:1611990

  14. Whey protein suppresses the osteoclast-mediated bone resorption and osteoclast cell formation

    Microsoft Academic Search

    Yukihiro Takada; Naomichi Kobayashi; Hiroaki Matsuyama; Ken Kato; Junichi Yamamura; Masatoshi Yahiro; Masayoshi Kumegawa; Seiichiro Aoe

    1997-01-01

    Effects of whey protein on bone resorption and osteoclastic cell formation were evaluated. In the pre-existed and newly formed osteoclast, in bone resorption methods using an unfractionated bone cell culturing system, whey protein suppressed the area of pits formed by osteoclasts. In the osteoclastic cell formation method using the hemopoietic blast cell culturing system, whey protein also suppressed osteoclastic cell

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

    Microsoft Academic Search

    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

    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

  16. Vaccination with DKK1-derived peptides promotes bone formation and bone mass in an aged mouse osteoporosis model.

    PubMed

    Wu, Qiong; Li, Rui-Shu; Zhao, Yue; Wang, Zhi-Xia; Tang, Yan-Chun; Zhang, Jing; Liu, Jian-Ning; Tan, Xiang-Yang

    2014-08-01

    The investigation of agents for the treatment of osteoporosis has been a long-standing effort. The Wnt pathway plays an important role in bone formation and regeneration, and expression of Wnt pathway inhibitors, Dickkopf-1 (DKK1), appears to be associated with changes in bone mass. Inactivation of DKK1 leads to substantially increased bone mass in genetically manipulated animals. DKK1-derived peptides (DDPs) were added to BMP2-stimulated MC3T3-E1 preosteoblastic cells in vitro to evaluate inhibitory activity of DDPs in MC3T3-E1 cell differentiation. Study was extended in vivo on old female mice to show whether or not inhibition of endogenous DKK1 biological activity using DDPs vaccination approach leads to increase of bone formation, bone density, and improvement of bone microstructure. We reported that synthetic DDPs were able to reduce alkaline phosphatase activity, prevent mineralization and inhibit the differentiation of MC3T3-E1 cells in vitro. Furthermore, vaccination with these DDPs in aged female mice 4 times for a total period of 22 weeks promoted bone mass and bone microstructure. 3D microCT and histomorphometric analysis showed that there were significant increase in bone mineral densities, improvement of bone microstructure and promotion of bone formation in the vaccinated mice, especially in the mice vaccinated with DDP-A and DDP-C. Histological and scanning electron microscopy image analysis also indicated that vaccination increased trabecular bone mass and significantly decreased fragmentation of bone fibers. Taken together, these preclinical results suggest that vaccination with DDPs represents a promising new therapeutic approach for the treatment of bone-related disorders, such as osteoporosis. PMID:24907907

  17. Dual delivery of rhPDGF-BB and bone marrow mesenchymal stromal cells expressing the BMP2 gene enhance bone formation in a critical-sized defect model.

    PubMed

    Park, Shin-Young; Kim, Kyoung-Hwa; Shin, Seung-Yun; Koo, Ki-Tae; Lee, Yong-Moo; Seol, Yang-Jo

    2013-11-01

    Bone tissue healing is a dynamic, orchestrated process that relies on multiple growth factors and cell types. Platelet-derived growth factor-BB (PDGF-BB) is released from platelets at wound sites and induces cellular migration and proliferation necessary for bone regeneration in the early healing process. Bone morphogenetic protein-2 (BMP-2), the most potent osteogenic differentiation inducer, directs new bone formation at the sites of bone defects. This study evaluated a combinatorial treatment protocol of PDGF-BB and BMP-2 on bone healing in a critical-sized defect model. To mimic the bone tissue healing process, a dual delivery approach was designed to deliver the rhPDGF-BB protein transiently during the early healing phase, whereas BMP-2 was supplied by rat bone marrow stromal cells (BMSCs) transfected with an adenoviral vector containing the BMP2 gene (AdBMP2) for prolonged release throughout the healing process. In in vitro experiments, the dual delivery of rhPDGF-BB and BMP2 significantly enhanced cell proliferation. However, the osteogenic differentiation of BMSCs was significantly suppressed even though the amount of BMP-2 secreted by the AdBMP2-transfected BMSCs was not significantly affected by the rhPDGF-BB treatment. In addition, dual delivery inhibited the mRNA expression of BMP receptor type II and Noggin in BMSCs. In in vivo experiments, critical-sized calvarial defects in rats showed enhanced bone regeneration by dual delivery of autologous AdBMP2-transfected BMSCs and rhPDGF-BB in both the amount of new bone formed and the bone mineral density. These enhancements in bone regeneration were greater than those observed in the group treated with AdBMP2-transfected BMSCs alone. In conclusion, the dual delivery of rhPDGF-BB and AdBMP2-transfected BMSCs improved the quality of the regenerated bone, possibly due to the modulation of PDGF-BB on BMP-2-induced osteogenesis. PMID:23901900

  18. The proteasome inhibitor, bortezomib suppresses primary myeloma and stimulates bone formation in myelomatous and nonmyelomatous bones in vivo.

    PubMed

    Pennisi, Angela; Li, Xin; Ling, Wen; Khan, Sharmin; Zangari, Maurizio; Yaccoby, Shmuel

    2009-01-01

    Multiple myeloma (MM), a hematologic malignancy of terminally differentiated plasma cells is closely associated with induction of osteolytic bone disease, induced by stimulation of osteoclastogenesis and suppression of osteoblastogenesis. The ubiquitin-proteasome pathway regulates differentiation of bone cells and MM cell growth. The proteasome inhibitor, bortezomib, is a clinical potent antimyeloma agent. The main goal of this study was to investigate the effect of bortezomib on myeloma-induced bone resorption and tumor growth in SCID-rab mice engrafted with MM cells from 16 patients. Antimyeloma response of bortezomib, which was evident in >50% of 16 experiments and resembled clinical response, was associated with significant increased bone mineral density (BMD) and osteoblast numbers, and reduced osteoclast numbers in myelomatous bones. This bone anabolic effect, which was also visualized on X-ray radiographs and confirmed by static and dynamic histomorphometric analyses, was unique to bortezomib and was not observed in hosts responding to melphalan, a chemotherapeutic drug widely used to treat MM. Bortezomib also increased BMD and osteoblasts number and reduced osteoclasts number in nonmyelomatous implanted bones. In vitro bortezomib directly suppressed human osteoclast formation and promoted maturation of osteoblasts. We conclude that bortezomib promotes bone formation in myelomatous and nonmyelomatous bones by simultaneously inhibiting osteoclastogenesis and stimulating osteoblastogenesis. As clinical and experimental studies indicate that bone disease is both a consequence and necessity of MM progression our results suggest and that bortezomib's effects on bone remodeling contribute to the antimyeloma efficacy of this drug. PMID:18980173

  19. Interleukin-1 receptor antagonist and tumor necrosis factor binding protein decrease osteoclast formation and bone resorption in ovariectomized mice.

    PubMed Central

    Kitazawa, R; Kimble, R B; Vannice, J L; Kung, V T; Pacifici, R

    1994-01-01

    To investigate the contribution of IL-1, IL-6, and TNF to the increased osteoclastogenesis induced by estrogen deficiency, ovariectomized (ovx) mice were treated with either IL-1 receptor antagonist (IL-1ra), a competitive inhibitor of IL-1, TNF binding protein (TNFbp), an inhibitor of TNF, or the anti-IL-6 antibody (Ab) 20F3 for the first 2 wk after surgery. ovx increased the bone marrow cells secretion of IL-1 and TNF, but not IL-6, and the formation of TRAP-positive osteoclast-like multinucleated cells (MNCs) in bone marrow cultures treated with 1,25(OH)2D3. The increase in MNC formation induced by ovx was prevented by in vivo treatment with either 17 beta estradiol, IL-1ra, TNFbp, or anti-IL-6 Ab. However, the percent change in MNC formation induced by the anti-IL-6 Ab was similar in ovx and sham-operated animals, whereas IL-1ra and TNFbp were effective only in ovx mice. MNC formation was also decreased by in vitro treatment of bone marrow cultures with IL-1ra and TNFbp, but not with anti-IL-6 Ab. Ovx also increased bone resorption in vivo and in vitro, as assessed by the urinary excretion of pyridinoline cross links and the formation of resorption pits, respectively. IL-1ra, TNFbp and estrogen decreased bone resorption in vivo and in vitro whereas the anti-IL-6 Ab inhibited bone resorption in vitro but not in vivo. In conclusion, these data indicate that IL-1 and TNF play a direct role in mediating the effects of ovx on osteoclastogenesis and bone resorption. The data also suggest that IL-6 is not essential for increasing bone resorption in the early postovariectomy period. Images PMID:7989596

  20. Annual skeletal balance and metabolic bone marker changes in healthy early postmenopausal women: results of a prospective study.

    PubMed

    Mazzuoli, G; Acca, M; Pisani, D; Diacinti, D; Scarda, A; Scarnecchia, L; Pacitti, M T; D'Erasmo, E; Minisola, S; Bianchi, G; Manfredi, G

    2000-04-01

    The aim of this study was to establish the duration and annual rate of menopause-related bone loss and to investigate the relationship between bone turnover and bone loss in early healthy postmenopausal women. The rate of change in bone mineral density (BMD) at the lumbar spine and in bone turnover was measured twice at the exact interval of 12 months by dual-energy X-ray absorptiometry (DXA) and by the determination of plasma alkaline phosphatase levels (ALP) and fasting urinary hydroxyproline/creatinine ratio (OHPr/Cr), respectively, in 123 healthy premenopausal and postmenopausal women 45-60 years of age. The subjects were divided into nine groups according to their menstrual status and years since menopause (YSM). Annual bone loss at the lumbar spine of women who were menopausal for 1, 2, 3, 4, and 5 years was -2.62 +/- 0.37 (95% confidence interval -3.66, -1.58), -3.87 +/- 0.96 (-6.02, -1.73), -2.50 +/- 0. 37 (-3.29, -1.70), -2.86 +/- 0.73 (-4.44, -1.27), and -1.54 +/- 0.41 (-2.42, -0.66), respectively, and was significantly less than zero. But, the annual bone loss of women who were premenopausal or menopausal for 6, 7, and 8 years was -0.76 +/- 0.60 (-2.04, +0.53), -1.16 +/- 0.68 (-2.61, +0.29), 0.24 +/- 0.48 (-0.78, +1.26), and 0. 16 +/- 0.63 (-1.18, -1.49), respectively, and was not significantly different from zero. These results demonstrate that the early hormone-dependent bone loss commences in the first year after menopause and is arrested within 6 years after the onset of menopause. The overall bone loss for this phase is estimated to be approximately 15%. Annual change in ALP and OHPr/Cr seems to indicate that bone resorption prevails on bone formation in the first 2 YSM, whereas osteoblastic activity relatively prevails from YSM 3 to YSM 5, which explains the progressive repairing of the imbalance between bone resorption and formation. PMID:10719282

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

    USGS Publications Warehouse

    Donahue, S.W.; Vaughan, M.R.; Demers, L.M.; Donahue, H.J.

    2003-01-01

    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 suggest that black bears Ursus americanus do not lose bone mass during hibernation (i.e. disuse). There is also evidence suggesting that muscle mass and strength are preserved in black bears during hibernation. The question of whether bears can prevent bone loss during hibernation has not been conclusively answered. The goal of the current study was to further assess bone metabolism in hibernating black bears. Using the same serum markers of bone remodeling used to evaluate human patients with osteoporosis, we assayed serum from five black bears, collected every 10 days over a 196-day period, for bone resorption and formation markers. Here we show that bone resorption remains elevated over the entire hibernation period compared to the pre-hibernation period, but osteoblastic bone formation is not impaired by hibernation and is rapidly accelerated during remobilization following hibernation.

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

    PubMed Central

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

    2013-01-01

    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

  3. Essential physics of early galaxy formation

    NASA Astrophysics Data System (ADS)

    Dayal, Pratika; Ferrara, Andrea; Dunlop, James S.; Pacucci, Fabio

    2014-12-01

    We present a theoretical model embedding the essential physics of early galaxy formation (z ? 5-12) based on the single premise that any galaxy can form stars with a maximal limiting efficiency that provides enough energy to expel all the remaining gas, quenching further star formation. This simple idea is implemented into a merger-tree-based semi-analytical model that utilizes two mass and redshift-independent parameters to capture the key physics of supernova feedback in ejecting gas from low-mass haloes, and tracks the resulting impact on the subsequent growth of more massive systems via halo mergers and gas accretion. Our model shows that: (i) the smallest haloes (halo mass Mh ? 1010 M?) build up their gas mass by accretion from the intergalactic medium; (ii) the bulk of the gas powering star formation in larger haloes (Mh ? 1011.5 M?) is brought in by merging progenitors; (iii) the faint-end UV luminosity function slope evolves according to ? = -1.75 log z - 0.52. In addition, (iv) the stellar mass-to-light ratio is well fitted by the functional form log M* = -0.38MUV - 0.13 z + 2.4, which we use to build the evolving stellar mass function to compare to observations. We end with a census of the cosmic stellar mass density (SMD) across galaxies with UV magnitudes over the range -23 ? MUV ? -11 spanning redshifts 5 < z < 12; (v) while currently detected LBGs contain ?50 per cent (10 per cent) of the total SMD at z = 5 (8), the James Webb Space Telescope will detect up to 25 per cent of the SMD at z ? 9.5.

  4. Formation and early development of wingtip vortices

    NASA Astrophysics Data System (ADS)

    Giuni, Michea

    Wingtip vortices are extremely important phenomena in fluid dynamics for their negative effects in many applications. Despite the many studies on this particular flow, the current understanding is still poor in providing a form base for the design of effective tip geometry modifications and vortex control devices. A rectangular wing with squared and rounded wingtips was tested in order to identify the main mechanisms involved in the formation of the vortex on the wing and in its early development in the wake. The complementarity of a number of experimental techniques adopted, such as surface flow visualizations, wall pressure measurements, smoke visualizations and stereoscopic particle image velocimetry (SPIV), gave a richer insight of the physics and the basic mechanisms of the vortex development. Furthermore, a large number of configurations were tested exploring the effects of several parameters such as wing chord, aspect ratio, wingtip geometry, angle of attack and Reynolds number. The development of the vortex along the wing showed the formation of several secondary vortices which interacted with the primary vortex generating low frequency fluctuations. The structure of the flow at this stage was analysed introducing a compact description through characteristic lines of the vortex system defined from the velocity vector field in the vicinity of the wing surface. The high spatial resolution achieved by the SPIV arrangement allowed a deeper understanding of the vortex structure in the early wake and the turbulence production and dissipation within the vortex core. The relaminarization process of the vortex core promoted by centrifugal motion was observed. The relation between vortex meandering, turbulence, secondary vortices and wake sheet was discussed. A comparison of different methods for the averaging of instantaneous planar vector fields was performed showing the effects and importance of the meandering. An axial acceleration of the flow within the vortex was observed and the formation of different axial flow distributions was discussed. A minimum wake-like flow of 0.62 and a maximum jet-like flow of 1.7 times the freestream velocity were measured and a linear relation between a vortex circulation parameter and the axial velocity peak was found.

  5. Ibuprofen Administered Pre- or Post- Simulated Resistance Exercise Training Does Not Diminsh Gains in Bone Formation or Bone Mass

    E-print Network

    Cunningham, David

    2012-02-14

    Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to suppress bone formation when administered before, but not if administered after, an acute bout of mechanical load in rats. The NSAID ibuprofen inhibits cyclooxygenase-2 enzyme...

  6. Bone formation in a rat tibial defect model using carboxymethyl cellulose/BioC/bone morphogenic protein-2 hybrid materials.

    PubMed

    Song, Sang-Heon; Yun, Young-Pil; Kim, Hak-Jun; Park, Kyeongsoon; Kim, Sung Eun; Song, Hae-Ryong

    2014-01-01

    The objective of this study was to assess whether carboxymethyl cellulose- (CMC-) based hydrogel containing BioC (biphasic calcium phosphate (BCP); tricalcium phosphate (TCP)?: hydroxyapatite (Hap) = 70 : 30) and bone morphogenic protein-2 (BMP-2) led to greater bone formation than CMC-based hydrogel containing BioC without BMP-2. In order to demonstrate bone formation at 4 and 8 weeks, plain radiographs, microcomputed tomography (micro-CT) evaluation, and histological studies were performed after implantation of all hybrid materials on an 8 mm defect of the right tibia in rats. The plain radiographs and micro-CT analyses revealed that CMC/BioC/BMP-2 (0.5 mg) led to much greater mineralization at 4 and 8 weeks than did CMC/BioC or CMC/Bio/BMP-2 (0.1 mg). Likewise, bone formation and bone remodeling studies revealed that CMC/BioC/BMP-2 (0.5 mg) led to a significantly greater amount of bone formation and bone remodeling at 4 and 8 weeks than did CMC/BioC or CMC/BioC/BMP-2 (0.1 mg). Histological studies revealed that mineralized bone tissue was present around the whole circumference of the defect site with CMC/BioC/BMP-2 (0.5 mg) but not with CMC/BioC or CMC/BioC/BMP-2 (0.1 mg) at 4 and 8 weeks. These results suggest that CMC/BioC/BMP-2 hybrid materials induced greater bone formation than CMC/BioC hybrid materials. Thus, CMC/BioC/BMP-2 hybrid materials may be used as an injectable substrate to regenerate bone defects. PMID:24804202

  7. Association between ultrasonographic findings and bone/cartilage biomarkers in patients with early-stage knee osteoarthritis.

    PubMed

    Kumm, Jaanika; Tamm, Ann; Lintrop, Mare; Tamm, Agu

    2009-12-01

    Little is known regarding the association between ultrasonographic (US) findings and biomarkers of bone and cartilage in individuals with knee osteoarthritis (OA). We investigated (1) US findings in early-stage knee OA and (2) the association between US findings and bone/cartilage biomarkers. A population cohort aged 35-55 years (n = 106) with early-stage knee OA was investigated. US examination was performed according to European League against Rheumatism (EULAR) guidelines using a 7.5-MHz probe. Biomarkers of bone resorption (CTx-I) and formation (PINP), cartilage resorption (U-CTx-II) and synthesis (S-PIIANP), and general bone and cartilage biomarkers (OC, COMP) were assessed. The most prevalent US findings were tendon calcification, synovial thickening, and suprapatellar effusion. In women, the presence of tendon calcification and Baker's cysts could predict 36% of the variability in U-CTx-II levels. The presence of osteophytes and tendon calcification predicted up to 38% of the variability of PIIANP concentration. Defects in subchondral bone, meniscal changes, and effusion predicted up to 29% of the variability in COMP levels. Tendon calcification was related to cartilage synthesis (based on PIIANP levels) in men and to cartilage degradation (based on U-CTx-II concentrations) in women. US signs of synovitis were reflected metabolically by markers of joint tissue metabolism. Tendon calcification, synovial thickening, and effusion were common US findings in early-stage knee OA. US-detectable findings were substantially responsible for the variability in bone and cartilage biomarkers, associations reflective of the active metabolism of soft tissues in early-stage OA. PMID:19862466

  8. In vitro bone formation using muscle-derived cells: a new paradigm for bone tissue engineering using polymer–bone morphogenetic protein matrices

    Microsoft Academic Search

    Helen H. Lu; Michelle D. Kofron; Saadiq F. El-Amin; Mohammed A. Attawia; Cato T. Laurencinb

    2003-01-01

    Over 800,000 bone grafting procedures are performed in the United States annually, creating a demand for viable alternatives to autogenous bone, the grafting standard in osseous repair. The objective of this study was to examine the efficacy of a BMP-polymer matrix in inducing the expression of the osteoblastic phenotype and in vitro bone formation by muscle-derived cells. Specifically, we evaluated

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

    PubMed Central

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

    2013-01-01

    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

  10. Osteocytes as a record of bone formation dynamics: a mathematical model of osteocyte generation in bone matrix.

    PubMed

    Buenzli, Pascal R

    2015-01-01

    The formation of new bone involves both the deposition of bone matrix, and the formation of a network of cells embedded within the bone matrix, called osteocytes. Osteocytes derive from bone-synthesising cells (osteoblasts) that become buried in bone matrix during bone deposition. The generation of osteocytes is a complex process that remains incompletely understood. Whilst osteoblast burial determines the density of osteocytes, the expanding network of osteocytes regulates in turn osteoblast activity and osteoblast burial. In this paper, a spatiotemporal continuous model is proposed to investigate the osteoblast-to-osteocyte transition. The aims of the model are (i) to link dynamic properties of osteocyte generation with properties of the osteocyte network imprinted in bone, and (ii) to investigate Marotti?s hypothesis that osteocytes prompt the burial of osteoblasts when they become covered with sufficient bone matrix. Osteocyte density is assumed in the model to be generated at the moving bone surface by a combination of osteoblast density, matrix secretory rate, rate of entrapment, and curvature of the bone substrate, but is found to be determined solely by the ratio of the instantaneous burial rate and matrix secretory rate. Osteocyte density does not explicitly depend on osteoblast density nor curvature. Osteocyte apoptosis is also included to distinguish between the density of osteocyte lacuna and the density of live osteocytes. Experimental measurements of osteocyte lacuna densities are used to estimate the rate of burial of osteoblasts in bone matrix. These results suggest that: (i) burial rate decreases during osteonal infilling, and (ii) the control of osteoblast burial by osteocytes is likely to emanate as a collective signal from a large group of osteocytes, rather than from the osteocytes closest to the bone deposition front. PMID:25285894

  11. Lanthanum salts improve bone formation in a small animal model of post-menopausal osteoporosis.

    PubMed

    von Rosenberg, S J; Wehr, U A

    2012-10-01

    Two different lanthanum salts, lanthanum carbonate (LaCO(3)) and Lancer(®), a lanthanide citrate mixture, were tested for their effects on bone metabolism in a small animal model for post-menopausal osteoporosis. Forty female outbred Wistar Han rats, sham-operated (SHAM, positive control, n = 10) or ovariectomized (OVX, n = 30) at 4 months of age, were allotted into following groups (n = 10/group): (i) SHAM, (ii) OVX control (negative control), (iii) OVX + LaCO(3) (1.74 g/kg feed) and (iv) OVX + Lancer(®) (8 g/kg feed). Effects on bone were investigated by bone markers [osteocalcin (Oc) in serum and excretion of pyridinoline (PYD) in urine] and by physical parameters of bone structure and bone composition (bone mass, calcium, phosphorus and magnesium content in bone crude ash). Bone micro-architecture and bone mineral density were evaluated by peripheral quantitative computed tomography and micro-computed tomography (?CT). The animal model could be validated by differences between OVX control and SHAM. Body mass and feed intake were the same among the four groups. Oc was clearly increased in the two experimental groups (p < 0.001) vs. SHAM and OVX control. Bone mass and calcium content in bone ash were significantly higher than in OVX control. The Ca/P ratio in bone ash of the two lanthanide groups did not differ from SHAM. Bone-protecting effects of lanthanides were clearly demonstrated by an increased trabecular density which is the region of interest for osteoporotic bone loss. A 3D imaging of bone micro-architecture by ?CT visualized descriptively the positive effects of lanthanides on bone formation. The results of this study demonstrate an improvement of bone formation and bone-protecting effects of lanthanides in the OVX rat. Thus, lanthanum salts suggest a prevention of post-menopausal bone loss and may be of benefit in experimental osteopenia following ovariectomy. PMID:22845174

  12. Type XII collagen regulates osteoblast polarity and communication during bone formation

    PubMed Central

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

    2011-01-01

    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

  13. Dexamethasone Enhances Osteogenic Differentiation of Bone Marrow- and Muscle-Derived Stromal Cells and Augments Ectopic Bone Formation Induced by Bone Morphogenetic Protein-2

    PubMed Central

    Yuasa, Masato; Yamada, Tsuyoshi; Taniyama, Takashi; Masaoka, Tomokazu; Xuetao, Wei; Yoshii, Toshitaka; Horie, Masaki; Yasuda, Hiroaki; Uemura, Toshimasa; Okawa, Atsushi; Sotome, Shinichi

    2015-01-01

    We evaluated whether dexamethasone augments the osteogenic capability of bone marrow-derived stromal cells (BMSCs) and muscle tissue-derived stromal cells (MuSCs), both of which are thought to contribute to ectopic bone formation induced by bone morphogenetic protein-2 (BMP-2), and determined the underlying mechanisms. Rat BMSCs and MuSCs were cultured in growth media with or without 10-7 M dexamethasone and then differentiated under osteogenic conditions with dexamethasone and BMP-2. The effects of dexamethasone on cell proliferation and osteogenic differentiation, and also on ectopic bone formation induced by BMP-2, were analyzed. Dexamethasone affected not only the proliferation rate but also the subpopulation composition of BMSCs and MuSCs, and subsequently augmented their osteogenic capacity during osteogenic differentiation. During osteogenic induction by BMP-2, dexamethasone also markedly affected cell proliferation in both BMSCs and MuSCs. In an in vivo ectopic bone formation model, bone formation in muscle-implanted scaffolds containing dexamethasone and BMP-2 was more than two fold higher than that in scaffolds containing BMP-2 alone. Our results suggest that dexamethasone potently enhances the osteogenic capability of BMP-2 and may thus decrease the quantity of BMP-2 required for clinical application, thereby reducing the complications caused by excessive doses of BMP-2. Highlights: 1. Dexamethasone induced selective proliferation of bone marrow- and muscle-derived cells with higher differentiation potential. 2. Dexamethasone enhanced the osteogenic capability of bone marrow- and muscle-derived cells by altering the subpopulation composition. 3. Dexamethasone augmented ectopic bone formation induced by bone morphogenetic protein-2. PMID:25659106

  14. 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

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

    2014-01-01

    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. PMID:25429218

  15. Epigenetic regulation of Tbx18 gene expression during endochondral bone formation.

    PubMed

    Haraguchi, Ryuma; Kitazawa, Riko; Kitazawa, Sohei

    2015-02-01

    Endochondral bone formation is tightly regulated by the spatial and sequential expression of a series of transcription factors. To disclose the roles of TBX18, a member of the T-box transcription factor family, during endochondral bone formation, its spatial and temporal expression patterns were characterized in the limb skeletal region of the developing mouse together with those of established osteochondrogenic markers Sox9, Col2a1, and Runx2. TBX18 expression first appeared in condensed mesenchymal cells (chondro-progenitors) in embryonic-day-10.5 (E10.5) limb bud and was co-localized with Sox9 expression, whereas at E11.5 and E12.5, it became undetectable in mesenchymal cells committed to the chondrocyte lineage. From E13.5 to E18.5, TBX18 expression reappeared in chondrocytes, correlating strongly with Col2a1 expression; furthermore, low level TBX18 expression was found in the Runx2-positive perichondral osteoblastic cell lineage. At the postnatal stage, TBX18 expression was observed in epiphyseal chondrocytes and osteocytes within the lacunae of mature trabecular bone. On the assumption that such characteristic Tbx18 gene expression is epigenetically regulated during mouse limb development, we examined the methylation status of the CpG-island in the mouse Tbx18 gene by methylation-specific polymerase chain reaction. Hypermethylation of the Tbx18 gene promoter became evident at an early embryonic stage in TBX18-negative cells and then disappeared at a late embryonic stage in TBX18-positive cells. Therefore, the temporal suppression of Tbx18 gene expression by the hypermethylation of its promoter seems to trigger the differentiation of mesenchymal cells into hypertrophic chondrocytes in the early stages of endochondral ossification. PMID:25380565

  16. Time since onset of walking predicts tibial bone strength in early childhood.

    PubMed

    Ireland, Alex; Rittweger, Jörn; Schönau, Eckhard; Lamberg-Allardt, Christel; Viljakainen, Heli

    2014-11-01

    Bone strength in adulthood is known to be affected by health at birth and early childhood. Habitual bone loading is a primary determinant of bone strength in later childhood and adulthood. However, the effects of physical activity in early childhood (e.g. crawling, standing and walking) on bone strength are unknown. Fifty-three children (twenty-seven males) were included in a longitudinal study in their early infancy. Shortly after birth (0.3±0.3months), details of mass and height were obtained along with a pQCT scan at 20% distal-proximal tibia length. At 14.8±0.5months of age the same data were collected, along with details of age at onset of standing, crawling, supported and unsupported walking. Time since onset of walking unsupported was associated with greater bone mass, cortical bone area, pericortical circumference and polar moment of inertia of both total and cortical bone (all P<0.05). There were no significant associations between other physical activity timepoints and bone measures. Age at onset of walking was not significantly related to mass, length or bone measures at birth. The results suggest that time since attainment of independent walking - representing exposure of the tibia to the large reaction and muscular forces associated with locomotion - is a primary determinant of bone strength in early childhood. This finding raises the possible opportunity of physical activity interventions at young age in paediatric populations associated with low childhood bone strength and late walking (e.g. low birth weight, cerebral palsy and Down's Syndrome, etc.). PMID:25132490

  17. Hydroxyapatite grafting promotes new bone formation and osseointegration of smooth titanium implants

    Microsoft Academic Search

    Sergio Allegrini; Elisabeth Rumpel; Ellen Kauschke; Jochen Fanghänel; Bruno König

    2006-01-01

    Summary Titanium is the ideal metal for intra-osseous dental implants. It permits the natural formation of an oxide layer on its surface and thereby it prevents the release of potentially toxic molecules. New formation of bone around implants, partially placed into the bone marrow cavity, is a gradual process that runs from the endosteum to the surface of the implant.

  18. Programmed administration of parathyroid hormone increases bone formation and reduces bone loss in hindlimb-unloaded ovariectomized rats

    NASA Technical Reports Server (NTRS)

    Turner, R. T.; Evans, G. L.; Cavolina, J. M.; Halloran, B.; Morey-Holton, E.

    1998-01-01

    Gonadal insufficiency and reduced mechanical usage are two important risk factors for osteoporosis. The beneficial effects of PTH therapy to reverse the estrogen deficiency-induced bone loss in the laboratory rat are well known, but the influence of mechanical usage in this response has not been established. In this study, the effects of programed administration of PTH on cancellous bone volume and turnover at the proximal tibial metaphysis were determined in hindlimb-unloaded, ovariectomized (OVX), 3-month-old Sprague-Dawley rats. PTH was administered to weight-bearing and hindlimb-unloaded OVX rats with osmotic pumps programed to deliver 20 microg human PTH (approximately 80 microg/kg x day) during a daily 1-h infusion for 7 days. Compared with sham-operated rats, OVX increased longitudinal and radial bone growth, increased indexes of cancellous bone turnover, and resulted in net resorption of cancellous bone. Hindlimb unloading of OVX rats decreased longitudinal and radial bone growth, decreased osteoblast number, increased osteoclast number, and resulted in a further decrease in cancellous bone volume compared with those in weight-bearing OVX rats. Programed administration of PTH had no effect on either radial or longitudinal bone growth in weight-bearing and hindlimb-unloaded OVX rats. PTH treatment had dramatic effects on selected cancellous bone measurements; PTH maintained cancellous bone volume in OVX weight-bearing rats and greatly reduced cancellous bone loss in OVX hindlimb-unloaded rats. In the latter animals, PTH treatment prevented the hindlimb unloading-induced reduction in trabecular thickness, but the hormone was ineffective in preventing either the increase in osteoclast number or the loss of trabecular plates. Importantly, PTH treatment increased the retention of a baseline flurochrome label, osteoblast number, and bone formation in the proximal tibial metaphysis regardless of the level of mechanical usage. These findings demonstrate that programed administration of PTH is effective in increasing osteoblast number and bone formation and has beneficial effects on bone volume in the absence of weight-bearing and gonadal hormones. We conclude that the actions of PTH on cancellous bone are independent of the level of mechanical usage.

  19. Feeding blueberry diets during early development is sufficient to prevent senescence of osteoblasts and bone loss in adulthood

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Appropriate nutrition during early development is essential for optimal bone mass accretion; however, linkage between early nutrition, childhood bone mass and prevention of bone loss later in life has not been extensively studied. In this report, we show that feeding a high quality diet supplemented...

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

    PubMed Central

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

    2013-01-01

    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

  1. Two models of early weaning decreases bone structure by different changes in hormonal regulation of bone metabolism in neonate rat.

    PubMed

    de Albuquerque Maia, L; Lisboa, P C; de Oliveira, E; da Silva Lima, N; da Costa, C A S; de Moura, E G

    2013-05-01

    During the last decade a great concern has developed for determining what factors influence bone mineral accretion in healthy children. Mother's milk represents the primary source of calcium and other nutrients in the neonate. The development of bone and adipose tissue has common origins. Since early weaning decreases adipogenesis in neonate, our aim was to evaluate bone metabolism in 2 models of early weaning (EW) in neonate rats. Lactating rats were separated into 3 groups: control: pups had free access to milk; MEW: dams were involved with a bandage mechanically (M) interrupting lactation in the last 3 days; and PEW: dams were pharmacologically (P) treated to block prolactin (0.5 mg bromocryptine/twice a day) 3 days before standard weaning. Significant difference had p<0.05. At weaning, MEW and PEW pups presented lower body weight (-18% and -15%), total body fat (-26% and -27%), total bone mineral density (-7% and -6%), total bone mineral content (-30% and -32%), bone area (-28% and -30%), serum osteocalcin (-20% and -55%), and higher C-terminal cross-linked telopeptide of type I collagen (CTX-I) (1.3 and 1.1-fold increase). However, serum ionized calcium was lower only in MEW pups (-34%), 25-hydroxyvitamin D was higher (1.4-fold increase), and PTH was lower (-26%) only in PEW group. The present study shows that both early weaning models leads to an impairment of osteogenesis associated with lower adipogenesis by different mechanisms, involving mainly changes in vitamin D and PTH. PMID:23264036

  2. Bone particles disturb new bone formation on the interface of the titanium implant after reaming of the marrow cavity

    Microsoft Academic Search

    M. Ishizaka; T. Tanizawa; M. Sofue; Y. Dohmae; N. Endo; H. E. Takahashi

    1996-01-01

    Histomorphometric studies were conducted in rats to determine whether bone particles would disturb new bone formation on the interface of titanium implants inserted after reaming of the marrow cavity. In eighty 10-week-old female Wistar rats, smooth-surfaced titanium alloy implants were inserted bilaterally into the marrow cavity after reaming in the distal femur. There were three experimental groups: in the irrigated

  3. Fresh-frozen human bone allograft in vertical ridge augmentation: clinical and tomographic evaluation of bone formation and resorption

    Microsoft Academic Search

    Luis Guilherme Scavone Macedo; Luiz Antonio Mazzucchelli-Cosmo; Nelson Luiz Macedo; Adriana Socorro Ferreira Monteiro; Wilson Roberto Sendyk

    The aim of the current study is to evaluate fresh-frozen human bone allografts (FHBAs) used in vertical ridge augmentation\\u000a clinically and by computed tomography, and to analyze the resulting bone formation and graft resorption. Sixteen FHBAs were\\u000a grafted in the maxillae and mandibles of 9 patients. The FHBAs, which were provided by the Musculoskeletal Tissue Bank of\\u000a Marilia Hospital (Unioss),

  4. Bone marrow-derived osteoblast progenitor cells in circulating blood contribute to ectopic bone formation in mice

    SciTech Connect

    Otsuru, Satoru [Division of Gene Therapy Science, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871 (Japan); Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871 (Japan); Tamai, Katsuto [Division of Gene Therapy Science, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871 (Japan)]. E-mail: tamai@gts.med.osaka-u.ac.jp; Yamazaki, Takehiko [Division of Gene Therapy Science, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871 (Japan); Yoshikawa, Hideki [Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871 (Japan); Kaneda, Yasufumi [Division of Gene Therapy Science, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871 (Japan)

    2007-03-09

    Recent studies have suggested the existence of osteoblastic cells in the circulation, but the origin and role of these cells in vivo are not clear. Here, we examined how these cells contribute to osteogenesis in a bone morphogenetic protein (BMP)-induced model of ectopic bone formation. Following lethal dose-irradiation and subsequent green fluorescent protein-transgenic bone marrow cell-transplantation (GFP-BMT) in mice, a BMP-2-containing collagen pellet was implanted into muscle. Three weeks later, a significant number of GFP-positive osteoblastic cells were present in the newly generated ectopic bone. Moreover, peripheral blood mononuclear cells (PBMNCs) from the BMP-2-implanted mouse were then shown to include osteoblast progenitor cells (OPCs) in culture. Passive transfer of the PBMNCs isolated from the BMP-2-implanted GFP-mouse to the BMP-2-implanted nude mouse led to GFP-positive osteoblast accumulation in the ectopic bone. These data provide new insight into the mechanism of ectopic bone formation involving bone marrow-derived OPCs in circulating blood.

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

    SciTech Connect

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

    1991-08-01

    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.

  6. Poly(vinylidene-trifluoroethylene)/barium titanate composite for in vivo support of bone formation.

    PubMed

    Lopes, Helena B; Santos, Thiago de S; de Oliveira, Fabiola S; Freitas, Gileade P; de Almeida, Adriana Lg; Gimenes, Rossano; Rosa, Adalberto L; Beloti, Marcio M

    2013-12-01

    In this study, we evaluated the effect of poly(vinylidene fluoride-trifluoroethylene)/barium titanate (P(VDF-TrFE)/BT) membrane on in vivo bone formation. Rat calvarial bone defects were implanted with P(VDF-TrFE)/BT and polytetrafluoroethylene (PTFE) membranes, and at 4 and 8 weeks, histomorphometric and gene expression analyses were performed. A higher amount of bone formation was noticed on P(VDF-TrFE)/BT compared with PTFE. The gene expression of RUNX2, bone sialoprotein, osteocalcin, receptor activator of nuclear factor-kappa B ligand, and osteoprotegerin indicates that P(VDF-TrFE)/BT favored the osteoblast differentiation compared with PTFE. These results evidenced the benefits of using P(VDF-TrFE)/BT to promote new bone formation, which may represent a promising alternative to be employed in guided bone regeneration. PMID:24319054

  7. Endochondral bone formation in gelatin methacrylamide hydrogel with embedded cartilage-derived matrix particles.

    PubMed

    Visser, Jetze; Gawlitta, Debby; Benders, Kim E M; Toma, Selynda M H; Pouran, Behdad; van Weeren, P René; Dhert, Wouter J A; Malda, Jos

    2015-01-01

    The natural process of endochondral bone formation in the growing skeletal system is increasingly inspiring the field of bone tissue engineering. However, in order to create relevant-size bone grafts, a cell carrier is required that ensures a high diffusion rate and facilitates matrix formation, balanced by its degradation. Therefore, we set out to engineer endochondral bone in gelatin methacrylamide (GelMA) hydrogels with embedded multipotent stromal cells (MSCs) and cartilage-derived matrix (CDM) particles. CDM particles were found to stimulate the formation of a cartilage template by MSCs in the GelMA hydrogel in vitro. In a subcutaneous rat model, this template was subsequently remodeled into mineralized bone tissue, including bone-marrow cavities. The GelMA was almost fully degraded during this process. There was no significant difference in the degree of calcification in GelMA with or without CDM particles: 42.5 ± 2.5% vs. 39.5 ± 8.3% (mean ± standard deviation), respectively. Interestingly, in an osteochondral setting, the presence of chondrocytes in one half of the constructs fully impeded bone formation in the other half by MSCs. This work offers a new avenue for the engineering of relevant-size bone grafts, by the formation of endochondral bone within a degradable hydrogel. PMID:25453948

  8. Osteostatin-loaded onto mesoporous ceramics improves the early phase of bone regeneration in a rabbit osteopenia model.

    PubMed

    Lozano, Daniel; Trejo, Cynthia G; Gómez-Barrena, Enrique; Manzano, Miguel; Doadrio, Juan C; Salinas, Antonio J; Vallet-Regí, María; García-Honduvilla, Natalio; Esbrit, Pedro; Buján, Julia

    2012-07-01

    Parathyroid hormone-related protein (PTHrP) is an important modulator of bone formation. Recently, we reported that PTHrP (107-111) (osteostatin) coating onto mesoporous ceramics confers osteogenic activity to these materials. Bone repair is dramatically compromised in osteopenia/osteoporosis. Thus, we examined the efficacy of unmodified and organically modified SBA15 ceramics loaded with osteostatin in promoting bone repair in an osteoporotic rabbit model. Osteoporosis was induced in New Zealand rabbits by methylprednisolone administration, and healthy rabbits were used as controls. Tested materials were implanted into a femoral cavitary defect, and animals were sacrificed at 2 weeks post-implantation. At this time, implants were encapsulated by a variable layer of fibrotic tissue with no evidence of inflammation. Similarly to observations in normal rabbits, both types of osteostatin-loaded bioceramics induced tissue regeneration associated with increased staining for PCNA, Runx2, osteopontin, and/or vascular endothelial growth factor in osteoporotic rabbits. Our present findings demonstrate that these osteostatin-bearing bioceramics increase the early repair response not only in normal bone but also in osteoporotic bone after a local injury. PMID:22414621

  9. Constitutive E2F1 Overexpression Delays Endochondral Bone Formation by Inhibiting Chondrocyte Differentiation

    PubMed Central

    Scheijen, Blanca; Bronk, Marieke; van der Meer, Tiffany; Bernards, René

    2003-01-01

    Longitudinal bone growth results from endochondral ossification, a process that requires proliferation and differentiation of chondrocytes. It has been shown that proper endochondral bone formation is critically dependent on the retinoblastoma family members p107 and p130. However, the precise functional roles played by individual E2F proteins remain poorly understood. Using both constitutive and conditional E2F1 transgenic mice, we show that ubiquitous transgene-driven expression of E2F1 during embryonic development results in a dwarf phenotype and significantly reduced postnatal viability. Overexpression of E2F1 disturbs chondrocyte maturation, resulting in delayed endochondral ossification, which is characterized by reduced hypertrophic zones and disorganized growth plates. Employing the chondrogenic cell line ATDC5, we investigated the effects of enforced E2F expression on the different phases of chondrocyte maturation that are normally required for endochondral ossification. Ectopic E2F1 expression strongly inhibits early- and late-phase differentiation of ATDC5 cells, accompanied by diminished cartilage nodule formation as well as decreased type II collagen, type X collagen, and aggrecan gene expression. In contrast, overexpression of E2F2 or E2F3a results in only a marginal delay of chondrocyte maturation, and increased E2F4 levels have no effect. These data are consistent with the notion that E2F1 is a regulator of chondrocyte differentiation. PMID:12724423

  10. Effects of dietary DHA and ?-tocopherol on bone development, early mineralisation and oxidative stress in Sparus aurata (Linnaeus, 1758) larvae.

    PubMed

    Izquierdo, M S; Scolamacchia, M; Betancor, M; Roo, J; Caballero, M J; Terova, G; Witten, P E

    2013-05-28

    DHA deficiency has been related to skeletal malformations in fish, but high DHA levels have produced controversial results that could relate to the oxidative status of fish tissues in the different reports. In the present study, gilthead seabream (Sparus aurata) larvae were fed deficient, adequate or high DHA levels, or high DHA levels supplemented with the antioxidant ?-tocopherol. Larvae fed deficient DHA levels tended to be smaller, and showed the highest incidence of urinary bladder calculi, lordosis and kyphosis and the lowest number of mineralised vertebrae for any given size class. Elevation of dietary DHA increased larval growth and significantly enhanced the expression of the insulin-like growth factor 1 (IGF-1) gene. However, a DHA level increase up to 5 % raised the degree of lipid oxidation in larval tissues and deformities in cranial endochondral bones and in axial skeletal haemal and neural arches. The increase in dietary ?-tocopherol supplementation in high-DHA feeds reduced again the occurrence of skeletal deformities. Moreover, the expression of genes coding for specific antioxidants such as catalase, superoxide dismutase or glutathione peroxidase, which neutralised reactive oxygen substances formed by increased dietary DHA, was significantly decreased in larvae fed high ?-tocopherol levels. These results denoted the importance of DHA for early bone formation and mineralisation. Low dietary DHA levels delay early mineralisation and increase the risk of cranial and axial skeletal deformities. Excessive DHA levels, without an adequate balance of antioxidant nutrients, increase the production of free radicals damaging cartilaginous structures before bone formation. PMID:23046500

  11. Directly auto-transplanted mesenchymal stem cells induce bone formation in a ceramic bone substitute in an ectopic sheep model

    PubMed Central

    Boos, Anja M; Loew, Johanna S; Deschler, Gloria; Arkudas, Andreas; Bleiziffer, Oliver; Gulle, Heinz; Dragu, Adrian; Kneser, Ulrich; Horch, Raymund E; Beier, Justus P

    2011-01-01

    Abstract Bone tissue engineering approaches increasingly focus on the use of mesenchymal stem cells (MSC). In most animal transplantation models MSC are isolated and expanded before auto cell transplantation which might be critical for clinical application in the future. Hence this study compares the potential of directly auto-transplanted versus in vitro expanded MSC with or without bone morphogenetic protein-2 (BMP-2) to induce bone formation in a large volume ceramic bone substitute in the sheep model. MSC were isolated from bone marrow aspirates and directly auto-transplanted or expanded in vitro and characterized using fluorescence activated cell sorting (FACS) and RT-PCR analysis before subcutaneous implantation in combination with BMP-2 and ?-tricalcium phosphate/hydroxyapatite (?-TCP/HA) granules. Constructs were explanted after 1 to 12 weeks followed by histological and RT-PCR evaluation. Sheep MSC were CD29+, CD44+ and CD166+ after selection by Ficoll gradient centrifugation, while directly auto-transplanted MSC-populations expressed CD29 and CD166 at lower levels. Both, directly auto-transplanted and expanded MSC, were constantly proliferating and had a decreasing apoptosis over time in vivo. Directly auto-transplanted MSC led to de novo bone formation in a heterotopic sheep model using a ?-TCP/HA matrix comparable to the application of 60 ?g/ml BMP-2 only or implantation of expanded MSC. Bone matrix proteins were up-regulated in constructs following direct auto-transplantation and in expanded MSC as well as in BMP-2 constructs. Up-regulation was detected using immunohistology methods and RT-PCR. Dense vascularization was demonstrated by CD31 immunohistology staining in all three groups. Ectopic bone could be generated using directly auto-transplanted or expanded MSC with ?-TCP/HA granules alone. Hence BMP-2 stimulation might become dispensable in the future, thus providing an attractive, clinically feasible approach to bone tissue engineering. PMID:20636333

  12. Directly auto-transplanted mesenchymal stem cells induce bone formation in a ceramic bone substitute in an ectopic sheep model.

    PubMed

    Boos, Anja M; Loew, Johanna S; Deschler, Gloria; Arkudas, Andreas; Bleiziffer, Oliver; Gulle, Heinz; Dragu, Adrian; Kneser, Ulrich; Horch, Raymund E; Beier, Justus P

    2011-06-01

    Bone tissue engineering approaches increasingly focus on the use of mesenchymal stem cells (MSC). In most animal transplantation models MSC are isolated and expanded before auto cell transplantation which might be critical for clinical application in the future. Hence this study compares the potential of directly auto-transplanted versus in vitro expanded MSC with or without bone morphogenetic protein-2 (BMP-2) to induce bone formation in a large volume ceramic bone substitute in the sheep model. MSC were isolated from bone marrow aspirates and directly auto-transplanted or expanded in vitro and characterized using fluorescence activated cell sorting (FACS) and RT-PCR analysis before subcutaneous implantation in combination with BMP-2 and ?-tricalcium phosphate/hydroxyapatite (?-TCP/HA) granules. Constructs were explanted after 1 to 12 weeks followed by histological and RT-PCR evaluation. Sheep MSC were CD29(+), CD44(+) and CD166(+) after selection by Ficoll gradient centrifugation, while directly auto-transplanted MSC-populations expressed CD29 and CD166 at lower levels. Both, directly auto-transplanted and expanded MSC, were constantly proliferating and had a decreasing apoptosis over time in vivo. Directly auto-transplanted MSC led to de novo bone formation in a heterotopic sheep model using a ?-TCP/HA matrix comparable to the application of 60 ?g/ml BMP-2 only or implantation of expanded MSC. Bone matrix proteins were up-regulated in constructs following direct auto-transplantation and in expanded MSC as well as in BMP-2 constructs. Up-regulation was detected using immunohistology methods and RT-PCR. Dense vascularization was demonstrated by CD31 immunohistology staining in all three groups. Ectopic bone could be generated using directly auto-transplanted or expanded MSC with ?-TCP/HA granules alone. Hence BMP-2 stimulation might become dispensable in the future, thus providing an attractive, clinically feasible approach to bone tissue engineering. PMID:20636333

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

    Microsoft Academic Search

    Ego Seeman

    2003-01-01

    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

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

    PubMed

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

    2013-10-15

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

  15. Activation of the Acquired Immune Response Reduces Coupled Bone Formation in Response to a Periodontal Pathogen

    PubMed Central

    Behl, Yugal; Siquiera, Michelle; Ortiz, Javier; Desta, Tesfahun; Faibish, Dan; Graves, Dana T.

    2009-01-01

    Osteoimmunology involves the interaction of the immune system with skeletal elements. This interaction can lead to the formation of osseous lesions. To investigate how the acquired immune response could contribute to osteolytic lesions we injected the periodontal pathogen Porphyromonas gingivalis adjacent to calvarial bone with or without prior immunization against the bacterium. Activation of the acquired immune response increased osteoclastogenesis and decreased coupled bone formation. The latter was accompanied by an increase in nuclear translocation of the transcription factor FOXO1 in vivo, increased apoptosis of bone-lining cells and a decrease in bone lining cell density. Further studies were carried out with MC3T3 osteoblastic cells. Apoptosis and increased FOXO1 DNA binding activity were induced when a combination of cytokines was tested, IL-?, TNF-?, and IFN-?. Knockdown of FOXO1 by siRNA significantly reduced cytokine stimulated apoptosis, cleaved caspase-3/7 activity and decreased mRNA levels of the proapoptotic genes, TNF-?, FADD, caspase-3, -8 and -9. These results indicate that activation of the acquired immunity by a periodontal pathogen reduces the coupling of bone formation and resorption. This may occur by enhancing bone lining cell apoptosis through a mechanism that involves increased FOXO1 activation. These studies give insight into inflammatory bone diseases such as periodontal disease and arthritis were the formation of lytic lesions occurs in conjunction with deficient bone formation and activation of an acquired immune response. PMID:19050291

  16. CER1 gene variations associated with bone mineral density, bone markers, and early menopause in postmenopausal women

    PubMed Central

    2013-01-01

    Background Osteoporosis has a multifactorial pathogenesis characterized by a combination of low bone mass and increased fragility. In our study, we focused on the effects of polymorphisms in CER1 and DKK1 genes, recently reported as important susceptibility genes for osteoporosis, on bone mineral density (BMD) and bone markers in osteoporotic women. Our objective was to evaluate the effect of CER1 and DKK1 variations in 607 postmenopausal women. The entire DKK1 gene sequence and five selected CER1 SNPs were amplified and resequenced to assess whether there is a correlation between these genes and BMD, early menopause, and bone turnover markers in osteoporotic patients. Results Osteoporotic women seem to suffer menopause 2 years earlier than the control group. The entire DKK1 gene sequence analysis revealed six variations. There was no correlation between the six DKK1 variations and osteoporosis, in contrast to the five common CER1 variations that were significantly associated with BMD. Additionally, osteoporotic patients with rs3747532 and rs7022304 CER1 variations had significantly higher serum levels of parathyroid hormone and calcitonin and lower serum levels of osteocalcin and IGF-1. Conclusions No significant association between the studied DKK1 variations and osteoporosis was found, while CER1 variations seem to play a significant role in the determination of osteoporosis and a potential predictive role, combined with bone markers, in postmenopausal osteoporotic women. PMID:24138842

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

    PubMed

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

    2006-05-01

    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

  18. Tricalcium phosphate/hydroxyapatite (TCP-HA) bone scaffold as potential candidate for the formation of tissue engineered bone

    PubMed Central

    Sulaiman, Shamsul Bin; Keong, Tan Kok; Cheng, Chen Hui; Saim, Aminuddin Bin; Idrus, Ruszymah Bt. Hj

    2013-01-01

    Background & objectives: Various materials have been used as scaffolds to suit different demands in tissue engineering. One of the most important criteria is that the scaffold must be biocompatible. This study was carried out to investigate the potential of HA or TCP/HA scaffold seeded with osteogenic induced sheep marrow cells (SMCs) for bone tissue engineering. Methods: HA-SMC and TCP/HA-SMC constructs were induced in the osteogenic medium for three weeks prior to implantation in nude mice. The HA-SMC and TCP/HA-SMC constructs were implanted subcutaneously on the dorsum of nude mice on each side of the midline. These constructs were harvested after 8 wk of implantation. Constructs before and after implantation were analyzed through histological staining, scanning electron microscope (SEM) and gene expression analysis. Results: The HA-SMC constructs demonstrated minimal bone formation. TCP/HA-SMC construct showed bone formation eight weeks after implantation. The bone formation started on the surface of the ceramic and proceeded to the centre of the pores. H&E and Alizarin Red staining demonstrated new bone tissue. Gene expression of collagen type 1 increased significantly for both constructs, but more superior for TCP/HA-SMC. SEM results showed the formation of thick collagen fibers encapsulating TCP/HA-SMC more than HA-SMC. Cells attached to both constructs surface proliferated and secreted collagen fibers. Interpretation & conclusions: The findings suggest that TCP/HA-SMC constructs with better osteogenic potential compared to HA-SMC constructs can be a potential candidate for the formation of tissue engineered bone. PMID:23852290

  19. Principles of bone formation driven by biophysical forces in craniofacial surgery.

    PubMed

    Meyer, U; Kruse-Lösler, B; Wiesmann, H P

    2006-08-01

    Biophysical forces, particularly mechanical loading and electromagnetic signals, are important regulators of bone formation. Indeed, the regenerative capacity of bony tissue is largely the result of the bone's capacity to recognise the functional environment required for the emergence and maintenance of a structurally intact bone. Biophysical methods of stimulation have therefore been introduced and have proved successful in clinical practice with craniofacial bones. Distraction osteogenesis, application of ultrasound, calculated transfer of stresses, and exposure to an electromagnetic field are some examples of biophysically driven approaches to influencing bone formation. The purpose of this review is to provide an insight into cellular and tissue models that are used to study the effects of biophysical stimuli on bone. PMID:16162373

  20. DETERMINANTS OF BONE CALCIUM ACCRETION DURING EARLY ADOLESCENCE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bone mineral status during adolescence may be related to genetic and dietary factors. We evaluated 49 female and 49 male adolescents (Tanner 2/3) randomized to receive 8g of Synergl (Orafti Inc., Belgium), a non-digestible inulin-type fructan daily for a year or placebo. Fractional calcium (Ca) abso...

  1. Paget's disease of bone in early adult life

    PubMed Central

    Holgado, S; Rotes, D; Guma, M; Monfort, J; Olive, A; Carbonell, J; Tena, X

    2005-01-01

    Methods: A retrospective two centre study of 314 patients with Paget's disease of bone from two university hospitals. The disease was diagnosed by radiological, serum alkaline phosphatase (AP) levels, or clinical features, and bone scintigraphy in most patients. Demographic data, reason for diagnosis, bones affected, disease extent using Coutris' index, complications during progression, and disease activity using Renier's index were assessed. Patients over and under 40 were compared. Results: 18/314 (5.7%) patients were diagnosed before the age of 40; median (SD) age was 35.4 (5.5) (range 18–40) and AP 555.6 (566.3) IU/l (range 70–1949). Coutris' extension index was 12.8 (10.5) and Renier's activity index 35.9 (31.9). Younger patients had more affected bones (p<0.05) than those aged >40, higher level of extension (p<0.05), higher AP value (p = 0.05), and greater incidence of thoracolumbar spine disease. Disease activity did not differ significantly between the groups. Conclusions: Paget's disease diagnosed before the age of 40 is more extensive but not more active, with higher AP values than in those diagnosed after age 40. PMID:15647439

  2. Cannabinoids Stimulate Fibroblastic Colony Formation by Bone Marrow Cells Indirectly via CB 2 Receptors

    Microsoft Academic Search

    A. Scutt; E. M. Williamson

    2007-01-01

    Recently, the cannabinoid receptors CB1 and CB2 were shown to modulate bone formation and resorption in vivo, although little is known of the mechanisms underlying this. The effects of cannabinoids on mesenchymal stem cell (MSC) recruitment\\u000a in whole bone marrow were investigated using either the fibroblastic colony-forming unit (CFU-f) assay or high-density cultures\\u000a of whole bone marrow. Levels of the

  3. Formation of biologically active bone-like apatite on metals and polymers by a biomimetic process

    Microsoft Academic Search

    T. Kokubo

    1996-01-01

    Some ceramics bond to living bone through a bone-like apatite layer which is formed on their surfaces in the living body. The formation of the apatite layer is induced by Si?OH or Ti?OH groups on their surfaces. These findings provide us with a biomimetic process with which to form a bone-like apatite layer on metals and organic polymers. Titanium metal

  4. Aminobisphosphonates Cause Osteoblast Apoptosis and Inhibit Bone Nodule Formation In Vitro

    Microsoft Academic Search

    Aymen I. Idris; Javier Rojas; Iain R. Greig; Rob J. van’t Hof; Stuart H. Ralston

    2008-01-01

    Bisphosphonates are widely used for the treatment of bone diseases associated with increased osteoclastic bone resorption.\\u000a Bisphosphonates are known to inhibit biochemical markers of bone formation in vivo, but it is unclear to what extent this\\u000a is a consequence of osteoclast inhibition or a direct inhibitory effect on cells of the osteoblast lineage. In order to investigate\\u000a this issue, we

  5. Joint Loading Modality: Its Application to Bone Formation and Fracture Healing

    PubMed Central

    Zhang, Ping; Malacinski, George M.; Yokota, Hiroki

    2010-01-01

    Sports related injuries such as impact and stress fractures often require a rehabilitation program to stimulate bone formation and accelerate fracture healing. This review introduces a recently developed joint loading modality and evaluates its potential applications to bone formation and fracture healing in post-injury rehabilitation. Bone is a dynamic tissue whose structure is constantly altered in response to its mechanical environments. Indeed, many loading modalities can influence the bone remodeling process. The joint loading modality is, however, able to enhance anabolic responses and accelerate wound healing without inducing significant in situ strain at the site of bone formation or fracture healing. This review highlights the unique features of this loading modality and discusses its potential underlying mechanisms as well as possible clinical applications. PMID:18048437

  6. Suppressive effects of Anoectochilus formosanus extract on osteoclast formation in vitro and bone resorption in vivo.

    PubMed

    Masuda, Kikuko; Ikeuchi, Mayumi; Koyama, Tomoyuki; Yamaguchi, Kohji; Woo, Je-Tae; Nishimura, Tomio; Yazawa, Kazunaga

    2008-01-01

    Anoectochilus formosanus, a plant native to Taiwan, is used as a folk medicine. It was found that oral administration of A. formosanus extract (AFE) (500 mg/kg) for 4 weeks suppressed bone weight loss and trabecular bone loss in ovariectomized mice, an experimental model of osteoporosis. Although AFE at 12.5 and 25 mug/ml inhibited osteoclast formation in co-culture of osteoblasts and bone marrow cells, AFE did not inhibit the formation of osteoclast progenitor cells and preosteoclast cells in bone marrow cells and RAW264 cells. However, AFE (at 12.5 and 25 microg/ml) decreased RANKL expression. These results suggested that AFE might suppress the bone loss caused by estrogen deficiency through suppression of RANKL expression required for osteoclast formation. PMID:18301967

  7. Gene Expression Analyses of Subchondral Bone in Early Experimental Osteoarthritis by Microarray

    PubMed Central

    Chen, YuXian; Shen, Jun; Lu, HuaDing; Zeng, Chun; Ren, JianHua; Zeng, Hua; Li, ZhiFu; Chen, ShaoMing; Cai, DaoZhang; Zhao, Qing

    2012-01-01

    Osteoarthritis (OA) is a degenerative joint disease that affects both cartilage and bone. A better understanding of the early molecular changes in subchondral bone may help elucidate the pathogenesis of OA. We used microarray technology to investigate the time course of molecular changes in the subchondral bone in the early stages of experimental osteoarthritis in a rat model. We identified 2,234 differentially expressed (DE) genes at 1 week, 1,944 at 2 weeks and 1,517 at 4 weeks post-surgery. Further analyses of the dysregulated genes indicated that the events underlying subchondral bone remodeling occurred sequentially and in a time-dependent manner at the gene expression level. Some of the identified dysregulated genes that were identified have suspected roles in bone development or remodeling; these genes include Alp, Igf1, Tgf ?1, Postn, Mmp3, Tnfsf11, Acp5, Bmp5, Aspn and Ihh. The differences in the expression of these genes were confirmed by real-time PCR, and the results indicated that our microarray data accurately reflected gene expression patterns characteristic of early OA. To validate the results of our microarray analysis at the protein level, immunohistochemistry staining was used to investigate the expression of Mmp3 and Aspn protein in tissue sections. These analyses indicate that Mmp3 protein expression completely matched the results of both the microarray and real-time PCR analyses; however, Aspn protein expression was not observed to differ at any time. In summary, our study demonstrated a simple method of separation of subchondral bone sample from the knee joint of rat, which can effectively avoid bone RNA degradation. These findings also revealed the gene expression profiles of subchondral bone in the rat OA model at multiple time points post-surgery and identified important DE genes with known or suspected roles in bone development or remodeling. These genes may be novel diagnostic markers or therapeutic targets for OA. PMID:22384228

  8. The Prevention of Early Postmenopausal Bone Loss by Cyclical Etidronate Therapy

    Microsoft Academic Search

    Staines Middlesex

    1997-01-01

    PURPOSE: To determine whether intermittent cyclical etidronate therapy can prevent early postmenopausal bone loss.PATIENTS AND METHOD: This was a 2-year outpatient, randomized, double-blind, placebo-controlled clinical trial. The subjects were 152 women within 1 to 10 years of the onset of menopause and bone mineral density (BMD) between 0 and ?2 SD of normal values for a 50 year old woman.

  9. The reversal phase of the bone-remodeling cycle: cellular prerequisites for coupling resorption and formation

    PubMed Central

    Delaisse, Jean-Marie

    2014-01-01

    The reversal phase couples bone resorption to bone formation by generating an osteogenic environment at remodeling sites. The coupling mechanism remains poorly understood, despite the identification of a number of ‘coupling' osteogenic molecules. A possible reason is the poor attention for the cells leading to osteogenesis during the reversal phase. This review aims at creating awareness of these cells and their activities in adult cancellous bone. It relates cell events (i) on the bone surface, (ii) in the mesenchymal envelope surrounding the bone marrow and appearing as a canopy above remodeling surfaces and (iii) in the bone marrow itself within a 50-?m distance of this canopy. When bone remodeling is initiated, osteoprogenitors at these three different levels are activated, likely as a result of a rearrangement of cell–cell and cell–matrix interactions. Notably, canopies are brought under the osteogenic influence of capillaries and osteoclasts, whereas bone surface cells become exposed to the eroded matrix and other osteoclast products. In several diverse pathophysiological situations, including osteoporosis, a decreased availability of osteoprogenitors from these local reservoirs coincides with decreased osteoblast recruitment and impaired initiation of bone formation, that is, uncoupling. Overall, this review stresses that coupling does not only depend on molecules able to activate osteogenesis, but that it also demands the presence of osteoprogenitors and ordered cell rearrangements at the remodeling site. It points to protection of local osteoprogenitors as a critical strategy to prevent bone loss. PMID:25120911

  10. Role of Subchondral Bone during Early-stage Experimental TMJ Osteoarthritis

    PubMed Central

    Embree, M.; Ono, M.; Kilts, T.; Walker, D.; Langguth, J.; Mao, J.; Bi, Y.; Barth, J.L.; Young, M.

    2011-01-01

    Temporomandibular joint osteoarthritis (TMJ OA) is a degenerative disease that affects both cartilage and subchondral bone. We used microarray to identify changes in gene expression levels in the TMJ during early stages of the disease, using an established TMJ OA genetic mouse model deficient in 2 extracellular matrix proteins, biglycan and fibromodulin (bgn-/0fmod-/-). Differential gene expression analysis was performed with RNA extracted from 3-week-old WT and bgn-/0fmod-/- TMJs with an intact cartilage/subchondral bone interface. In total, 22 genes were differentially expressed in bgn-/0fmod-/- TMJs, including 5 genes involved in osteoclast activity/differentiation. The number of TRAP-positive cells were three-fold higher in bgn-/0fmod-/- TMJs than in WT. Quantitative RT-PCR showed up-regulation of RANKL and OPG, with a 128% increase in RANKL/OPG ratio in bgn-/0fmod-/- TMJs. Histology and immunohistochemistry revealed tissue disorganization and reduced type I collagen in bgn-/0fmod-/- TMJ subchondral bone. Early changes in gene expression and tissue defects in young bgn-/0fmod-/- TMJ subchondral bone are likely attributed to increased osteoclast activity. Analysis of these data shows that biglycan and fibromodulin are critical for TMJ subchondral bone integrity and reveal a potential role for TMJ subchondral bone turnover during the initial early stages of TMJ OA disease in this model. PMID:21917603

  11. Circulating leptin is negatively associated with the isotopically-measured bone formation rate in pubertal adolescents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    BACKGROUND: Animal studies show that serum leptin (SL) is associated with decreased bone formation (BF) and increased bone resorption (BR) rates via its effects on the sympathetic nervous system. Pediatric data on these relationships are limited due to lack of accurate methodology for in vivo assess...

  12. Rapid Establishment of Chemical and Mechanical Properties during Lamellar Bone Formation

    E-print Network

    Rapid Establishment of Chemical and Mechanical Properties during Lamellar Bone Formation B. Busa,1 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

  13. Trigeminal nitric oxide synthase expression correlates with new bone formation during distraction osteogenesis.

    PubMed

    de Albuquerque, Rubens Ferreira; Aparecida Del Bel, Elaine; Brentegani, Luiz Guilherme; Moura de Oliveira, Maria Tereza; Mardegan Issa, João Paulo

    2008-04-01

    Nitric oxide synthase (NOS) has been reported to be involved with both bone healing and bone metabolism. The aim of this study was to test the null hypothesis that there is no correlation between new bone formation during mandibular distraction osteogenesis and NOS expression in the trigeminal ganglion of rats. Newly formed tissue during distraction osteogenesis and trigeminal NOS expression measured by the NADPH-diaphorase (NADPH-d) reaction were evaluated in 72 male Wistar rats by histomorphometric and histochemical methods. In animals submitted to 0.5 mm/day distraction osteogenesis, the percentage of bone tissue was higher in the basal area of the mandibles compared with the center and significantly increased through the experimental periods (P < 0.05). At the sixth postoperative week, the difference in bone formation between the continuous and acute distraction osteogenesis groups was the highest. Significant correlation between new bone formation by distraction osteogenesis and NADPH-d-reactive neurons was found, varying according to neuronal cell size (r = -0.6, P = 0.005, small cells strongly stained; r = 0.5, P = 0.018, large cells moderately stained). The results suggest that NOS may play a role in the bone healing process via neurogenic pathways, and the phenomenon seems to be neuronal cell morphotype-dependent. Further studies are now warranted to investigate the mechanistic link between the expression of trigeminal NOS and mandibular new bone formation by distraction osteogenesis. PMID:18330484

  14. Regulation of bone resorption and formation by purines and pyrimidines

    E-print Network

    Burnstock, Geoffrey

    an organic collagen matrix, and three major cell types: osteoclasts, osteoblasts and osteocytes (Table 1; Fig. Some osteoblasts become incorporated in the bone matrix they secrete, differentiating into osteocytes Differentiate into osteocytes (network of strain- detecting cells) when engulfed by bone matrix; p

  15. 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

    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

    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

  16. Normal Tempo of Bone Formation in Turner Syndrome despite Signs of Accelerated Bone Resorption

    Microsoft Academic Search

    Line Cleemann; Kirsten Holm; Hanne Kobbernagel; Sven O. Skouby; Bent Kristensen; Heidi Smedegaard; Anna-Maria Andersson; Arieh Cohen; Claus H. Gravholt

    2011-01-01

    Aims: To evaluate area bone mineral density (aBMD) and volumetric BMD (vBMD) by dual-energy X-ray absorptiometry, and relations to bone markers and hormones in adolescent women with Turner syndrome (TS). Methods: Cross-sectional study in TS patients (n = 37, 16.7 ± 3.4 years) and control group (n = 49), assessed by dual-energy X-ray absorptiometry, bone markers and hormones. TS patients

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

    Microsoft Academic Search

    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

    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

  18. Prevention of Stone Formation and Bone Loss In Absorptive Hypercalciuria by Combined Dietary and Pharmacological Interventions

    Microsoft Academic Search

    CHARLES Y. C. PAK; HOWARD J. HELLER; MARGARET S. PEARLE; CLARITA V. ODVINA; JOHN R. POINDEXTER; ROY D. PETERSON

    2003-01-01

    PurposeWe determined whether dietary restriction of calcium and oxalate, combined with thiazide and potassium citrate treatment, would prevent stone formation and avert bone loss in 18 men and 10 women with type I absorptive hypercalciuria.

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

    PubMed

    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

    2013-09-15

    We generated a new Bmp2 conditional-knockout allele without a neo cassette that removes the Bmp2 gene from osteoblasts (Bmp2-cKO(ob)) using the 3.6Col1a1-Cre transgenic model. Bones of Bmp2-cKO(ob) 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-cKO(ob) 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

  20. Enhanced prostacyclin formation and Wnt signaling in sclerostin deficient osteocytes and bone.

    PubMed

    Ryan, Zachary C; Craig, Theodore A; Salisbury, Jeffrey L; Carpio, Lomeli R; McGee-Lawrence, Meghan; Westendorf, Jennifer J; Kumar, Rajiv

    2014-05-23

    We show that prostacyclin production is increased in bone and osteocytes from sclerostin (Sost) knockout mice which have greatly increased bone mass. The addition of prostacyclin or a prostacyclin analog to bone forming osteoblasts enhances differentiation and matrix mineralization of osteoblasts. The increase in prostacyclin synthesis is linked to increases in ?-catenin concentrations and activity as shown by enhanced binding of lymphoid enhancer factor, Lef1, to promoter elements within the prostacyclin synthase promoter. Blockade of Wnt signaling reduces prostacyclin production in osteocytes. Increased prostacyclin production by osteocytes from sclerostin deficient mice could potentially contribute to the increased bone formation seen in this condition. PMID:24780398

  1. Influence of early zoledronic acid administration on bone marrow fat in ovariectomized rats.

    PubMed

    Li, Guan-Wu; Xu, Zheng; Chang, Shi-Xin; Zhou, Lei; Wang, Xiao-Yan; Nian, Hua; Shi, Xiao

    2014-12-01

    Although the primary target cell of bisphosphonates is the osteoclast, increasing attention is being given to other effector cells influenced by bisphosphonates, such as osteoblasts and marrow adipocytes. Early zoledronic acid (ZA) treatment to ovariectomized (OVX) rats has been found to fully preserve bone microarchitecture over time. However, little is known regarding the influence of ZA on marrow adipogenesis. The purpose of this study was to monitor the ability of early administration of ZA in restoring marrow adiposity in an estrogen-deficient rat model. Thirty female Sprague-Dawley rats were randomly divided into sham-operated (SHAM), OVX + vehicle, and OVX + ZA groups (n=10/group). Dual-energy x-ray absorptiometry and water/fat magnetic resonance imaging were performed at baseline, 6 weeks, and 12 weeks after treatment to assess bone mineral density and marrow fat fraction. Serum biochemical markers, bone remodeling, and marrow adipocyte parameters were analyzed using biochemistry, histomorphometry, and histopathology, respectively. The expression levels of osteoblast, adipocyte, and osteoclast-related genes in bone marrow were assessed using RT-PCR. The OVX rats showed marked bone loss, first detected at 12 weeks, but estrogen deficiency resulted in a remarked increase in marrow fat fraction, first detected at 6 weeks compared with the SHAM rats (all P < .001). Similarly, the OVX rats had a substantially larger percent adipocyte area (+163.0%), mean diameter (+29.5%), and higher density (+57.3%) relative to the SHAM rats. Bone histomorphometry, levels of osteoclast-related gene expression, and a serum resorption marker confirmed that ZA significantly suppressed bone resorption activities. Furthermore, ZA treatment returned adipocyte-related gene expression and marrow adipocyte parameters toward SHAM levels. These data suggest that a single dose of early ZA treatment acts to reverse marrow adipogenesis occurring during estrogen deficiency, which may contribute to its capacity to reduce bone loss. PMID:25243855

  2. Best5: a novel interferon-inducible gene expressed during bone formation

    Microsoft Academic Search

    TARLOCHAN SINGH GREWAL; PAUL G. GENEVER; ALEX C. BRABBS; MARK BIRCH; TIMOTHY M. SKERRY

    Regulation of bone formation is im- portant in the pathogenesis of many conditions such as osteoporosis, fracture healing, and loosening of orthopedic implants. We have recently identified a novel rat cDNA (best5) by differential display PCR that is regulated during osteoblast differentiation and bone formation in vitro and in vivo. Expression of best5 mRNA is induced in cultures of osteoblasts

  3. Induction of bone formation in biphasic calcium phosphate scaffolds by bone morphogenetic protein-2 and primary osteoblasts.

    PubMed

    Strobel, L A; Rath, S N; Maier, A K; Beier, J P; Arkudas, A; Greil, P; Horch, R E; Kneser, U

    2014-03-01

    Bone tissue engineering strategies mainly depend on porous scaffold materials. In this study, novel biphasic calcium phosphate (BCP) matrices were generated by 3D-printing. High porosity was achieved by starch consolidation. This study aimed to characterise the porous BCP-scaffold properties and interactions of osteogenic cells and growth factors under in vivo conditions. Five differently treated constructs were implanted subcutaneously in syngeneic rats: plain BCP constructs (group A), constructs pre-treated with BMP-2 (group B; 1.6?µg BMP-2 per scaffold), seeded with primary osteoblasts (OB) (group C), seeded with OB and BMP-2 (group D) and constructs seeded with OB and pre-cultivated in a flow bioreactor for 6?weeks (group E). After 2, 4 and 6?weeks, specimens were explanted and subjected to histological and molecular biological analyses. Explanted scaffolds were invaded by fibrovascular tissue without significant foreign body reactions. Morphometric analysis demonstrated significantly increased bone formation in samples from group D (OB?+?BMP-2) compared to all other groups. Samples from groups B-E displayed significant mRNA expression of bone-specific genes after 6?weeks. Pre-cultivation in the flow bioreactor (group E) induced bone formation comparable with group B. In this study, differences in bone distribution between samples with BMP-2 or osteoblasts could be observed. In conclusion, combination of osteoblasts and BMP-2 synergistically enhanced bone formation in novel ceramic scaffolds. These results provide the basis for further experiments in orthotopic defect models with a focus on future applications in orthopaedic and reconstructive surgery. PMID:22740314

  4. Gene therapy for new bone formation using adeno-associated viral bone morphogenetic protein-2 vectors

    Microsoft Academic Search

    Y Chen; K D K Luk; K M C Cheung; R Xu; M C Lin; W W Lu; J C Y Leong; H-F Kung; KDK Luk

    2003-01-01

    Previous reports have suggested that bone morphogenetic protein (BMP) gene therapy could be applied for in vivo bone regeneration. However, these studies were conducted either using immunodeficient animals because of immunogenicity of adenovirus vectors, or using ex vivo gene transfer technique, which is much more difficult to handle. Adeno-associated virus (AAV) is a replication-defective virus without any association with immunogenicity

  5. Is suppression of bone formation during simulated weightlessness related to glucocorticoid levels

    NASA Technical Reports Server (NTRS)

    Morey-Holton, E. R.; Bomalaski, M. D.; Enayati-Gordon, E.; Gonsalves, M. R.; Wronski, T. J.

    1982-01-01

    To investigate the hypothesis that suppression of bone formation in the suspended rat model was the result of increased levels of corticosterone, experiments were performed on young, growing, male rats exposed either to 4 C or suspended for two weeks. Rats suspended on the model system, designed to simulate certain aspects of spaceflight, gained weight at a rate at least equal to control animals but still showed a significant suppression of bone formation within 7 days. Cold-exposed rats gained less weight than their corresponding control group and did not demonstrate any suppression of bone formation. These findings suggest: (1) tail suspension is less stressful than previously used harness systems; (2) suspension in young, rapidly growing rats causes a significant suppression of cortical bone formation; (3) cold exposure does not alter bone formation rate in rats of a similar age and strain to those suspended in this study; and (4) suppression of bone formation provoked by unloading the rear limbs is not due solely to sustained stimulation of the pituitary-adrenal system.

  6. Effect of low gravity on calcium metabolism and bone formation (L-7)

    NASA Technical Reports Server (NTRS)

    Suda, Tatsuo

    1993-01-01

    Recently, attention has been focused on the disorders of bone and calcium metabolism during space flight. The skeletal system has evolved on the Earth under 1-g. Space flights under low gravity appear to cause substantial changes in bone and calcium homeostasis of the animals adapted to 1-g. A space experiment for the First Materials Processing Test (FMPT) was proposed to examine the effects of low gravity on calcium metabolism and bone formation using chick embryos loaded in a space shuttle. This space experiment was proposed based on the following two experimental findings. First, it has been reported that bone density decreases significantly during prolonged space flight. The data obtained from the US Skylab and the U.S.S.R. Salyut-6 cosmonauts have also documented that the degree of bone loss is related to the duration of space flight. Second, the US-Soviet joints space experiment demonstrated that the decrease in bone density under low gravity appears to be due to the decrease in bone formation rather than the increase in bone resorption. The purpose of our space experiment is, therefore, to investigate further the mechanisms of bone growth under low gravity using fertilized chick embryos.

  7. Fibrodysplasia ossificans progressiva (FOP): A human genetic disorder of extra-skeletal bone formation, or - How does one tissue become another?

    PubMed Central

    Shore, Eileen M.

    2011-01-01

    Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic disease in which de novo osteogenesis – a developmental process occurring during embryonic skeletal formation – is induced aberrantly and progressively beginning during early childhood in soft connective tissues. Episodic initiation of spontaneous bone forming lesions occurs over time, affecting a generally predictable sequence of body locations following a pattern similar to that of the developing embryonic skeleton. The heterotopic (extra-skeletal) bone formation in FOP can also be induced by connective tissue injury. At the tissue level, an initial tissue degradation phase is followed by a tissue formation phase during which soft connective tissues are replaced by bone tissue through endochondral osteogenesis. This extra-skeletal bone is physiologically normal and develops through the same series of tissue differentiation events that occurs during normal embryonic skeletal development. The underlying genetic mutation in FOP alters the signals that regulate induction of cell differentiation leading to bone formation. In addition to post-natal heterotopic ossification, FOP patients show specific malformations of skeletal elements indicating effects on bone formation during embryonic development as well. Nearly all cases of FOP are caused by the identical mutation in the ACVR1 gene that causes a single amino acid substitution, R206H, in the bone morphogenetic protein (BMP) type I receptor ACVR1 (formerly known as ALK2). This mutation causes mild constitutive activation of the BMP signaling pathway and identifies ACVR1 as a key regulator of cell fate decisions and bone formation, providing opportunities to investigate previously unrecognized functions for this receptor during tissue development and homeostasis. PMID:22408652

  8. Emodin regulates bone remodeling by inhibiting osteoclastogenesis and stimulating osteoblast formation.

    PubMed

    Kim, Ju-Young; Cheon, Yoon-Hee; Kwak, Sung Chul; Baek, Jong Min; Yoon, Kwon-Ha; Lee, Myeung Su; Oh, Jaemin

    2014-07-01

    Bone remodeling, a physiological process in which new bone is formed by osteoblasts and the preexisting bone matrix is resorbed by osteoclasts, is vital for the maintenance of healthy bone tissue in adult humans. Imbalances in this process can cause various pathological conditions, including osteoporosis. Emodin, a naturally occurring anthraquinone derivative found in Asian herbal medicines, has numerous beneficial pharmacologic effects, including anticancer and antidiabetic activities. However, the effect of emodin on the regulation of osteoblast and osteoclast activity has not yet been investigated. We show here that emodin is a potential target for osteoporosis therapeutics, as treatment with this agent enhances osteoblast differentiation and bone growth and suppresses osteoclast differentiation and bone resorption. In this study, emodin suppressed receptor activator of nuclear factor-?B (NF-?B) ligand (RANKL)-induced osteoclast differentiation of bone marrow macrophages (BMMs) and the bone-resorbing activity of mature osteoclasts by inhibiting RANKL-induced NF-?B, c-Fos, and NFATc1 expression. Emodin also increased ALP, Alizarin Red-mineralization activity, and the expression of osteoblastogenic gene markers, such as Runx2, osteocalcin (OCN), and ALP in mouse calvarial primary osteoblasts, as well as activated the p38-Runx2 pathway, which enhanced osteoblast differentiation. Moreover, mice treated with emodin showed marked attenuation of lipopolysaccharide (LPS)-induced bone erosion and increased bone-forming activity in a mouse calvarial bone formation model based on micro-computed tomography and histologic analysis of femurs. Our findings reveal a novel function for emodin in bone remodeling, and highlight its potential for use as a therapeutic agent in the treatment of osteoporosis that promotes bone anabolic activity and inhibits osteoclast differentiation. © 2014 American Society for Bone and Mineral Research. PMID:25832436

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

    Microsoft Academic Search

    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

    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

  10. Adaptive bone formation in acellular vertebrae of sea bass (Dicentrarchus labrax L.).

    PubMed

    Kranenbarg, Sander; van Cleynenbreugel, Tim; Schipper, Henk; van Leeuwen, Johan

    2005-09-01

    Mammalian bone is an active tissue in which osteoblasts and osteoclasts balance bone mass. This process of adaptive modelling and remodelling is probably regulated by strain-sensing osteocytes. Bone of advanced teleosts is acellular yet, despite the lack of osteocytes, it is capable of an adaptive response to physical stimuli. Strenuous exercise is known to induce lordosis. Lordosis is a ventrad curvature of the vertebral column, and the affected vertebrae show an increase in bone formation. The effects of lordosis on the strain distribution in sea bass (Dicentrarchus labrax L.) vertebrae are assessed using finite element modelling. The response of the local tissue is analyzed spatially and ontogenetically in terms of bone volume. Lordotic vertebrae show a significantly increased strain energy due to the increased load compared with normal vertebrae when loaded in compression. High strain regions are found in the vertebral centrum and parasagittal ridges. The increase in strain energy is attenuated by a change in architecture due to the increased bone formation. The increased bone formation is seen mainly at the articular surfaces of the vertebrae, although some extra bone is formed in the vertebral centrum. Regions in which the highest strains are found do not spatially correlate with regions in which the most extensive bone apposition occurs in lordotic vertebrae of sea bass. Mammalian-like strain-regulated bone modelling is probably not the guiding mechanism in adaptive bone modelling of acellular sea bass vertebrae. Chondroidal ossification is found at the articular surfaces where it mediates a rapid adaptive response, potentially attenuating high stresses on the dorsal zygapophyses. PMID:16155222

  11. Arthritis Induces Early Bone High Turnover, Structural Degradation and Mechanical Weakness

    PubMed Central

    Vidal, Bruno; Cascão, Rita; Vale, Ana Catarina; Cavaleiro, Inês; Vaz, Maria Fátima; Brito, José Américo Almeida; Canhão, Helena; Fonseca, João Eurico

    2015-01-01

    Background We have previously found in the chronic SKG mouse model of arthritis that long standing (5 and 8 months) inflammation directly leads to high collagen bone turnover, disorganization of the collagen network, disturbed bone microstructure and degradation of bone biomechanical properties. The main goal of the present work was to study the effects of the first days of the inflammatory process on the microarchitecture and mechanical properties of bone. Methods Twenty eight Wistar adjuvant-induced arthritis (AIA) rats were monitored during 22 days after disease induction for the inflammatory score, ankle perimeter and body weight. Healthy non-arthritic rats were used as controls for compar-ison. After 22 days of disease progression rats were sacrificed and bone samples were collected for histomorphometrical, energy dispersive X-ray spectroscopical analysis and 3-point bending. Blood samples were also collected for bone turnover markers. Results AIA rats had an increased bone turnover (as inferred from increased P1NP and CTX1, p = 0.0010 and p = 0.0002, respectively) and this was paralleled by a decreased mineral content (calcium p = 0.0046 and phos-phorus p = 0.0046). Histomorphometry showed a lower trabecular thickness (p = 0.0002) and bone volume (p = 0.0003) and higher trabecular sepa-ration (p = 0.0009) in the arthritic group as compared with controls. In addition, bone mechanical tests showed evidence of fragility as depicted by diminished values of yield stress and ultimate fracture point (p = 0.0061 and p = 0.0279, re-spectively) in the arthritic group. Conclusions We have shown in an AIA rat model that arthritis induc-es early bone high turnover, structural degradation, mineral loss and mechanical weak-ness. PMID:25617902

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

    SciTech Connect

    Gilmour, Peter S., E-mail: Peter.Gilmour@astrazeneca.com [New Opportunities Innovative Medicines group, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); O'Shea, Patrick J.; Fagura, Malbinder [New Opportunities Innovative Medicines group, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Pilling, James E. [Discovery Sciences, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Sanganee, Hitesh [New Opportunities Innovative Medicines group, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Wada, Hiroki [R and I IMed, AstraZeneca R and D, Molndal (Sweden); Courtney, Paul F. [DMPK, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Kavanagh, Stefan; Hall, Peter A. [Safety Assessment, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Escott, K. Jane [New Opportunities Innovative Medicines group, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom)

    2013-10-15

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

  13. Micromotion-induced strain fields influence early stages of repair at bone-implant interfaces

    PubMed Central

    Wazen, Rima M.; Currey, Jennifer A.; Guo, Hongqiang; Brunski, John B.; Helms, Jill A.; Nanci, Antonio

    2013-01-01

    Implant loading can create micromotion at the bone-implant interface. The interfacial strain associated with implant micromotion could contribute to regulating the tissue healing response. Excessive micromotion can lead to fibrous encapsulation and implant loosening. Our objective was to characterize the influence of interfacial strain on bone regeneration around implants in mouse tibiae. A micromotion system was used to create strain under conditions of (1) no initial contact between implant and bone, and (2) a direct bone-implant contact. Pin- and screw-shaped implants were subjected to displacements of 150 ?m or 300 ?m, 60 cycles/day, for 7 days. Pin-shaped implants placed in 5 animals were subjected to 3 sessions of 150 ?m displacement per day, with 60 cycles per session. Control implants in both types of interfaces were stabilized throughout the healing period. Experimental strain analyses, microtomography, image-based displacement mapping, and finite element simulations were used to characterize interfacial strain fields. Calcified tissue sections were prepared and stained with Goldner to evaluate tissue reaction in higher and lower strain regions. In stable implants, bone formation occurred consistently around the implants. In implants subjected to micromotion, bone regeneration was disrupted in areas of high strain concentrations (e.g. > 30%), whereas lower strain values were permissive of bone formation. Increasing implant displacement or number of cycles per day also changed the strain distribution and disturbed bone healing. These results indicate that not only implant micromotion but also the associated interfacial strain field contributes to regulating the interfacial mechanobiology at healing bone-implant interfaces. PMID:23337705

  14. In vivo molecular imaging of adenoviral versus lentiviral gene therapy in two bone formation models.

    PubMed

    Feeley, Brian T; Conduah, Augustine H; Sugiyama, Osamu; Krenek, Lucie; Chen, Irvin S Y; Lieberman, Jay R

    2006-08-01

    Regional gene therapy techniques are promising methods to enhance bone formation in large bone defects that would be difficult to treat with allograft or autograft bone stock. In this study, we compared in vivo temporal expression patterns of adenoviral- and lentiviral-mediated gene therapy in two bone formation models. Primary rat bone marrow cells (RBMC) were transduced with lentiviral or adenoviral vectors containing luciferase (Luc) or BMP-2 cDNA, or cotransduced with vectors containing Luc and bone morphogenetic protein 2 (BMP-2). In vitro protein production was determined with luciferase assay or ELISA (for BMP-2 production) weekly for 12 weeks. Two bone formation models were used -- a hind limb muscle pouch or radial defect -- in SCID mice. A cooled charged-coupled device (CCD) camera was used to image in vivo luciferase expression weekly for 12 weeks. In vitro, adenoviral expression of BMP-2 and luciferase was detected by ELISA or luciferase assay, respectively, for 4 weeks. Lentiviral expression of BMP-2 and luciferase was sustained in culture for 3 months. Using the CCD camera, we found that adenoviral vectors expressed luciferase expression for up to 21 days, but lentiviral vectors expressed target gene expression for 3 months in vivo in both bone formation models. There was no detectable difference in the amount of bone formed between the adenoviral and lentiviral groups. Lentiviral-mediated delivery of BMP-2 can induce long term in vitro and in vivo gene expression, which may be beneficial when developing tissue engineering strategies to heal large bone defects or defects with a compromised biologic environment. PMID:16788987

  15. Effect of Dual Treatment with SDF-1 and BMP-2 on Ectopic and Orthotopic Bone Formation

    PubMed Central

    Jung, Hong-Moon; Lee, Jung-Tae; Kwon, Tae-Geon

    2015-01-01

    Purposes The potent stem cell homing factor stromal cell-derived factor-1 (SDF-1) actively recruits mesenchymal stem cells from circulation and from local bone marrow. It is well established that bone morphogenetic protein-2 (BMP-2) induces ectopic and orthotopic bone formation. However, the exact synergistic effects of BMP-2 and SDF-1 in ectopic and orthotopic bone regeneration models have not been fully investigated. The purpose of this study was to evaluate the potential effects of simultaneous SDF-1 and BMP-2 treatment on bone formation. Materials and Methods Various doses of SDF-1 were loaded onto collagen sponges with or without BMP-2.These sponges were implanted into subcutaneous pockets and critical-size calvarial defects in C57BL/6 mice. The specimens were harvested 4 weeks post-surgery and the degree of bone formation in specimens was evaluated by histomorphometric and radiographic density analyses. Osteogenic potential and migration capacity of mesenchymal cells and capillary tube formation of endothelial cells following dual treatment with SDF-1 and BMP-2 were evaluated with in vitro assays. Results SDF-1-only-treated implants did not yield significant in vivo bone formation and SDF-1 treatment did not enhance BMP-2-induced ectopic and orthotopic bone regeneration. In vitro experiments showed that concomitant use of BMP-2 and SDF-1 had no additive effect on osteoblastic differentiation, cell migration or angiogenesis compared to BMP-2 or SDF-1 treatment alone. Conclusions These findings imply that sequence-controlled application of SDF-1 and BMP-2 must be further investigated for the enhancement of robust osteogenesis in bone defects. PMID:25781922

  16. Microporous "honeycomb" films support enhanced bone formation in vitro.

    PubMed

    Birch, Mark A; Tanaka, Masaru; Kirmizidis, George; Yamamoto, Sadaaki; Shimomura, Masatsugu

    2013-09-01

    Substrate topography influences cell adhesion, proliferation, and differentiation. In this study, poly (?-caprolactone) (PCL) films with a well-defined honeycomb structure of porosity 3-4, 5-6, 10-11, or 15-16 ?m were contrasted with flat surfaces for their ability to support primary rat osteoblast adhesion and mineralized extracellular matrix deposition in vitro. Immunofluorescent visualization of vinculin and rhodamine phalloidin binding of actin were used to investigate cell adhesion and morphology. Localization of the alkaline phosphatase activity and Alizarin Red staining were performed to assess the osteoblast activity and deposition of a mineralized matrix. Scanning electron microscopy together with energy-dispersive X-ray spectroscopy was used to provide morphological analysis of cell-film interactions, the deposited matrix, and elemental analysis of the mineralized structures. After 24 h of culture, there were no differences in cell numbers on porous or flat PCL surfaces, but there were changes in cell morphology. Osteoblasts on honeycomb films had a smaller surface area and were less circular than cells on flat PCL. Analysis of cells cultured for 35 days under osteogenic conditions revealed that osteoblasts on all substrates acquired alkaline phosphatase activity, but levels of mineralized matrix were increased on films with 3-4-?m pore sizes. The bone-like matrix with a Ca:P ratio of 1.69±0.08 could be identified in larger areas often aligning with substrate topography. In addition, smaller spherical deposits (0.5-1 ?m in diameter) with a Ca:P ratio of 1.3±0.08 were observed at the surface and particularly within the pores of the PCL film. Localization of vinculin showed significant decreases in the number of focal adhesion structures per unit cell area on 5-6, 10-11, and 15-16-?m surfaces compared to flat PCL, while focal complexes with a smaller area (0-2 ?m(2)) were more abundant on 3-4 and 5-6-?m surfaces. Observation of cell interaction with these surfaces identified cytoplasmic protrusions that extended into and sealed the pores of these PCL films creating an extracellular space in which, the conditions could influence the deposition and formation of the mineralized matrix. PMID:23688155

  17. Effects of Jupiter's formation and migration: the Jovian Early Bombardment

    NASA Astrophysics Data System (ADS)

    Turrini, D.; Coradini, A.; Magni, G.

    2011-10-01

    The first phase in the lifetime of the Solar System is that of the Solar Nebula, when the Solar System is constituted by a circumsolar disk of gas and dust particles where planetesimals and planetary embryos are forming. The giant planets should have formed during this phase, since the nebular gas represents the source material for their gaseous envelopes. Here we report the results of our investigation of the effects of Jupiter's formation on the planetesimals populating the Solar Nebula using Vesta and Ceres as case studies. Our results show that the formation of Jupiter triggered a brief yet intense phase of bombardment, which we called the Jovian Early Bombardment and whose intensity varies with the extent and the timescale of Jupiter's migration. The data that the Dawn mission will supply on Vesta and Ceres will allow us to test the Jovian Early Bombardment hypothesis and possibly gather information on the formation and the early dynamical evolution of Jupiter.

  18. The Allied Health BONE Team:An interdisciplinary approach to orthopaedic early discharge and admission prevention

    Microsoft Academic Search

    SUSAN BRANDIS; Shelley Murtagh; Robyn Solia

    1998-01-01

    This paper presents the conceptual framework, activities and outcomes of the Allied Health BONE (Best Orthopaedic New Enterprise) Team, an early discharge incentive at the Gold Coast Hospital. The clinical team of a physiotherapist, occupational therapist and social worker provided services within an interdisciplinary model of care with the aim of reducing the length of stay of acute adult orthopaedic

  19. Deletion of Nrf2 reduces skeletal mechanical properties and decreases load-driven bone formation.

    PubMed

    Sun, Yong-Xin; Li, Lei; Corry, Kylie A; Zhang, Pei; Yang, Yang; Himes, Evan; Mihuti, Cristina Layla; Nelson, Cecilia; Dai, Guoli; Li, Jiliang

    2015-05-01

    Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor expressed in many cell types, including osteoblasts, osteocytes, and osteoclasts. Nrf2 has been considered a master regulator of cytoprotective genes against oxidative and chemical insults. The lack of Nrf2 can induce pathologies in multiple organs. The aim of this study was to investigate the role of Nrf2 in load-driven bone metabolism using Nrf2 knockout (KO) mice. Compared to age-matched littermate wild-type controls, Nrf2 KO mice have significantly lowered femoral bone mineral density (-7%, p<0.05), bone formation rate (-40%, p<0.05), as well as ultimate force (-11%, p<0.01). The ulna loading experiment showed that Nrf2 KO mice were less responsive than littermate controls, as indicated by reduction in relative mineralizing surface (rMS/BS, -69%, p<0.01) and relative bone formation rate (rBFR/BS, -84%, p<0.01). Furthermore, deletion of Nrf2 suppressed the load-driven gene expression of antioxidant enzymes and Wnt5a in cultured primary osteoblasts. Taken together, the results suggest that the loss-of-function mutation of Nrf2 in bone impairs bone metabolism and diminishes load-driven bone formation. PMID:25576674

  20. A Computational Analysis of Bone Formation in the Cranial Vault in the Mouse

    PubMed Central

    Lee, Chanyoung; Richtsmeier, Joan T.; Kraft, Reuben H.

    2015-01-01

    Bones of the cranial vault are formed by the differentiation of mesenchymal cells into osteoblasts on a surface that surrounds the brain, eventually forming mineralized bone. Signaling pathways causative for cell differentiation include the actions of extracellular proteins driven by information from genes. We assume that the interaction of cells and extracellular molecules, which are associated with cell differentiation, can be modeled using Turing’s reaction–diffusion model, a mathematical model for pattern formation controlled by two interacting molecules (activator and inhibitor). In this study, we hypothesize that regions of high concentration of an activator develop into primary centers of ossification, the earliest sites of cranial vault bone. In addition to the Turing model, we use another diffusion equation to model a morphogen (potentially the same as the morphogen associated with formation of ossification centers) associated with bone growth. These mathematical models were solved using the finite volume method. The computational domain and model parameters are determined using a large collection of experimental data showing skull bone formation in mouse at different embryonic days in mice carrying disease causing mutations and their unaffected littermates. The results show that the relative locations of the five ossification centers that form in our model occur at the same position as those identified in experimental data. As bone grows from these ossification centers, sutures form between the bones.

  1. Synovial mesenchymal stem cells accelerate early remodeling of tendon-bone healing.

    PubMed

    Ju, Young-Jin; Muneta, Takeshi; Yoshimura, Hideya; Koga, Hideyuki; Sekiya, Ichiro

    2008-06-01

    Tendon-bone healing is important for the successful reconstruction of the anterior cruciate ligament by using the hamstring tendon. Mesenchymal stem cells (MSCs) have attracted much interest because of their self-renewing potential and multipotentiality for possible clinical use. We previously reported that MSCs derived from synovium had a higher proliferation and differentiation potential than the other MSCs that we examined. The purpose of this study was to investigate the effect and mechanism of the implantation of the synovial MSCs on tendon-bone healing in rats. Half of the Achilles' tendon grafts of rats were inserted into a bone tunnel from the tibial plateau to the tibial tuberosity with a suture-post fixation. The bone tunnel was filled with MSCs labeled with fluorescent marker DiI or without MSCs as the control. The tendon-bone interface was analyzed histologically, and collagen fibers were quantified. At 1 week, the tendon-bone interface was filled with abundant DiI-positive cells, and the proportion of collagen fiber area was significantly higher in the MSC group than in the control group. By 2 weeks, the proportion of oblique collagen fibers, which appeared to be Sharpey's fibers, was significantly higher in the MSC group than in the control group. At 4 weeks, the interface tissue disappeared, and the implanted tendon appeared to attach to the bone directly in both groups. DiI-labeled cells could no longer be observed. Implantation of synovial MSCs into bone tunnel thus accelerated early remodeling of tendon-bone healing, as shown histologically. PMID:18418628

  2. Sustained BMP Signaling in Osteoblasts Stimulates Bone Formation by Promoting Angiogenesis and Osteoblast Differentiation

    PubMed Central

    Zhang, Fengjie; Qiu, Tao; Wu, Xiangwei; Wan, Chao; Shi, Weibin; Wang, Ying; Chen, Jian-guo; Wan, Mei; Clemens, Thomas L.; Cao, Xu

    2009-01-01

    Angiogenesis and bone formation are tightly coupled during the formation of the skeleton. Bone morphogenetic protein (BMP) signaling is required for both bone development and angiogenesis. We recently identified endosome-associated FYVE-domain protein (endofin) as a Smad anchor for BMP receptor activation. Endofin contains a protein-phosphatase pp1c binding domain, which negatively modulates BMP signals through dephosphorylation of the BMP type I receptor. A single point mutation of endofin (F872A) disrupts interaction between the catalytic subunit pp1c and sensitizes BMP signaling in vitro. To study the functional impact of this mutation in vivo, we targeted expression of an endofin (F872A) transgene to osteoblasts. Mice expressing this mutant transgene had increased levels of phosphorylated Smad1 in osteoblasts and showed increased bone formation. Trabecular bone volume was significantly increased in the transgenic mice compared with the wildtype littermates with corresponding increases in trabecular bone thickness and number. Interestingly, the transgenic mice also had a pronounced increase in the density of the bone vasculature measured using contrast-enhanced ?CT imaging of Microfil-perfused bones. The vessel surface and volume were both increased in association with elevated levels of vascular endothelial growth factor (VEGF) in osteoblasts. Endothelial sprouting from the endofin (F872A) mutant embryonic metatarsals cultured ex vivo was increased compared with controls and was abolished by an addition of a VEGF neutralizing antibody. In conclusion, osteoblast targeted expression of a mutant endofin protein lacking the pp1c binding activity results in sustained signaling of the BMP type I receptor, which increases bone formation and skeletal angiogenesis. PMID:19257813

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

    PubMed Central

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

    2014-01-01

    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

  4. Formation of hollow bone-like morphology of calcium carbonate on surfactant/polymer templates

    NASA Astrophysics Data System (ADS)

    Mantilaka, M. M. M. G. P. G.; Pitawala, H. M. T. G. A.; Rajapakse, R. M. G.; Karunaratne, D. G. G. P.; Upul Wijayantha, K. G.

    2014-04-01

    Novel hollow, bone-like structures of Precipitated Calcium Carbonate (PCC) are fabricated, for the first time, starting from naturally occurring dolomite. The hollow, bone-like structures are prepared by precipitating calcium carbonate on self-assembled poly(acrylic acid)/cetyltrimethylammonium chloride (PAA/CTAC) template. Fourier Transform Infrared Spectroscopy (FT-IR), X-ray diffraction (XRD), Transmission Electron Microscopy (TEM) and Field Emission Scanning Electron Microscopic (FE-SEM) studies reveal that the bone-like structure is composed of Amorphous Calcium Carbonate (ACC) nanoparticles in the center and calcite nanoparticles at the edges. Bone-like PCC particles are in particle length of 2-3 ?m and particle width of 1 ?m. The internal hollow structures of bone-like particles are observed from TEM images. As identified by FE-SEM images, the bone-like structure has been formed through the crystal growth of initially formed ACC nanoparticles. The ACC particles are stabilized in the center while the calcite crystals have been grown from the ACC toward the edges of the structure to form a bone-like morphology. We also propose a possible mechanism for the formation of hollow bone-like PCC in this study. The fabricated hollow, bone-like PCC has potential applications in the preparation of release systems such as drugs, cosmetics and pigments.

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

    PubMed Central

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

    2013-01-01

    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

  6. Adeno-associated virus-mediated bone morphogenetic protein-4 gene therapy for in vivo bone formation

    Microsoft Academic Search

    Keith D. K. Luk; Yan Chen; Kenneth M. C. Cheung; Hsiang-fu Kung; William W. Lu; John C. Y. Leonga

    2003-01-01

    Adeno-associated virus (AAV) is so far the most valuable vehicle for gene therapy because it has no association with immune response and human disease. The present study was conducted to investigate the feasibility of AAV-mediated BMP4 gene transfer for bone formation. In vitro study suggested that AAV-BMP4 vectors could transduce myoblast C2C12 cells and produce osteogenic BMP4. In vivo study

  7. Low-Level Mechanical Vibrations can Reduce Bone Resorption and Enhance Bone Formation in the Growing Skeleton

    SciTech Connect

    Xie,L.; Jacobsen, J.; Busa, B.; Donahue, L.; Miller, L.; Rubin, C.; Judex, S.

    2006-01-01

    Short durations of extremely small magnitude, high-frequency, mechanical stimuli can promote anabolic activity in the adult skeleton. Here, it is determined if such signals can influence trabecular and cortical formative and resorptive activity in the growing skeleton, if the newly formed bone is of high quality, and if the insertion of rest periods during the loading phase would enhance the efficacy of the mechanical regimen. Eight-week-old female BALB/cByJ mice were divided into four groups, baseline control (n = 8), age-matched control (n = 10), whole-body vibration (WBV) at 45 Hz (0.3 g) for 15 min day{sup -1} (n = 10), and WBV that were interrupted every second by 10 of rest (WBV-R, n = 10). In vivo strain gaging of two additional mice indicated that the mechanical signal induced strain oscillations of approximately 10 microstrain on the periosteal surface of the proximal tibia. After 3 weeks of WBV, applied for 15 min each day, osteoclastic activity in the trabecular metaphysis and epiphysis of the tibia was 33% and 31% lower (P < 0.05) than in age-matched controls. Bone formation rates (BFR{center_dot}BS{sup -1}) on the endocortical surface of the metaphysis were 30% greater (P < 0.05) in WBV than in age-matched control mice but trabecular and middiaphyseal BFR were not significantly altered. The insertion of rest periods (WBV-R) failed to potentiate the cellular effects. Three weeks of either WBV or WBV-R did not negatively influence body mass, bone length, or chemical bone matrix properties of the tibia. These data indicate that in the growing skeleton, short daily periods of extremely small, high-frequency mechanical signals can inhibit trabecular bone resorption, site specifically attenuate the declining levels of bone formation, and maintain a high level of matrix quality. If WBV prove to be efficacious in the growing human skeleton, they may be able to provide the basis for a non-pharmacological and safe means to increase peak bone mass and, ultimately, reduce the incidence of osteoporosis or stress fractures later in life.

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

    USGS Publications Warehouse

    Modreski, P.J.

    2001-01-01

    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.

  9. Permian Bone Spring formation: Sandstone play in the Delaware basin. Part I - slope

    SciTech Connect

    Montgomery, S.L. [Petroleum Consultant, Seattle, WA (United States)

    1997-08-01

    New exploration in the Permian (Leonardian) Bone Spring formation has indicated regional potential in several sandstone sections across portions of the northern Delaware basin. Significant production has been established in the first, second, and third Bone Spring sandstones, as well as in a new reservoir interval, the Avalon sandstone, above the first Bone Spring sandstone. These sandstones were deposited as submarine-fan systems within the northern Delaware basin during periods of lowered sea level. The Bone Spring as a whole consists of alternating carbonate and siliciclastic intervals representing the downdip equivalents to thick Abo-Yeso/Wichita-Clear Fork carbonate buildups along the Leonardian shelf margin. Hydrocarbon exploration in the Bone Spring has traditionally focused on debris-flow carbonate deposits restricted to the paleoslope. Submarine-fan systems, in contrast, extend a considerable distance basinward of these deposits and have been recently proven productive as much as 40-48 km south of the carbonate trend.

  10. The role of vitamin D in the medullary bone formation in egg-laying Japanese quail and in immature male chicks treated with sex hormones.

    PubMed

    Takahashi, N; Shinki, T; Abe, E; Horiuchi, N; Yamaguchi, A; Yoshiki, S; Suda, T

    1983-07-01

    The effect of vitamin D3 on medullary bone formation was investigated in egg-laying Japanese quail and in immature male chicks treated with sex hormones. When laying quail were fed a vitamin D-deficient diet for 16 days, their eggshell weights and egg production rate were markedly reduced in a time-dependent manner with a significant decrease in plasma calcium and 25-hydroxyvitamin D3 levels. The calcium content of the medullary bone of femurs decreased markedly with the progress of vitamin D deficiency, whereas that of the cortical bone remained unchanged. Quantitative histological examination also showed that the area of the mineralized portion of medullary bone in quail that were fed the vitamin D-deficient diet markedly decreased compared with that in the control laying quail, whereas the total area of the mineralized and unmineralized portions of medullary bone in the bone marrow cavity increased moderately. Daily administration of vitamin D3 (0.75 microgram/day) to the vitamin D-deficient quail increased the mineralization of medullary bone as early as day 4. Daily administration of both estradiol (0.3 mg/day) and testosterone (0.9 mg/day) for 3 weeks to immature male chicks induced an apparent hypercalcemia and matrix formation of medullary bone, regardless of the vitamin D status of the chicks. Mineralization of medullary bone was observed only when vitamin D3 was administered together with the sex hormones. These results suggest that vitamin D3 is directly involved in the mineralization of medullary bone in birds. PMID:6311373

  11. Dystrophic Cutaneous Calcification and Metaplastic Bone Formation due to Long Term Bisphosphonate Use in Breast Cancer

    PubMed Central

    Tatl?, Ali Murat; Göksu, Sema Sezgin; Arslan, Deniz; Ba?sorgun, Cumhur ?brahim; Co?kun, Hasan ?enol

    2013-01-01

    Bisphosphonates are widely used in the treatment of breast cancer with bone metastases. We report a case of a female with breast cancer presented with a rash around a previous mastectomy site and a discharge lesion on her right chest wall in August 2010. Biopsy of the lesion showed dystrophic calcification and metaplastic bone formation. The patient's history revealed a long term use of zoledronic acid for the treatment of breast cancer with bone metastasis. We stopped the treatment since we believed that the cutaneous dystrophic calcification could be associated with her long term bisphosphonate therapy. Adverse cutaneous events with bisphosphonates are very rare, and dystrophic calcification has not been reported previously. The dystrophic calcification and metaplastic bone formation in this patient are thought to be due to long term bisphosphonate usage. PMID:23956898

  12. The effect of three hemostatic agents on early bone healing in an animal model

    PubMed Central

    2010-01-01

    Background Resorbable bone hemostasis materials, oxidized regenerated cellulose (ORC) and microfibrillar collagen (MFC), remain at the site of application for up to 8 weeks and may impair osteogenesis. Our experimental study compared the effect of a water-soluble alkylene oxide copolymer (AOC) to ORC and MFC versus no hemostatic material on early bone healing. Methods Two circular 2.7 mm non-critical defects were made in each tibia of 12 rabbits. Sufficient AOC, ORC or MFC was applied to achieve hemostasis, and effectiveness recorded. An autologous blood clot was applied to control defects. Rabbits were sacrificed at 17 days, tibiae excised and fixed. Bone healing was quantitatively measured by micro-computed tomography (micro-CT) expressed as fractional bone volume, and qualitatively assessed by histological examination of decalcified sections. Results Hemostasis was immediate after application of MFC and AOC, after 1-2 minutes with ORC, and >5 minutes for control. At 17 days post-surgery, micro-CT analysis showed near-complete healing in control and AOC groups, partial healing in the ORC group and minimal healing in the MFC group. Fractional bone volume was 8 fold greater in the control and AOC groups than in the MFC group (0.42 ± 0.06, 0.40 ± 0.03 vs 0.05 ± 0.01, P < 0.001) and over 1.5-fold greater than in the ORC group (0.25 ± 0.03, P < 0.05). By histology, MFC remained at the application site with minimal healing at the defect margins and early fibrotic tissue within the defect. ORC-treated defects showed partial healing but with early fibrotic tissue in the marrow space. Conversely, control and AOC-treated defects demonstrated newly formed woven bone rich in cellular activity with no evidence of AOC remaining at the application site. Conclusions Early healing appeared to be impaired by the presence of MFC and impeded by the presence of ORC. In contrast, AOC did not inhibit bone healing and suggest that AOC may be a better bone hemostatic material for procedures where bony fusion is critical and immediate hemostasis required. PMID:21167039

  13. Early Family Formation among White, Black, and Mexican American Women

    ERIC Educational Resources Information Center

    Landale, Nancy S.; Schoen, Robert; Daniels, Kimberly

    2010-01-01

    Using data from Waves I and III of Add Health, this study examines early family formation among 6,144 White, Black, and Mexican American women. Drawing on cultural and structural perspectives, models of the first and second family transitions (cohabitation, marriage, or childbearing) are estimated using discrete-time multinomial logistic…

  14. Glucocorticoid-induced bone loss can be reversed by the actions of PTH and Risedronate on different pathways for bone formation and mineralization

    PubMed Central

    Yao, Wei; Cheng, Zhiqiang; Pham, Aaron; Busse, Cheryl; Zimmermann, Elizabeth A.; Ritchie, Robert O.; Lane, Nancy E.

    2008-01-01

    Glucocorticoid (GC) excess decreases bone mineralization and microarchitecture and lead to reduced bone strength. Both anabolic (PTH) and anti-resorptive agents are used to prevent and treat GC-induced bone loss, yet these bone active agents alter bone turnover by very different mechanisms. Our study objective was to determine how PTH and risedronate (Ris) alter bone quality following GC excess. Five-month-old Swiss-Webster male mice were treated with the glucocorticoid (GC) prednisolone (5 mg/kg 60-day slow-release pellet) or placebo (PL)]. At day 28?56, two groups of GC-treated animals had either PTH (5?g/kg, 5x/wk) or Ris (5?g/kg, 5x/wk) intervention. Bone quality and quantity measurements include x-ray tomography microscopy (XTM) for the degree of bone mineralization (DBM), microCT for bone microarchitecture, compression testing for trabecular bone strength, biochemistry and histomorphometry for bone turnover. In addition, real-time PCR and immunohistochemistry were performed to monitor the expression of several key genes regulating Wnt signaling (bone formation) and mineralization. Results Compared to the placebo treated mice, GC treatment decreased trabecular bone volume (BV/TV) and serum osteocalcin, but increased serum CTX and osteoclast surface with a peak at day 28. GC+PTH increased and GC+Ris restored BV/TV to the PL levels after a 28 day treatment period. Average DBM was lowered after GC treatment (?27%), and it was restored to PL level with GC+Ris and GC+PTH. At day 56, RT-PCR revealed that continuous exposure to GC and GC+PTH increased, while GC+Ris decreased the expression of genes that inhibit bone mineralization (Dmp1 and Phex), compared to the PL group. Wnt signaling antagonists Dkk1, Sost and Wif1 were up-regulated by GC treatment but were down-regulated after GC+PTH treatment. Immunohistochemistry of bone sections found GC increased N terminal dmp-1 while PTH treatment increased both N and C terminal dmp-1 staining around osteocytes. Summary GC excess reduced expression of genes that regulate mineralization and increased expression of genes that inhibit Wnt signaling which were associated with reduced bone formation and bone volume over a 60 day treatment period. The addition of both PTH and Ris improved bone mass, DBM and bone strength during concurrent GC treatment, with PTH lowering expression of Wnt inhibitors and increasing bone formation; while Ris lowered the expression of mineralization inhibitors and reversed the deterioration of bone mineralization induced by GC excess. PMID:18975341

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

    Microsoft Academic Search

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

    1994-01-01

    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

  16. In vitro formation of osteoclasts from long-term cultures of bone marrow mononuclear phagocytes

    Microsoft Academic Search

    E. H. Burger; J. S. van de Gevel; J. C. Gribnau; C. W. Thesingh; R. van Furth

    1982-01-01

    The origin of osteoclasts was studied in an in vitro model using organ cultures of periosteum-free embryonic mouse long-bone primordia, which were co-cultured with various cell populations. The bone rudiments were freed of their periosteum-perichondrium by collagenase treatment in a stage before cartilage erosion and osteoclast formation, and co-cultured for 7 d with either embryonic liver or mononuclear phagocytes from

  17. Mechanical load increases in bone formation via a sclerostin-independent pathway.

    PubMed

    Morse, A; McDonald, M M; Kelly, N H; Melville, K M; Schindeler, A; Kramer, I; Kneissel, M; van der Meulen, M C H; Little, D G

    2014-11-01

    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. PMID:24821585

  18. cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo

    PubMed Central

    Siddappa, Ramakrishnaiah; Martens, Anton; Doorn, Joyce; Leusink, Anouk; Olivo, Cristina; Licht, Ruud; van Rijn, Linda; Gaspar, Claudia; Fodde, Riccardo; Janssen, Frank; van Blitterswijk, Clemens; de Boer, Jan

    2008-01-01

    Tissue engineering of large bone defects is approached through implantation of autologous osteogenic cells, generally referred to as multipotent stromal cells or mesenchymal stem cells (MSCs). Animal-derived MSCs successfully bridge large bone defects, but models for ectopic bone formation as well as recent clinical trials demonstrate that bone formation by human MSCs (hMSCs) is inadequate. The expansion phase presents an attractive window to direct hMSCs by pharmacological manipulation, even though no profound effect on bone formation in vivo has been described so far using this approach. We report that activation of protein kinase A elicits an immediate response through induction of genes such as ID2 and FosB, followed by sustained secretion of bone-related cytokines such as BMP-2, IGF-1, and IL-11. As a consequence, PKA activation results in robust in vivo bone formation by hMSCs derived from orthopedic patients. PMID:18490653

  19. cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo.

    PubMed

    Siddappa, Ramakrishnaiah; Martens, Anton; Doorn, Joyce; Leusink, Anouk; Olivo, Cristina; Licht, Ruud; van Rijn, Linda; Gaspar, Claudia; Fodde, Riccardo; Janssen, Frank; van Blitterswijk, Clemens; de Boer, Jan

    2008-05-20

    Tissue engineering of large bone defects is approached through implantation of autologous osteogenic cells, generally referred to as multipotent stromal cells or mesenchymal stem cells (MSCs). Animal-derived MSCs successfully bridge large bone defects, but models for ectopic bone formation as well as recent clinical trials demonstrate that bone formation by human MSCs (hMSCs) is inadequate. The expansion phase presents an attractive window to direct hMSCs by pharmacological manipulation, even though no profound effect on bone formation in vivo has been described so far using this approach. We report that activation of protein kinase A elicits an immediate response through induction of genes such as ID2 and FosB, followed by sustained secretion of bone-related cytokines such as BMP-2, IGF-1, and IL-11. As a consequence, PKA activation results in robust in vivo bone formation by hMSCs derived from orthopedic patients. PMID:18490653

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

    PubMed

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

    2012-06-01

    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

  1. Early archosauromorph remains from the Permo-Triassic Buena Vista Formation of north-eastern Uruguay.

    PubMed

    Ezcurra, Martín D; Velozo, Pablo; Meneghel, Melitta; Piñeiro, Graciela

    2015-01-01

    The Permo-Triassic archosauromorph record is crucial to understand the impact of the Permo-Triassic mass extinction on the early evolution of the group and its subsequent dominance in Mesozoic terrestrial ecosystems. However, the Permo-Triassic archosauromorph record is still very poor in most continents and hampers the identification of global macroevolutionary patterns. Here we describe cranial and postcranial bones from the Permo-Triassic Buena Vista Formation of northeastern Uruguay that contribute to increase the meagre early archosauromorph record from South America. A basioccipital fused to both partial exoccipitals and three cervical vertebrae are assigned to Archosauromorpha based on apomorphies or a unique combination of characters. The archosauromorph remains of the Buena Vista Formation probably represent a multi-taxonomic assemblage composed of non-archosauriform archosauromorphs and a 'proterosuchid-grade' animal. This assemblage does not contribute in the discussion of a Late Permian or Early Triassic age for the Buena Vista Formation, but reinforces the broad palaeobiogeographic distribution of 'proterosuchid grade' diapsids in Permo-Triassic beds worldwide. PMID:25737816

  2. Early archosauromorph remains from the Permo-Triassic Buena Vista Formation of north-eastern Uruguay

    PubMed Central

    Velozo, Pablo; Meneghel, Melitta; Piñeiro, Graciela

    2015-01-01

    The Permo-Triassic archosauromorph record is crucial to understand the impact of the Permo-Triassic mass extinction on the early evolution of the group and its subsequent dominance in Mesozoic terrestrial ecosystems. However, the Permo-Triassic archosauromorph record is still very poor in most continents and hampers the identification of global macroevolutionary patterns. Here we describe cranial and postcranial bones from the Permo-Triassic Buena Vista Formation of northeastern Uruguay that contribute to increase the meagre early archosauromorph record from South America. A basioccipital fused to both partial exoccipitals and three cervical vertebrae are assigned to Archosauromorpha based on apomorphies or a unique combination of characters. The archosauromorph remains of the Buena Vista Formation probably represent a multi-taxonomic assemblage composed of non-archosauriform archosauromorphs and a ‘proterosuchid-grade’ animal. This assemblage does not contribute in the discussion of a Late Permian or Early Triassic age for the Buena Vista Formation, but reinforces the broad palaeobiogeographic distribution of ‘proterosuchid grade’ diapsids in Permo-Triassic beds worldwide. PMID:25737816

  3. Physical Mechanisms of Pattern Formation in the Early Chick Embryo

    NASA Astrophysics Data System (ADS)

    Balter, Ariel; Glazier, James; Zaitlen, Benji; Chaplain, Mark; Weijer, Cornelis

    2007-03-01

    Gastrulation marks a critical step in early embryogenesis when the first recognizable patterns are laid down. Although the genome maintains ultimate responsibility for this pattern formation, it cannot actually control the organization of individual cells. The robustness of embryogenic pattern formation suggests that a few simple, physical mechanisms are unleashed and that self-organization results. We perform numerical simulations of early chick gastrulation using an agent based method in which individual cells interact via a handful of behaviors including adhesivity, secretion and chemotaxis. Through these simulations we have identified certain behaviors as being important for various stages and morphological events. For instance, experimental results on primitive streak formation are best reproduced by a model in which the Kohler's Sickle secretes a chemo repellant for streak tip cells, and cell polarization appears to be important for initiating polonaise motion during streak elongation.

  4. WNT7B Promotes Bone Formation in part through mTORC1

    PubMed Central

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

    2014-01-01

    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

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

    PubMed Central

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

    2013-01-01

    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

  6. Circulating Bone Marrow Cells Can Contribute to Neointimal Formation

    Microsoft Academic Search

    Chih-lu Han; Gordon R. Campbell; Julie H. Campbell

    2001-01-01

    To examine the source of smooth muscle-like cells during vascular healing, C57BL\\/6 (Ly 5.2) female mice underwent whole body irradiation followed by transfusion with 106 nucleated bone marrow cells from congenic (Ly 5.1) male donors. Successful repopulation (88.4 ± 4.9%) by donor marrow was demonstrated in the female mice by flow cytometry with FITC-conjugated A20.1\\/Ly 5.1 monoclonal antibody after 4

  7. Perlecan modulates VEGF signaling and is essential for vascularization in endochondral bone formation

    PubMed Central

    Ishijima, Muneaki; Suzuki, Nobuharu; Hozumi, Kentaro; Matsunobu, Tomoya; Kosaki, Keisuke; Kaneko, Haruka; Hassell, John R.; Arikawa-Hirasawa, Eri; Yamada, Yoshihiko

    2012-01-01

    Perlecan (Hspg2) is a heparan sulfate proteoglycan expressed in basement membranes and cartilage. Perlecan deficiency (Hspg2?/?) in mice and humans causes lethal chondrodysplasia, which indicates that perlecan is essential for cartilage development. However, the function of perlecan in endochondral ossification is not clear. Here, we report the critical role of perlecan in VEGF signaling and angiogenesis in growth plate formation. The Hspg2?/? growth plate was significantly wider but shorter due to severely impaired endochondral bone formation. Hypertrophic chondrocytes were differentiated in Hspg2?/? growth plates; however, removal of the hypertrophic matrix and calcified cartilage was inhibited. Although the expression of MMP-13, CTGF, and VEGFA was significantly upregulated in Hspg2?/? growth plates, vascular invasion into the hypertrophic zone was impaired, which resulted in an almost complete lack of bone marrow and trabecular bone. We demonstrated that cartilage perlecan promoted activation of VEGF/VEGFR by binding to the VEGFR of endothelial cells. Expression of the perlecan transgene specific to the cartilage of Hspg2?/? mice rescued their perinatal lethality and growth plate abnormalities, and vascularization into the growth plate was restored, indicating that perlecan in the growth plate, not in endothelial cells, is critical in this process. These results suggest that perlecan in cartilage is required for activating VEGFR signaling of endothelial cells for vascular invasion and for osteoblast migration into the growth plate. Thus, perlecan in cartilage plays a critical role in endochondral bone formation by promoting angiogenesis essential for cartilage matrix remodeling and subsequent endochondral bone formation. PMID:22421594

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

    Microsoft Academic Search

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

    2002-01-01

    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

  9. Apoptosis-associated uncoupling of bone formation and resorption in osteomyelitis

    PubMed Central

    Marriott, Ian

    2013-01-01

    The mechanisms underlying the destruction of bone tissue in osteomyelitis are only now being elucidated. While some of the tissue damage associated with osteomyelitis likely results from the direct actions of bacteria and infiltrating leukocytes, perhaps exacerbated by bacterial manipulation of leukocyte survival pathways, infection-induced bone loss predominantly results from an uncoupling of the activities of osteoblasts and osteoclasts. Bacteria or their products can directly increase osteoclast formation and activity, and the inflammatory milieu at sites of infection can further promote bone resorption. In addition, osteoclast activity is critically regulated by osteoblasts that can respond to bacterial pathogens and foster both inflammation and osteoclastogenesis. Importantly, bone loss during osteomyelitis is also brought about by a decline in new bone deposition due to decreased bone matrix synthesis and by increased rates of osteoblast apoptosis. Extracellular bacterial components may be sufficient to reduce osteoblast viability, but the causative agents of osteomyelitis are also capable of inducing continuous apoptosis of these cells by activating intrinsic and extrinsic cell death pathways to further uncouple bone formation and resorption. Interestingly, bacterial internalization appears to be required for maximal osteoblast apoptosis, and cytosolic inflammasome activation may act in concert with autocrine/paracrine death receptor-ligand signaling to induce cell death. The manipulation of apoptotic pathways in infected bone cells could be an attractive new means to limit inflammatory damage in osteomyelitis. However, the mechanism that is the most important in bacterium-induced bone loss has not yet been identified. Furthermore, it remains to be determined whether the host would be best served by preventing osteoblast cell death or by promoting apoptosis in infected cells. PMID:24392356

  10. Effects of designed PLLA and 50:50 PLGA scaffold architectures on bone formation in vivo.

    PubMed

    Saito, Eiji; Liao, Elly E; Hu, Wei-Wen; Krebsbach, Paul H; Hollister, Scott J

    2013-02-01

    Biodegradable porous scaffolds have been investigated as an alternative approach to current metal, ceramic, and polymer bone graft substitutes for lost or damaged bone tissues. Although there have been many studies investigating the effects of scaffold architecture on bone formation, many of these scaffolds were fabricated using conventional methods such as salt leaching and phase separation, and were constructed without designed architecture. To study the effects of both designed architecture and material on bone formation, this study designed and fabricated three types of porous scaffold architecture from two biodegradable materials, poly (L-lactic acid) (PLLA) and 50:50 Poly(lactic-co-glycolic acid) (PLGA), using image based design and indirect solid freeform fabrication techniques, seeded them with bone morphogenetic protein-7 transduced human gingival fibroblasts, and implanted them subcutaneously into mice for 4 and 8?weeks. Micro-computed tomography data confirmed that the fabricated porous scaffolds replicated the designed architectures. Histological analysis revealed that the 50:50 PLGA scaffolds degraded but did not maintain their architecture after 4?weeks implantation. However, PLLA scaffolds maintained their architecture at both time points and showed improved bone ingrowth, which followed the internal architecture of the scaffolds. Mechanical properties of both PLLA and 50:50 PLGA scaffolds decreased but PLLA scaffolds maintained greater mechanical properties than 50:50 PLGA after implantation. The increase of mineralized tissue helped support the mechanical properties of bone tissue and scaffold constructs between 4-8?weeks. The results indicate the importance of choice of scaffold materials and computationally designed scaffolds to control tissue formation and mechanical properties for desired bone tissue regeneration. PMID:22162220

  11. Effects of designed PLLA and 50:50PLGA scaffold architectures on bone formation in vivo

    PubMed Central

    Saito, Eiji; Liao, Elly E.; Hu, Wei-Wen; Krebsbach, Paul H.; Hollister, Scott J.

    2015-01-01

    Biodegradable porous scaffolds have been investigated as an alternative approach to current metal, ceramic, and polymer bone graft substitutes for lost or damaged bone tissues. Although there have been many studies investigating the effects of scaffold architecture on bone formation, many of these scaffolds were fabricated using conventional methods, such as salt leaching and phase separation, and were constructed without designed architecture. To study the effects of both designed architecture and material on bone formation, we designed and fabricated three types of porous scaffold architecture from two biodegradable materials, poly (L-lactic acid) (PLLA) and 50:50Poly (lactic-co-glycolic acid) (PLGA) using image based design and indirect solid freeform fabrication techniques, seeded them with bone morphogenic protein-7 transduced human gingival fibroblasts and implanted them subcutaneously into mice for 4 and 8 weeks. Micro-computed tomography data confirmed that the fabricated porous scaffolds replicated the designed architectures. Histological analysis revealed that the 50:50PLGA scaffolds degraded and did not maintain their architecture after 4 weeks. The PLLA scaffolds maintained their architecture at both time points and showed improved bone ingrowth which followed the internal architecture of the scaffolds. Mechanical properties of both PLLA and 50:50PLGA scaffolds decreased, but PLLA scaffolds maintained greater mechanical properties than 50:50PLGA after implantation. The increase of mineralized tissue helped to support mechanical properties of bone tissue and scaffold constructs from 4 to 8 weeks. The results indicated the importance of choice of scaffold materials and computationally designed scaffolds to control tissue formation and mechanical properties for desired bone tissue regeneration. PMID:22162220

  12. Bone mineral content in early-postmenopausal and postmenopausal osteoporotic women: comparison of measurement methods

    SciTech Connect

    Reinbold, W.D.; Genant, H.K.; Reiser, U.J.; Harris, S.T.; Ettinger, B.

    1986-08-01

    To investigate associations among methods for noninvasive measurement of skeletal bone mass, we studied 40 healthy early postmenopausal women and 68 older postmenopausal women with osteoporosis. Methods included single- and dual-energy quantitative computed tomography (QCT) and dual-photon absorptiometry (DPA) of the lumbar spine, single-photon absorptiometry (SPA) of the distal third of the radius, and combined cortical thickness (CCT) of the second metacarpal shaft. Lateral thoracolumbar radiography was performed, and a spinal fracture index was calculated. There was good correlation between QCT and DPA methods in early postmenopausal women and modest correlation in postmenopausal osteoporotic women. Correlations between spinal measurements (QCT or DPA) and appendicular cortical measurements (SPA or CCT) were modest in healthy women and poor in osteoporotic women. Measurements resulting from one method are not predictive of those by another method for the individual patient. The strongest correlation with severity of vertebral fracture is provided by QCT; the weakest, by SPA. There was a high correlation between single- and dual-energy QCT results, indicating that errors due to vertebral fat are not substantial in these postmenopausal women. Single-energy QCT may be adequate and perhaps preferable for assessing postmenopausal women. The measurement of spinal trabecular bone density by QCT discriminates between osteoporotic women and younger healthy women with more sensitivity than measurements of spinal integral bone by DPA or of appendicular cortical bone by SPA or CCT.

  13. In vivo stimulation of bone formation by aluminum and oxygen plasma surface-modified magnesium implants.

    PubMed

    Wong, Hoi Man; Zhao, Ying; Tam, Vivian; Wu, Shuilin; Chu, Paul K; Zheng, Yufeng; To, Michael Kai Tsun; Leung, Frankie K L; Luk, Keith D K; Cheung, Kenneth M C; Yeung, Kelvin W K

    2013-12-01

    A newly developed magnesium implant is used to stimulate bone formation in vivo. The magnesium implant after undergoing dual aluminum and oxygen plasma implantation is able to suppress rapid corrosion, leaching of magnesium ions, as well as hydrogen gas release from the biodegradable alloy in simulated body fluid (SBF). No released aluminum is detected from the SBF extract and enhanced corrosion resistance properties are confirmed by electrochemical tests. In vitro studies reveal enhanced growth of GFP mouse osteoblasts on the aluminum oxide coated sample, but not on the untreated sample. In addition to that a small amount (50 ppm) of magnesium ions can enhance osteogenic differentiation as reported previously, our present data show a low concentration of hydrogen can give rise to the same effect. To compare the bone volume change between the plasma-treated magnesium implant and untreated control, micro-computed tomography is performed and the plasma-treated implant is found to induce significant new bone formation adjacent to the implant from day 1 until the end of the animal study. On the contrary, bone loss is observed during the first week post-operation from the untreated magnesium sample. Owing to the protection offered by the Al2O3 layer, the plasma-treated implant degrades more slowly and the small amount of released magnesium ions stimulate new bone formation locally as revealed by histological analyses. Scanning electron microscopy discloses that the Al2O3 layer at the bone-implant interface is still present two months after implantation. In addition, no inflammation or tissue necrosis is observed from both treated and untreated implants. These promising results suggest that the plasma-treated magnesium implant can stimulate bone formation in vivo in a minimal invasive way and without causing post-operative complications. PMID:24060425

  14. Quantitative analysis of factors influencing tissue-engineered bone formation by detecting the expression levels of alkaline phosphatase and bone ?-carboxyglutamate protein 2

    PubMed Central

    SONG, ZEZHONG; WU, CHANGSHUN; SUN, SHUI; LI, HUIBO; WANG, DONG; GONG, JIANBAO; YAN, ZEXING

    2015-01-01

    Bone tissue engineering is a promising alternative approach that permits the efficient reconstruction of bone defects. There are four elements involved in bone tissue engineering technology, including the seed cells, growth factors, scaffolds and culture environment. The aim of the present study was to evaluate the effect of these factors on bone formation in tissue engineering technology by analyzing the expression of osteogenetic markers using polymerase chain reaction (PCR). Bone marrow mesenchymal stem cells (BMSCs) were extracted from the bone marrow of the bilateral tibial platform of New Zealand white rabbits. In addition, platelet-rich plasma (PRP) samples were prepared from blood extracted from the ear vein of the rabbits. A perfusion bioreactor was used to provide the culture environment, and ?-tricalcium phosphate (?-TCP) was used to build the scaffolds. The ?-TCP scaffolds were divided into five groups and each group was treated with a different combination of the factors. Next, the composites were implanted into the rabbits. After three months, the expression levels of the new bone formation markers, alkaline phosphatase and bone ?-carboxyglutamate protein 2, were detected using quantitative reverse transcription-PCR analysis. The expression levels of the markers in the experimental groups were higher compared with the negative control group. Comparisons between the experimental groups also revealed statistical significance. Scanning electron microscopy revealed good adhesion and distribution of the BMSCs on the ?-TCP scaffold. In conclusion, the PCR results indicated that PRP, BMSCs and the bioreactor exhibited a promoting effect on bone formation. PMID:25780393

  15. The Importance of the Prenyl Group in the Activities of Osthole in Enhancing Bone Formation and Inhibiting Bone Resorption In Vitro

    PubMed Central

    Zhai, Yuan-Kun; Pan, Ya-Lei; Niu, Yin-Bo; Li, Chen-Rui; Wu, Xiang-Long; Fan, Wu-Tu; Lu, Ting-Li; Mei, Qi-Bing; Xian, Cory J.

    2014-01-01

    Osteoporosis treatment always aimed at keeping the balance of bone formation and bone resorption. Recently, prenyl group in natural products has been proposed as an active group to enhance the osteogenesis process. Osthole has both the prenyl group and bone-protective activities, but the relationship is still unknown. In this study we found that osthole exerted a potent ability to promote proliferation and osteogenic function of rat bone marrow stromal cells and osteoblasts, including improved cell viability, alkaline phosphatase activity, enhanced secretion of collagen-I, bone morphogenetic protein-2, osteocalcin and osteopontin, stimulated mRNA expression of insulin-like growth factor-1, runt-related transcription factor-2, osterix, OPG (osteoprotegerin), RANKL (receptor activator for nuclear factor-?B ligand), and the ratio of OPG/RANKL, as well as increasing the formation of mineralized nodules. However, 7-methoxycoumarin had no obvious effects. Osthole also inhibited osteoclastic bone resorption to a greater extent than 7-methoxycoumarin, as shown by a lower tartrate-resistant acid phosphatase activity and lower number and smaller area of resorption pits. Our findings demonstrate that osthole could be a potential agent to stimulate bone formation and inhibit bone resorption, and the prenyl group plays an important role in these bone-protective effects. PMID:25147567

  16. Transcriptional regulation of vascular bone morphogenetic protein by endothelin receptors in early autoimmune diabetes mellitus

    Microsoft Academic Search

    Philipp C. Nett; Jana Ortmann; Jennifer Celeiro; Elvira Haas; Regina Hofmann-Lehmann; Luigi Tornillo; Luigi M. Terraciano; Matthias Barton

    2006-01-01

    Endothelin (ET) and bone morphogenic proteins (BMP) have been implicated in the development of micro- and macrovascular complications of type 2 diabetes mellitus due to atherosclerosis. This study investigated vascular BMP-expression during early development of experimental autoimmune diabetes mellitus and whether ET(A) receptors are involved in its regulation, using the selective ET(A) receptor antagonist BSF461314. Specificity of BSF461314 was confirmed

  17. Breastfeeding in Early Life and Bone Mass in Prepubertal Children: A Longitudinal Study

    Microsoft Academic Search

    G. Jones; M. Riley; T. Dwyer

    2000-01-01

    :   The aim of this study was to determine whether breastfeeding in early life is associated with bone mass in prepubertal children.\\u000a We studied 330 8-year-old male and female children from Southern Tasmania representing 47% of those who originally took part\\u000a in a birth cohort study of risk factors for Sudden Infant Death Syndrome in 1988. Breastfeeding intention and habit

  18. Lipoic acid increases the expression of genes involved in bone formation in mice fed a high-fat diet

    Microsoft Academic Search

    Ying Xiao; Jue Cui; Yonghui Shi; Guowei Le

    2011-01-01

    Antioxidant lipoic acid (LA) has been reported to have a potential prophylactic effect on bone loss induced by high-fat diet (HFD). The aim of this work was to examine the hypothesis that LA decreases bone resorption–related gene expression and increases bone formation–related gene expression in HFD-fed mice, preventing a shift in the bone metabolism balance toward resorption. Male C57BL\\/6 mice

  19. Bone marrow-derived cells are the major source of MMP-9 contributing to blood-brain barrier dysfunction and infarct formation after ischemic stroke in mice

    PubMed Central

    Wang, Guangming; Guo, Qingmin; Hossain, Mohammed; Fazio, Vince; Zeynalov, Emil; Janigro, Damir; Mayberg, Marc R.; Namura, Shobu

    2009-01-01

    Matrix metalloproteinase (MMP)-9 has been shown to contribute to blood-brain barrier (BBB) disruption, infarct formation, and hemorrhagic transformation after ischemic stroke. The cellular source of MMP-9 detectable in the ischemic brain remains controversial since extracellular molecules in the brain may be derived from blood. We here demonstrate that bone marrow-derived cells are the major source of MMP-9 in the ischemic brain. We made bone marrow chimeric mice with MMP-9 null and wild-type as donor and recipient. After 90 min of transient focal cerebral ischemia, MMP-9 null mice receiving wild-type bone marrow showed comparable outcomes to wild-type in brain MMP-9 levels and BBB disruption (endogenous albumin extravasation) at 1 h post-reperfusion and infarct size at 24 h post-reperfusion. In contrast, wild-type animals replaced with MMP-9 null bone marrow showed barely detectable levels of MMP-9 in the ischemic brain, with attenuations in BBB disruption and infarct size. MMP-9 null mice receiving wild-type bone marrow showed enhanced Evans blue extravasation as early as 1 h post-reperfusion compared to wild-type mice replaced with MMP-9 null bone marrow. These findings suggest that MMP-9 released from bone marrow-derived cells influences the progression of BBB disruption in the ischemic brain. PMID:19646426

  20. Mild exercise early in life produces changes in bone size and strength but not density in proximal phalangeal, third metacarpal and third carpal bones of foals.

    PubMed

    Firth, Elwyn C; Rogers, Christopher W; van Weeren, P Rene; Barneveld, Albert; McIlwraith, C Wayne; Kawcak, Christopher E; Goodship, Allen E; Smith, Roger K W

    2011-12-01

    Exercise or lack of it in early life affects chondro-osseous development. Two groups of horses were used to investigate the effects of age and exercise regimen on bone parameters of diaphyseal, metaphyseal, epiphyseal and cuboidal bones of the distal limb of Thoroughbreds. One group had exercised only spontaneously from an early age at pasture (PASTEX group), while the other group of horses were exposed to a 30% greater workload through additional defined exercise (CONDEX). Longitudinal data from peripheral quantitative computed tomography (pQCT) were obtained from eight scan sites of the left forelimb (proximal phalangeal (P(p); 1 site), third metacarpal (Mc3; six sites) and third carpal (C(3); one site) bones) of 32 Thoroughbred foals scanned five times from ?3 weeks to 17 months of age. The primary outcome measures were bone mineral content (BMC), bone area (BA), and periosteal circumference (Peri C) in diaphyseal bone, with cortical thickness (CortTh), volumetric bone mineral density (BMD(v)) and a bone strength index (SSI) also being analysed. At the P(p) site within the model there was a significant effect (P=0.00-0.025) of conditioning exercise increasing bone parameters, except endosteal circumference (Endo C) and BMD(v). The BMC, BA, and SSI of P(p) were significantly greater in the CONDEX than PASTEX groups at 12 and 17 months (P=0.015-0.042) and CortTh at 17 months (P=0.033). At the M55 site of Mc3 BMC, BA and SSI (P=0.02-0.04), and at the M33 site, SSI (P=0.05) were higher in the CONDEX than PASTEX group. The adaptive responses, consistent with diaphyseal strengthening, were more marked in the diaphysis of P(p) than Mc3. In the Mc3, metaphysis, trabecular BMD(v) was less in the CONDEX than PASTEX group, associated with greater bone mineral accretion in the outer cortical-sub-cortical bone in the CONDEX group. There were no significant between-group differences in any epiphyseal or cuboidal bone parameter. Although the early imposed exercise regimen was not intensive, it had significant effects on diaphyseal bone strength, through change in size but not bone density. PMID:21186128

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

    NASA Technical Reports Server (NTRS)

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

    1985-01-01

    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.

  2. Titanium nanotubes activate genes related to bone formation in vitro

    PubMed Central

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

    2012-01-01

    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

  3. Unique Roles of Phosphorus in Endochondral Bone Formation and Osteocyte Maturation

    PubMed Central

    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

    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

  4. [The influence of direct electric current on bone formation (author's transl)].

    PubMed

    Harris, W H; Moyen, B; Lahey, P; Weinberg, E

    1979-09-01

    The authors have studied the effects of a 20 microampere current applied to bone in rabbits and dogs. The results have been analysed according to the age of animal, whether mature or immature, and the nature of the electrode (whether steel or platinum). They found no different in the osteogenesis produced in the medullary canal which was constant. The authors further studied the effects of currents on osteotomies of the radius in dogs which generally led to non-union in the absence of electrical currents. They failed to demonstrate any stimulation of bone repair by the current. They conclude that bone formation in the medullary canal of intact bones and the repair of fractures are two different processes. PMID:161635

  5. Erythropoietin Promotes Bone Formation through EphrinB2/EphB4 Signaling.

    PubMed

    Li, C; Shi, C; Kim, J; Chen, Y; Ni, S; Jiang, L; Zheng, C; Li, D; Hou, J; Taichman, R S; Sun, H

    2015-03-01

    Recent studies have demonstrated that erythropoietin (EPO) has extensive nonhematopoietic biological functions. However, little is known about how EPO regulates bone formation, although several studies suggested that EPO can affect bone homeostasis. In this study, we investigated the effects of EPO on the communication between osteoclasts and osteoblasts through the ephrinB2/EphB4 signaling pathway. We found that EPO slightly promotes osteoblastic differentiation with the increased expression of EphB4 in ST2 cells. However, EPO increased the expression of Nfatc1 and ephrinB2 but decreased the expression of Mmp9 in RAW264.7 cells, resulting in an increase of ephrinB2-expressing osteoclasts and a decrease in resorption activity. The stimulation of ephrinB2/EphB4 signaling via ephrinB2-Fc significantly promoted EPO-mediated osteoblastic differentiation in ST2 cells. EphB4 knockdown through EphB4 shRNA inhibited EPO-mediated osteoblastic phenotypes. Furthermore, in vivo assays clearly demonstrated that EPO efficiently induces new bone formation in the alveolar bone regeneration model. Taken together, these results suggest that ephrinB2/EphB4 signaling may play an important role in EPO-mediated bone formation. PMID:25586589

  6. Dual-phase osteogenic and vasculogenic engineered tissue for bone formation.

    PubMed

    Rao, Rameshwar R; Vigen, Marina L; Peterson, Alexis W; Caldwell, David J; Putnam, Andrew J; Stegemann, Jan P

    2015-02-01

    Minimally invasive, injectable bone tissue engineering therapies offer the potential to facilitate orthopedic repair procedures, including in indications where enhanced bone regeneration is needed for complete healing. In this study, we developed a dual-phase tissue construct consisting of osteogenic (Osteo) and vasculogenic (Vasculo) components. A modular tissue engineering approach was used to create collagen/fibrin/hydroxyapatite (COL/FIB/HA) hydrogel microbeads containing embedded human bone marrow-derived mesenchymal stem cells (bmMSC). These microbeads were predifferentiated toward the osteogenic lineage in vitro for 14 days, and they were then embedded within a COL/FIB vasculogenic phase containing a coculture of undifferentiated bmMSC and human umbilical vein endothelial cells (HUVEC). In vitro studies demonstrated homogenous dispersion of microbeads within the outer phase, with endothelial network formation around the microbeads over 14 days in the coculture conditions. Subcutaneous injection into immunodeficient mice was used to investigate the ability of dual-phase (Osteo+Vasculo) and control (Osteo, Vasculo, Blank) constructs to form neovasculature and ectopic bone. Laser Doppler imaging demonstrated blood perfusion through all constructs at 1, 4, and 8 weeks postimplantation. Histological quantification of total vessel density showed no significant differences between the conditions. Microcomputed tomography indicated significantly higher ectopic bone volume (BV) in the Osteo condition at 4 weeks. At 8 weeks both the Osteo and Blank groups exhibited higher BV compared to the Vasculo and dual Osteo+Vasculo groups. These data not only show that osteogenic microbeads can be used to induce ectopic bone formation, but also suggest an inhibitory effect on BV when undifferentiated bmMSC and HUVEC were included in dual-phase constructs. This work may lead to improved methods for engineering vascularized bone tissue, and to injectable therapies for the treatment of orthopedic pathologies in which bone regeneration is delayed or prevented. PMID:25228401

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

    Microsoft Academic Search

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

    2007-01-01

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

  8. Recombinant Vgr-1/BMP-6-expressing tumors induce fibrosis and endochondral bone formation in vivo

    PubMed Central

    1994-01-01

    Members of the TGF-beta superfamily appear to modulate mesenchymal differentiation, including the processes of cartilage and bone formation. Nothing is yet known about the function of the TGF-beta- related factor vgr-1, also called bone morphogenetic protein-6 (BMP-6), and only limited studies have been conducted on the most closely related factors BMP-5, osteogenic protein-1 (OP-1) or BMP-7, and OP-2. Because vgr-1 mRNA has been localized in hypertrophic cartilage, this factor may play a vital role in endochondral bone formation. We developed antibodies to vgr-1, and documented that vgr-1 protein was expressed in hypertrophic cartilage of mice. To further characterize the role of this protein in bone differentiation, we generated CHO cells that overexpressed recombinant murine vgr-1 protein. Western blot analysis documented that recombinant vgr-1 protein was secreted into the media and was proteolytically processed to yield the mature vgr-1 molecule. To assess the biological activity of recombinant vgr-1 in vivo, we introduced the vgr-1-expressing CHO cells directly into the subcutaneous tissue of athymic nude mice. CHO-vgr-1 cells produced localized tumors, and the continuous secretion of vgr-1 resulted in tumors with a strikingly different gross and histological appearance as compared to the parental CHO cells. The tumors of control CHO cells were hemorrhagic, necrotic, and friable, whereas the CHO-vgr-1 tumors were dense, firm, and fibrotic. In contrast with control CHO tumors, the nests of CHO-vgr-1 tumor cells were surrounded by extensive connective tissue, which contained large regions of cartilage and bone. Further analysis indicated that secretion of vgr-1 from the transfected CHO tumor cells induced the surrounding host mesenchymal cells to develop along the endochondral bone pathway. These findings suggest that endochondral bone formation. PMID:8089189

  9. 3D analysis of bone formation around titanium implants using micro-computed tomography (?CT)

    NASA Astrophysics Data System (ADS)

    Bernhardt, Ricardo; Scharnweber, Dieter; Müller, Bert; Beckmann, Felix; Goebbels, Jürgen; Jansen, John; Schliephake, Henning; Worch, Hartmut

    2006-08-01

    The quantitative analysis of bone formation around biofunctionalised metallic implants is an important tool for the further development of implants with higher success rates. This is, nowadays, especially important in cases of additional diseases like diabetes or osteoporosis. Micro computed tomography (?CT), as non-destructive technique, offers the possibility for quantitative three-dimensional recording of bone close to the implant's surface with micrometer resolution, which is the range of the relevant bony structures. Within different animal models using cylindrical and screw-shaped Ti6Al4V implants we have compared visualization and quantitative analysis of newly formed bone by the use of synchrotron-radiation-based CT-systems in comparison with histological findings. The SR?CT experiments were performed at the beamline BW 5 (HASYLAB at DESY, Hamburg, Germany; at the BAMline (BESSY, Berlin, Germany). For the experiments, PMMA-embedded samples were prepared with diameters of about 8 mm, which contain in the center the implant surrounded by the bony tissue. To (locally) quantify the bone formation, models were developed and optimized. The comparison of the results obtained by SR?CT and histology demonstrates the advantages and disadvantages of both approaches, although the bone formation values for the different biofunctionalized implants are identical within the error bars. SR?CT allows the clear identification of fully mineralized bone around the different titanium implants. As hundreds of virtual slices were easily generated for the individual samples, the quantification and interactive bone detection led to conclusions of high precision and statistical relevance. In this way, SR?CT in combination with interactive data analysis is proven to be more significant with respect to classical histology.

  10. Thrombospondin 1 promotes synaptic formation in bone marrow-derived neuron-like cells?

    PubMed Central

    Huang, Yun; Lu, Mingnan; Guo, Weitao; Zeng, Rong; Wang, Bin; Wang, Huaibo

    2013-01-01

    In this study, a combination of growth factors was used to induce bone marrow mesenchymal stem cells differentiation into neuron-like cells, in a broader attempt to observe the role of thrombospondin 1 in synapse formation. Results showed that there was no significant difference in the differentiation rate of neuron-like cells between bone marrow mesenchymal stem cells with thrombospondin induction and those without. However, the cell shape was more complex and the neurites were dendritic, with unipolar, bipolar or multipolar morphologies, after induction with thrombospondin 1. The induced cells were similar in morphology to normal neurites. Immunohistochemical staining showed that the number of positive cells for postsynaptic density protein 95 and synaptophysin 1 protein was significantly increased after induction with thrombospondin 1. These findings indicate that thrombospondin 1 promotes synapse formation in neuron-like cells that are differentiated from bone marrow mesenchymal stem cells. PMID:25206378

  11. Chondroid Syringoma with Extensive Bone Formation: A Case Report and Review of the Literature

    PubMed Central

    Yurdakul, Cuneyt; Sehitoglu, Ibrahim; Gucer, Hasan; Tunc, Suphan

    2014-01-01

    Chondroid syringoma is a rare, skin appendageal tumour, usually reported at the head and neck region. It is a mostly intradermal and rarely subcutaneous small painless nodule. The histopathological examination is characterized by a combination of epithelial and myoepithelial structures within a chondromyxoid and fibrous stroma. Herein, we present a rare case of chondroid syringoma with extensive bone formation. PMID:25478357

  12. Chondroid syringoma with extensive bone formation: a case report and review of the literature.

    PubMed

    Bedir, Recep; Yurdakul, Cuneyt; Sehitoglu, Ibrahim; Gucer, Hasan; Tunc, Suphan

    2014-10-01

    Chondroid syringoma is a rare, skin appendageal tumour, usually reported at the head and neck region. It is a mostly intradermal and rarely subcutaneous small painless nodule. The histopathological examination is characterized by a combination of epithelial and myoepithelial structures within a chondromyxoid and fibrous stroma. Herein, we present a rare case of chondroid syringoma with extensive bone formation. PMID:25478357

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

    E-print Network

    Lu, Helen H.

    Controlled delivery of platelet-rich plasma-derived growth factors for bone formation Helen H. Lu,1.interscience.wiley.com). DOI: 10.1002/jbm.a.31740 Abstract: Platelet-rich plasma (PRP) represents an autolo- gous source of PRP-derived growth factors using a hydrogel carrier system. Specifically, the release of platelet

  14. Bio-adhesive Surfaces to Promote Osteoblast Differentiation and Bone Formation

    Microsoft Academic Search

    A. J. García; C. D. Reyes

    2005-01-01

    Binding of integrin adhesion receptors to extracellular matrix components, such as fibronectin and type I collagen, activates signaling pathways directing osteoblast survival, cell-cycle progression, gene expression, and matrix mineralization. Biomimetic strategies exploit these adhesive interactions to engineer bio-inspired surfaces that promote osteoblast adhesion and differentiation, bone formation, and osseointegration. These emerging initiatives focus on directing integrin binding through presentation of

  15. Influence of fluoride in poly(d,l-lactide)/apatite composites on bone formation.

    PubMed

    Luo, X; Barbieri, D; Passanisi, G; Yuan, H; de Bruijn, J D

    2015-05-01

    The influence of fluoride in poly(d,l-lactide)/apatite composites on ectopic bone formation was evaluated in sheep. Nano-apatite powders with different replacement levels of OH groups by fluoride (F) (0% (F0), 50% (F50), 100% (F100), and excessive (F200)) were co-extruded with poly (d,l-lactide) at a weight ratio of 1:1. Fluoride release from the composites (CF0, CF50, CF100, and CF200) was evaluated in vitro and bone formation was assessed after intramuscular implantation in sheep. After 24 weeks in simulated physiological solution, CF0 and CF50 showed negligible fluoride release, whereas it was considerable from the CF100 and CF200 composites. Histology showed that the incidence of de novo bone formation decreased in implants with increasing fluoride content indicating a negative influence of fluoride on ectopic bone formation. Furthermore, a significant decrease in resorption of the high fluoride-content composites and a reduction in the number of multinucleated giant cells were seen. These results show that instead of promoting, the presence of fluoride in poly(d,l-lactide)/apatite composites seemed to suppresses their resorption and osteoinductive potential in non-osseous sites. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 103B: 841-852, 2015. PMID:25132540

  16. Intermittent administration of human parathyroid hormone enhances bone formation and union at the site of cancellous bone osteotomy in normal and ovariectomized rats.

    PubMed

    Nozaka, Koji; Miyakoshi, Naohisa; Kasukawa, Yuji; Maekawa, Shigeto; Noguchi, Hideaki; Shimada, Yoichi

    2008-01-01

    Intermittent administration of human parathyroid hormone (hPTH) has an anabolic effect on bone in animals and humans and is expected to be a potent agent for the treatment of osteoporosis. However, little is known about the effects of hPTH on cancellous bone healing after cancellous bone fractures or osteotomies. We evaluated whether hPTH enhanced bone union at the site of cancellous bone osteotomy and further elucidated the possible mechanisms of hPTH effects on cancellous bone healing. After a bilateral ovariectomy (OVX) or sham operation in mature female rats, cancellous bone osteotomy was performed on the right proximal tibia. After once-a-week administration of hPTH (1-34) (100 microg/kg) or its vehicle for 4 weeks, bilateral tibiae including osteotomy and non-osteotomy sites were harvested. Along with conventional bone histomorphometry, cancellous bone union at the osteotomy site and the rate of proliferating cells immunostained with proliferating cell nuclear antigen (PCNA) and adipocytes in the surrounding bone marrow were evaluated. hPTH increased cancellous bone volume by stimulating bone formation in both normal and OVX rats and suppressed adipocyte volume (p<0.05). The percentage of PCNA-positive cells at the osteotomy site after PTH treatment was 2- to 3-fold higher than that of vehicle treatment controls both in sham-operated and OVX rats (p<0.05). The magnitude of increase in the percentage of PCNA-positive cells after PTH treatment at the osteotomy site was two times higher than that at the non-osteotomy site. Furthermore, PTH treatment increased cancellous bone union after osteotomy both in sham-operated and OVX rats (p<0.05). These results suggest that hPTH enhances cancellous bone healing at the site of osteotomy with, at least in part, a local regulating action that increases osteoblastogenesis and decreases adipocytogenesis at and around the osteotomy. PMID:17997377

  17. Association of osteoprotegerin and bone loss after adjuvant chemotherapy in early-stage breast cancer

    PubMed Central

    Oostra, Drew R.; Lustberg, Maryam B.; Reinbolt, Raquel E.; Pan, Xueliang; Wesolowski, Robert; Shapiro, Charles L.

    2015-01-01

    Purpose Chemotherapy induced ovarian failure (CIOF) results in rapid bone loss. Receptor Activator of Nuclear Factor Kappa-B (RANK)-RANK ligand (RANK-L) signaling balances bone resorption and formation. Osteoprotegerin (OPG) acts as a decoy receptor for RANK, interrupting osteoclast activation and bone resorption. This study examined the relationship between OPG and bone loss in women with CIOF. Methods Premenopausal women with stage I/II breast cancers receiving adjuvant chemotherapy were evaluated at chemotherapy initiation, 6 and 12 months. Bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), follicle stimulating hormone (FSH), ionized calcium, osteocalcin, and OPG were serially measured. CIOF was defined as a negative pregnancy test, FSH levels >30 MIU/mL, and ?3 months of amenorrhea. Results Forty women were enrolled; 31 (77.5%) met CIOF criteria. BMD significantly decreased (p < 0.001) in the CIOF group at both time points: LS BMD decreased from a median of 0.993 g/cm2 to 0.976 g/cm2 and 0.937 g/cm2 at 6 and 12 months, respectively. OPG was significantly elevated at 6 months (median increase 0.30 pmol/L, p = 0.015) and then decreased at 12 months to levels still above baseline (median difference 0.2 pmol/L, p = 0.70). Conclusions In what was likely a compensatory response to rapid bone loss, CIOF patients’ OPG levels increased at 6 months and then decreased at 12 months to values greater than baseline assessments. This phenomenon is described in other diseases, but never before in CIOF. PMID:25575458

  18. Structure formation in inhomogeneous Early Dark Energy models

    SciTech Connect

    Batista, R.C. [Escola de Ciências e Tecnologia, Universidade Federal do Rio Grande do Norte, Caixa Postal 1524, 59072-970, Natal, Rio Grande do Norte (Brazil); Pace, F., E-mail: rbatista@ect.ufrn.br, E-mail: francesco.pace@port.ac.uk [Institute of Cosmology and Gravitation, University of Portsmouth, Dennis Sciama Building, Portsmouth, PO1 3FX (United Kingdom)

    2013-06-01

    We study the impact of Early Dark Energy fluctuations in the linear and non-linear regimes of structure formation. In these models the energy density of dark energy is non-negligible at high redshifts and the fluctuations in the dark energy component can have the same order of magnitude of dark matter fluctuations. Since two basic approximations usually taken in the standard scenario of quintessence models, that both dark energy density during the matter dominated period and dark energy fluctuations on small scales are negligible, are not valid in such models, we first study approximate analytical solutions for dark matter and dark energy perturbations in the linear regime. This study is helpful to find consistent initial conditions for the system of equations and to analytically understand the effects of Early Dark Energy and its fluctuations, which are also verified numerically. In the linear regime we compute the matter growth and variation of the gravitational potential associated with the Integrated Sachs-Wolf effect, showing that these observables present important modifications due to Early Dark Energy fluctuations, though making them more similar to the ?CDM model. We also make use of the Spherical Collapse model to study the influence of Early Dark Energy fluctuations in the nonlinear regime of structure formation, especially on ?{sub c} parameter, and their contribution to the halo mass, which we show can be of the order of 10%. We finally compute how the number density of halos is modified in comparison to the ?CDM model and address the problem of how to correct the mass function in order to take into account the contribution of clustered dark energy. We conclude that the inhomogeneous Early Dark Energy models are more similar to the ?CDM model than its homogeneous counterparts.

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

    PubMed

    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

    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

  20. The role of intracellular calcium phosphate in osteoblast-mediated bone apatite formation

    PubMed Central

    Boonrungsiman, Suwimon; Gentleman, Eileen; Carzaniga, Raffaella; Evans, Nicholas D.; McComb, David W.; Porter, Alexandra E.; Stevens, Molly M.

    2012-01-01

    Mineralization is a ubiquitous process in the animal kingdom and is fundamental to human development and health. Dysfunctional or aberrant mineralization leads to a variety of medical problems, and so an understanding of these processes is essential to their mitigation. Osteoblasts create the nano-composite structure of bone by secreting a collagenous extracellular matrix (ECM) on which apatite crystals subsequently form. However, despite their requisite function in building bone and decades of observations describing intracellular calcium phosphate, the precise role osteoblasts play in mediating bone apatite formation remains largely unknown. To better understand the relationship between intracellular and extracellular mineralization, we combined a sample-preparation method that simultaneously preserved mineral, ions, and ECM with nano-analytical electron microscopy techniques to examine osteoblasts in an in vitro model of bone formation. We identified calcium phosphate both within osteoblast mitochondrial granules and intracellular vesicles that transported material to the ECM. Moreover, we observed calcium-containing vesicles conjoining mitochondria, which also contained calcium, suggesting a storage and transport mechanism. Our observations further highlight the important relationship between intracellular calcium phosphate in osteoblasts and their role in mineralizing the ECM. These observations may have important implications in deciphering both how normal bone forms and in understanding pathological mineralization. PMID:22879397

  1. Erythropoietin augments bone formation in a rabbit posterolateral spinal fusion model.

    PubMed

    Rölfing, Jan Hendrik Duedal; Bendtsen, Michael; Jensen, Jonas; Stiehler, Maik; Foldager, Casper Bindzus; Hellfritzsch, Michel Bach; Bünger, Cody

    2012-07-01

    We tested the hypothesis that erythropoietin (EPO) enhances bone formation after posterolateral spinal fusion (PLF) in a rabbit model. Thirty-four adult rabbits underwent posterolateral intertransverse arthrodesis at the L5-L6 level using 2.0 g autograft per side. The animals were randomly divided into two groups receiving subcutaneous daily injections of either EPO or saline for 20 days. Treatment commenced 2 days preoperatively. Hemoglobin was monitored at baseline and 2, 4, and 6 weeks after fusion surgery. After euthanasia 6 weeks postoperatively, manual palpation, radiographic, and histomorphometric examinations were performed. Bone volume of the fusion mass was estimated by CT after 6 weeks. EPO increased bone fusion volume to 3.85 ccm (3.66-4.05) compared with 3.26 ccm (2.97-3.55) in the control group (p<0.01). EPO treatment improved vascularization of the fusion mass and increased hemoglobin levels (p<0.01). Fusion rate tended to be higher in the EPO group based on manual palpation, CT, and radiographic examinations. For the first time EPO has shown to augment bone formation after autograft PLF in a rabbit model. Increased vascularization provides a partial explanation for the efficacy of EPO as a bone autograft enhancer. PMID:22144136

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

    PubMed Central

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

    2010-01-01

    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

  3. A comparison of bone formation in biphasic calcium phosphate (BCP) and hydroxyapatite (HA) implanted in muscle and bone of dogs at different time periods.

    PubMed

    Yuan, H; van Blitterswijk, C A; de Groot, K; de Bruijn, J D

    2006-07-01

    Physicochemical modification could implement synthetic materials into osteoinductive materials, which induce bone formation in nonosseous tissues. We hereby studied the relevance between the osteogenic capacities of osteoinductive materials in nonosseous tissues and in osseous sites. Biphasic calcium phosphate ceramic (BCP) and hydroxyapatite ceramic (HA) were implanted in femoral muscles and femoral cortical bone of dogs for 7, 14, 21, 30, 45, 60, 90, 180, and 360 days, respectively. Two dogs were used in each time point. In each dog, four cylinders (phi5x6 mm) per material were implanted in femoral muscles and 2 cylinders (phi5x6 mm) per material in femoral cortical bone. The harvested samples were processed for both histological and histomorphometric analyses. Bone was observed in BCP implanted in femoral muscles since day 30, while in HA since day 45. Quantitatively, more bone was formed in BCP than in HA at each time point after day 30 (p<0.05). The earlier and more bone formed in BCP than in HA suggests BCP a higher osteoinductive potential than HA in muscle. In femoral cortical bone defects, a bridge of bone in the defect with BCP was observed at day 21, while with HA at day 30. At days 14, 21, and 30, significantly more bone was formed in BCP than in HA (p<0.05). The results herein show that osteogenic capacities of osteoinductive materials in nonosseous tissues and osseous sites are correlated: the higher the osteoinductive potential of the material, the faster the bone repair. PMID:16619253

  4. Maternal vitamin D status affects bone growth in early childhood—a prospective cohort study

    PubMed Central

    Korhonen, T.; Hytinantti, T.; Laitinen, E. K. A.; Andersson, S.; Mäkitie, O.; Lamberg-Allardt, C.

    2010-01-01

    Summary In this prospective study, 87 children were followed up from birth to 14 months with data on maternal vitamin D status during the pregnancy. Postnatal vitamin D supplementation improved vitamin D status but only partly eliminated the differences in bone variables induced by maternal vitamin D status during the fetal period. Introduction Intrauterine nutritional deficits may have permanent consequences despite improved nutritional status postnatally. We evaluated the role of prenatal and postnatal vitamin D status on bone parameters in early infancy. Methods Eighty-seven children were followed from birth to 14 months. Background data were collected with a questionnaire and a 3-day food record. At 14 months bone variables were measured with peripheral computed tomography (pQCT) from the left tibia. Serum 25-OHD and bone turnover markers were determined. Findings were compared with maternal vitamin D status during pregnancy. Results The children were divided into two groups based on vitamin D status during pregnancy. Despite discrepant S-25-OHD at baseline (median 36.3 vs. 52.5 nmol/l, p?bone mineral content (BMC) was lower at birth but BMC gain was greater (multivariate analysis of variance [MANOVA]; p?=?0.032) resulting in similar BMC at 14 months in the two groups. In High D, tibial total bone cross-sectional area was higher at baseline; the difference persisted at 14 months (MANOVA; p?=?0.068). Bone mineral density (BMD) and ?BMD were similar in the two groups. Conclusions Postnatal vitamin D supplementation improved vitamin D status but only partly eliminated the differences in bone variables induced by maternal vitamin D status during the fetal period. Further attention should be paid to improving vitamin D status during pregnancy. PMID:21153404

  5. Novel EP4 Receptor Agonist-Bisphosphonate Conjugate Drug (C1) Promotes Bone Formation and Improves Vertebral Mechanical Properties in the Ovariectomized Rat Model of Postmenopausal Bone Loss.

    PubMed

    Liu, Careesa C; Hu, Sally; Chen, Gang; Georgiou, John; Arns, Steve; Kumar, Nag S; Young, Robert N; Grynpas, Marc D

    2015-04-01

    Current treatments for postmenopausal osteoporosis aim to either promote bone formation or inhibit bone resorption. The C1 conjugate drug represents a new treatment approach by chemically linking the antiresorptive compound alendronate (ALN) with the anabolic agent prostanoid EP4 receptor agonist (EP4a) through a linker molecule (LK) to form a conjugate compound. This enables the bone-targeting ability of ALN to deliver EP4a to bone sites and mitigate the systemic side effects of EP4a, while also facilitating dual antiresorptive and anabolic effects. In vivo hydrolysis is required to release the EP4a and ALN components for pharmacological activity. Our study investigated the in vivo efficacy of this drug in treating established bone loss using an ovariectomized (OVX) rat model of postmenopausal osteopenia. In a curative experiment, 3-month-old female Sprague-Dawley rats were OVX, allowed to lose bone for 7 weeks, then treated for 6 weeks. Treatment groups consisted of C1 conjugate at low and high doses, vehicle-treated OVX and sham, prostaglandin E2 (PGE2 ), and mixture of unconjugated ALN-LK and EP4a to assess the effect of conjugation. Results showed that weekly administration of C1 conjugate dose-dependently increased bone volume in trabecular bone, which partially or completely reversed OVX-induced bone loss in the lumbar vertebra and improved vertebral mechanical strength. The conjugate also dose-dependently stimulated endocortical woven bone formation and intracortical resorption in cortical bone, with high-dose treatment increasing the mechanical strength but compromising the material properties. Conjugation between the EP4a and ALN-LK components was crucial to the drug's anabolic efficacy. To our knowledge, the C1 conjugate represents the first time that a combined therapy using an anabolic agent and the antiresorptive compound ALN has shown significant anabolic effects which reversed established osteopenia. © 2014 American Society for Bone and Mineral Research. PMID:25284325

  6. mTORC2 Signaling Promotes Skeletal Growth and Bone Formation in Mice

    PubMed Central

    Chen, Jianquan; Holguin, Nilsson; Shi, Yu; Silva, Matthew J.; Long, Fanxin

    2015-01-01

    Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase controlling many physiological processes in mammals. mTOR functions in two distinct protein complexes, namely mTORC1 and mTORC2. Compared to mTORC1, the specific roles of mTORC2 are less well understood. To investigate the potential contribution of mTORC2 to skeletal development and homeostasis, we have genetically deleted Rictor, an essential component of mTORC2, in the limb skeletogenic mesenchyme of the mouse embryo. Loss of Rictor leads to shorter and narrower skeletal elements in both embryos and postnatal mice. In the embryo, Rictor deletion reduces the width but not the length of the initial cartilage anlage. Subsequently, the embryonic skeletal elements are shortened due to a delay in chondrocyte hypertrophy, with no change in proliferation, apoptosis, cell size, or matrix production. Postnatally, Rictor-deficient mice exhibit impaired bone formation, resulting in thinner cortical bone, but the trabecular bone mass is relatively normal thanks to a concurrent decrease in bone resorption. Moreover, Rictor-deficient bones exhibit a lesser anabolic response to mechanical loading. Thus, mTORC2 signaling is necessary for optimal skeletal growth and bone anabolism. PMID:25196701

  7. Intrauterine growth restriction may not suppress bone formation at term, as indicated by circulating concentrations of undercarboxylated osteocalcin and Dickkopf-1.

    PubMed

    Briana, Despina D; Gourgiotis, Dimitrios; Georgiadis, Anestis; Boutsikou, Maria; Baka, Stavroula; Marmarinos, Antonios; Hassiakos, Dimitrios; Malamitsi-Puchner, Ariadne

    2012-03-01

    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

  8. 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

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

    1987-12-01

    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.

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

    PubMed Central

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

    2014-01-01

    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. PMID:25393478

  10. Enhancement of bone formation by drawn poly(L-lactide).

    PubMed

    Ikada, Y; Shikinami, Y; Hara, Y; Tagawa, M; Fukada, E

    1996-04-01

    Poly(L-lactide) (PLLA) was molded into films and rods, and drawn in the longitudinal direction to endow them with piezoelectricity. The piezoelectric constants of PLLA films increased with the draw ratio and, after passing a maximum at a draw ratio around 5, decreased. PLLA samples with a draw ratio 5 underwent fibrilization. The PLLA rods were intramedullarily implanted in the cut tibiae of cats for internal fixation up to 8 weeks. Fracture healing was clearly promoted with increased callus formation as the draw ratio of the PLLA rod increased, whereas the undrawn PLLA as well as a polyethylene control rod had no effect on callus formation, or rather, retarded it. This finding strongly suggests that the promotion of fracture healing by fixation with drawn PLLA can be ascribed to the piezoelectric current generated by the strains accompanying leg movement. PMID:8847364

  11. Photothermal tomography for the functional and structural evaluation, and early mineral loss monitoring in bones

    PubMed Central

    Kaiplavil, Sreekumar; Mandelis, Andreas; Wang, Xueding; Feng, Ting

    2014-01-01

    Salient features of a new non-ionizing bone diagnostics technique, truncated-correlation photothermal coherence tomography (TC-PCT), exhibiting optical-grade contrast and capable of resolving the trabecular network in three dimensions through the cortical region with and without a soft-tissue overlayer are presented. The absolute nature and early demineralization-detection capability of a marker called thermal wave occupation index, estimated using the proposed modality, have been established. Selective imaging of regions of a specific mineral density range has been demonstrated in a mouse femur. The method is maximum-permissible-exposure compatible. In a matrix of bone and soft-tissue a depth range of ~3.8 mm has been achieved, which can be increased through instrumental and modulation waveform optimization. Furthermore, photoacoustic microscopy, a comparable modality with TC-PCT, has been used to resolve the trabecular structure and for comparison with the photothermal tomography. PMID:25136480

  12. OBIF, an osteoblast induction factor, plays an essential role in bone formation in association with osteoblastogenesis.

    PubMed

    Mizuhashi, Koji; Kanamoto, Takashi; Ito, Masako; Moriishi, Takeshi; Muranishi, Yuki; Omori, Yoshihiro; Terada, Koji; Komori, Toshihisa; Furukawa, Takahisa

    2012-05-01

    In vertebrate bone formation, the functional mechanisms of transcription factors in osteoblastic differentiation have been relatively well elucidated; however, the exact roles of cell-extrinsic molecules are less clear. We previously identified human and mouse Obif, an osteoblast induction factor, also known as Tmem119, which encodes a single transmembrane protein. OBIF is predominantly expressed in osteoblasts in mouse. While exogenous Obif expression stimulated osteoblastic differentiation, knockdown of Obif inhibits the osteoblastic differentiation of pre-osteoblastic MC3T3-E1 cells. In order to investigate an in vivo role of OBIF in bone formation, we generated Obif-deficient mice by targeted gene disruption. Analyses of micro-computed tomography (mCT) revealed that Obif(-/-) mice exhibit significantly reduced cortical thickness in the mid-shaft of the femur at postnatal day 14 (P14). Furthermore, progressive bone hypoplasia is observed after 8 weeks. The expression levels of osteoblast marker genes, Collagen 1a1, Osteopontin, Runx2, and Osterix, in the calvaria were decreased in Obif(-/-) mice at P4. These data indicate that Obif plays an essential role in bone formation through regulating osteoblastogenesis. PMID:22416756

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

    PubMed Central

    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

    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 signaling 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 non-selective S1P receptor agonist FTY720 causes increased bone formation in wildtype, 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

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

    PubMed Central

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

    2013-01-01

    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

  15. Effects of epidermal growth factor on bone formation and resorption in vivo

    SciTech Connect

    Marie, P.J.; Hott, M.; Perheentupa, J. (Institut National de la Sante et de la Recherche Medicale, Paris (France))

    1990-02-01

    The effects of mouse epidermal growth factor (EGF) on bone formation and resorption were examined in male mice. EGF administration (2-200 ng.g-1.day-1 ip for 7 days) induced a dose-dependent rise in plasma EGF levels that remained within physiological range. Histomorphometric analysis of caudal vertebrae showed that EGF (20 and 200 ng.g-1.day-1) reduced the endosteal matrix and mineral appositional rates after 5 days of treatment as measured by double (3H)proline labeling and double tetracycline labeling, respectively. This effect was transitory and was not observed after 7 days of EGF administration. EGF administered for 7 days induced a dose-dependent increase in the periosteal osteoblastic and tetracycline double-labeled surfaces. At high dosage (200 ng.g-1.day-1) EGF administration increased the osteoclastic surface and the number of acid phosphatase-stained osteoclasts, although plasma calcium remained normal. The results show that EGF administration at physiological doses induces distinct effects on endosteal and periosteal bone formation and that the effects are dependent on EGF dosage and duration of treatment. This study indicates that EGF at physiological dosage stimulates periosteal bone formation and increases endosteal bone resorption in the growing mouse.

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

    PubMed

    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

    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

  17. Bone mineral density in partially recovered early onset anorexic patients - a follow-up investigation

    PubMed Central

    2010-01-01

    Background and aims There still is a lack of prospective studies on bone mineral development in patients with a history of early onset Anorexia nervosa (AN). Therefore we assessed associations between bone mass accrual and clinical outcomes in a former clinical sample. In addition to an expected influence of regular physical activity and hormone replacement therapy, we explored correlations with nutritionally dependent hormones. Methods 3-9 years (mean 5.2 ± 1.7) after hospital discharge, we re-investigated 52 female subjects with a history of early onset AN. By means of a standardized approach, we evaluated the general outcome of AN. Moreover, bone mineral content (BMC) and bone mineral density (BMD) as well as lean and fat mass were measured by dual-energy x-ray absorptiometry (DXA). In a substudy, we measured the serum concentrations of leptin and insulin-like growth factor-I (IGF-I). Results The general outcome of anorexia nervosa was good in 50% of the subjects (BMI ? 17.5 kg/m2, resumption of menses). Clinical improvement was correlated with BMC and BMD accrual (?2 = 5.62/?2 = 6.65, p = 0.06 / p = 0.036). The duration of amenorrhea had a negative correlation with BMD (r = -.362; p < 0.01), but not with BMC. Regular physical activity tended to show a positive effect on bone recovery, but the effect of hormone replacement therapy was not significant. Using age-related standards, the post-discharge sample for the substudy presented IGF-I levels below the 5th percentile. IGF-I serum concentrations corresponded to the general outcome of AN. By contrast, leptin serum concentrations showed great variability. They correlated with BMC and current body composition parameters. Conclusions Our results from the main study indicate a certain adaptability of bone mineral accrual which is dependent on a speedy and ongoing recovery. While leptin levels in the substudy tended to respond immediately to current nutritional status, IGF-I serum concentrations corresponded to the individual's age and general outcome of AN. PMID:20615217

  18. Helodermin, helospectin, and PACAP stimulate cyclic AMP formation in intact bone, isolated osteoblasts, and osteoblastic cell lines.

    PubMed

    Lerner, U H; Lundberg, P; Ransjö, M; Persson, P; Håkanson, R

    1994-04-01

    Helodermin and helospectin are peptides structurally similar to vasoactive intestinal polypeptide (VIP) which were recently isolated from the salivary gland venom of the lizard Heloderma suspectum. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been isolated from ovine hypothalamus and also shows sequence homology to VIP. A helodermin-like peptide has been detected by combined immunohistochemical and immunochemical techniques in the thyroid C-cells. In the present study, lizard helodermin was found to cause a time- and dose-dependent stimulation of cyclic AMP (cAMP) formation in neonatal mouse calvarial bones. Also, helospectin I, PACAP 27, and the C-terminally extended PACAP 38 stimulated cAMP accumulation in the mouse calvariae. The cAMP rise in response to helodermin was comparable to that induced by VIP, both in terms of potency and magnitude of the response. Helodermin, helospectin I, PACAP 27, and PACAP 38, at concentrations of 1 mumol/liter, stimulated cAMP accumulation in enzymatically isolated mouse calvarial bone cells. A significant response to all peptides was observed in both early and late released bone cells isolated from the calvariae, with low and high alkaline phosphatase activity, respectively. Helodermin and VIP stimulated cAMP accumulation in the cloned mouse calvarial osteoblastic cell line MC3T3-E1, in rat (UMR 106-01), and human (Saos-2) osteoblastic osteosarcoma cell lines, but not in the rat osteosarcoma cell line ROS 17/2.8. The effect of helodermin was synergistically and dose-dependently enhanced by forskolin (0.1 and 1 mumol/liter). These data show that bone cells, including osteoblasts, respond to several peptides of the VIP family, including helodermin, helospectin I, PACAP 27, and PACAP 38.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7914821

  19. Effects of in vitro chondrogenic priming time of bone-marrow-derived mesenchymal stromal cells on in vivo endochondral bone formation.

    PubMed

    Yang, Wanxun; Both, Sanne K; van Osch, Gerjo J V M; Wang, Yining; Jansen, John A; Yang, Fang

    2015-02-01

    Recapitulation of endochondral ossification leads to a new concept of bone tissue engineering via a cartilage intermediate as an osteoinductive template. In this study, we aimed to investigate the influence of in vitro chondrogenic priming time for the creation of cartilage template on the in vivo endochondral bone formation both qualitatively and quantitatively. To this end, rat bone-marrow-derived mesenchymal stromal cells (MSCs) were seeded onto two scaffolds with distinguished features: a fibrous poly(lactic-co-glycolic acid)/poly(?-caprolactone) electrospun scaffold (PLGA/PCL) and a porous hydroxyapatite/tricalcium phosphate composite (HA/TCP). The constructs were then chondrogenically differentiated for 2, 3 and 4 weeks in vitro, followed by subcutaneous implantation in vivo for up to 8 weeks. A longer chondrogenic priming time resulted in a significantly increased amount and homogeneous deposition of the cartilage matrix on both the PLGA/PCL and HA/TCP scaffolds in vitro. In vivo, all implanted constructs gave rise to endochondral bone formation, whereas the bone volume was not affected by the length of priming time. An unpolarized woven bone-like structure, with significant amounts of cartilage remaining, was generated in fibrous PLGA/PCL scaffolds, while porous HA/TCP scaffolds supported progressive lamellar-like bone formation with mature bone marrow development. These data suggest that, by utilizing a chondrogenically differentiated MSC-scaffold construct as cartilage template, 2 weeks of in vitro priming time is sufficient to generate a substantial amount of vascularized endochondral bone in vivo. The structure of the bone depends on the chemical and structural cues provided by the scaffold design. PMID:25463490

  20. The Formation and Early Evolution of Protostellar Accretion Disks

    E-print Network

    A. Konigl

    2003-12-11

    Newly formed stars are often observed to possess circumstellar disks, from which mass continues to be accreted onto the star and fed into outflowing jets, and which eventually may evolve into dusty debris disks and planetary systems. Recent modeling developments have made it possible, for the first time, to study the formation and early evolution of rotationally supported protostellar disks in the context of a realistic scenario of star formation in weakly ionized, magnetic, molecular cloud cores. The derived semianalytic solutions incorporate ambipolar diffusion and magnetic braking and may be extended to include centrifugally driven disk winds; they can be used to examine the full range of expected behaviors of real systems and their dependence on physical parameters.

  1. Immobilization hypercalcaemia due to low bone formation and responding to intravenous sodium sulphate.

    PubMed Central

    Evans, R. A.; Lawrence, P. J.; Thanakrishnan, G.; Hills, E.; Wong, S. Y.; Dunstan, C. R.

    1986-01-01

    A young man developed acute renal failure and hypercalcaemia following severe burns. The hypercalcaemia was initially controlled by haemodialysis, but it persisted after return of renal function. Plasma PTH was inappropriately elevated, but the nephrogenous cyclic adenosine monophosphate level was low; thus the PTH was probably not biologically active, and may have been artefactually elevated by the moderate renal impairment. Bone histology, showed a normal resorbing surface, but a zero forming surface, implying that the bone dissolution leading to hypercalcaemia resulted from a failure of bone formation. Because of widespread infection and impaired renal function, the hypercalcaemia could not be treated by corticosteroid drugs, mithramycin or phosphate, and there was no response to salmon calcitonin. He was therefore treated with intravenous sodium sulphate, which increased urinary calcium excretion and reduced the plasma calcium. Sodium sulphate still has a role in the treatment of patients with hypercalcaemia. Images Figure 3 PMID:3763550

  2. In Vivo Ectopic Bone Formation by Devitalized Mineralized Stem Cell Carriers Produced Under Mineralizing Culture Condition

    PubMed Central

    Chai, Yoke Chin; Geris, Liesbet; Bolander, Johanna; Pyka, Grzegorz; Van Bael, Simon; Luyten, Frank P.

    2014-01-01

    Abstract Functionalization of tissue engineering scaffolds with in vitro–generated bone-like extracellular matrix (ECM) represents an effective biomimetic approach to promote osteogenic differentiation of stem cells in vitro. However, the bone-forming capacity of these constructs (seeded with or without cells) is so far not apparent. In this study, we aimed at developing a mineralizing culture condition to biofunctionalize three-dimensional (3D) porous scaffolds with highly mineralized ECM in order to produce devitalized, osteoinductive mineralized carriers for human periosteal-derived progenitors (hPDCs). For this, three medium formulations [i.e., growth medium only (BM1), with ascorbic acid (BM2), and with ascorbic acid and dexamethasone (BM3)] supplemented with calcium (Ca2+) and phosphate (PO43?) ions simultaneously as mineralizing source were investigated. The results showed that, besides the significant impacts on enhancing cell proliferation (the highest in BM3 condition), the formulated mineralizing media differentially regulated the osteochondro-related gene markers in a medium-dependent manner (e.g., significant upregulation of BMP2, bone sialoprotein, osteocalcin, and Wnt5a in BM2 condition). This has resulted in distinguished cell populations that were identifiable by specific gene signatures as demonstrated by the principle component analysis. Through devitalization, mineralized carriers with apatite crystal structures unique to each medium condition (by X-ray diffraction and SEM analysis) were obtained. Quantitatively, BM3 condition produced carriers with the highest mineral and collagen contents as well as human-specific VEGF proteins, followed by BM2 and BM1 conditions. Encouragingly, all mineralized carriers (after reseeded with hPDCs) induced bone formation after 8 weeks of subcutaneous implantation in nude mice models, with BM2-carriers inducing the highest bone volume, and the lowest in the BM3 condition (as quantitated by nano-computed tomography [nano-CT]). Histological analysis revealed different bone formation patterns, either bone ossicles containing bone marrow surrounding the scaffold struts (in BM2) or bone apposition directly on the struts' surface (in BM1 and BM3). In conclusion, we have presented experimental data on the feasibility to produce devitalized osteoinductive mineralized carriers by functionalizing 3D porous scaffolds with an in vitro cell-made mineralized matrix under the mineralizing culture conditions. PMID:25469312

  3. In vivo ectopic bone formation by devitalized mineralized stem cell carriers produced under mineralizing culture condition.

    PubMed

    Chai, Yoke Chin; Geris, Liesbet; Bolander, Johanna; Pyka, Grzegorz; Van Bael, Simon; Luyten, Frank P; Schrooten, Jan

    2014-12-01

    Functionalization of tissue engineering scaffolds with in vitro-generated bone-like extracellular matrix (ECM) represents an effective biomimetic approach to promote osteogenic differentiation of stem cells in vitro. However, the bone-forming capacity of these constructs (seeded with or without cells) is so far not apparent. In this study, we aimed at developing a mineralizing culture condition to biofunctionalize three-dimensional (3D) porous scaffolds with highly mineralized ECM in order to produce devitalized, osteoinductive mineralized carriers for human periosteal-derived progenitors (hPDCs). For this, three medium formulations [i.e., growth medium only (BM1), with ascorbic acid (BM2), and with ascorbic acid and dexamethasone (BM3)] supplemented with calcium (Ca(2+)) and phosphate (PO4 (3-)) ions simultaneously as mineralizing source were investigated. The results showed that, besides the significant impacts on enhancing cell proliferation (the highest in BM3 condition), the formulated mineralizing media differentially regulated the osteochondro-related gene markers in a medium-dependent manner (e.g., significant upregulation of BMP2, bone sialoprotein, osteocalcin, and Wnt5a in BM2 condition). This has resulted in distinguished cell populations that were identifiable by specific gene signatures as demonstrated by the principle component analysis. Through devitalization, mineralized carriers with apatite crystal structures unique to each medium condition (by X-ray diffraction and SEM analysis) were obtained. Quantitatively, BM3 condition produced carriers with the highest mineral and collagen contents as well as human-specific VEGF proteins, followed by BM2 and BM1 conditions. Encouragingly, all mineralized carriers (after reseeded with hPDCs) induced bone formation after 8 weeks of subcutaneous implantation in nude mice models, with BM2-carriers inducing the highest bone volume, and the lowest in the BM3 condition (as quantitated by nano-computed tomography [nano-CT]). Histological analysis revealed different bone formation patterns, either bone ossicles containing bone marrow surrounding the scaffold struts (in BM2) or bone apposition directly on the struts' surface (in BM1 and BM3). In conclusion, we have presented experimental data on the feasibility to produce devitalized osteoinductive mineralized carriers by functionalizing 3D porous scaffolds with an in vitro cell-made mineralized matrix under the mineralizing culture conditions. PMID:25469312

  4. Golden bullet-denosumab: early rapid response of metastatic giant cell tumor of the bone.

    PubMed

    Demirsoy, Ugur; Karadogan, Meriban; Selek, Özgür; Anik, Yonca; Aksu, Görkem; Müezzinoglu, Bahar; Corapcioglu, Funda

    2014-03-01

    Giant cell tumor of the bone (GCTB) is usually a benign, locally aggressive tumor with metastatic potential. Histogenesis of GCTB is unknown and a correlation has not been found between histologic and clinical course. For this reason, many authors consider its prognosis unpredictable. Lung metastasis after GCTB treatment is well known and generally has unfavorable outcome, despite varied chemotherapy regimens. Denosumab, which inhibits RANK-RANKL interaction, is a new, promising actor among targeted therapeutic agents for GCTB. In this report, we emphasize on early rapid response to denosumab in metastatic GCTB. PMID:24072245

  5. The Formation and Early Evolution of Young Massive Clusters

    NASA Astrophysics Data System (ADS)

    Longmore, S. N.; Kruijssen, J. M. D.; Bastian, N.; Bally, J.; Rathborne, J.; Testi, L.; Stolte, A.; Dale, J.; Bressert, E.; Alves, J.

    We review the formation and early evolution of the most massive (> few 104 M?) and dense (radius of a few parsecs) young stellar clusters, focusing on the role that studies of these objects in our Galaxy can play in our understanding of star and planet formation as a whole. Comparing the demographics of young massive cluster (YMC) progenitor clouds and YMCs across the Galaxy shows that gas in the Galactic Center can accumulate to a high enough density that molecular clouds already satisfy the criteria used to define YMCs, without forming stars. In this case formation can proceed in situ — i.e., the stars form at protostellar densities close to the final stellar density. Conversely, in the disk, the gas either begins forming stars while it is being accumulated to high density, in a "conveyor belt" mode, or the timescale to accumulate the gas to such high densities must be much shorter than the star-formation timescale. The distinction between the formation regimes in the two environments is consistent with the predictions of environmentally dependent density thresholds for star formation. This implies that stars in YMCs of similar total mass and radius can have formed at widely different initial protostellar densities. The fact that no strong, systematic variations in fundamental properties (such as the IMF) are observed between YMCs in the disk and Galactic Center suggests that, statistically speaking, stellar mass assembly is not affected by the initial protostellar density. We then review recent theoretical advances and summarize the debate on three key open questions: the initial (proto)stellar distribution, infant (im)mortality, and age spreads within YMCs. We conclude that (1) the initial protostellar distribution is likely hierarchical, (2) YMCs likely experienced a formation history that was dominated by gas exhaustion rather than gas expulsion, (3) YMCs are dynamically stable from a young age, and (4) YMCs have age spreads much smaller than their mean age. Finally, we show that it is plausible that metal-rich globular clusters may have formed in a similar way to YMCs in nearby galaxies. In summary, the study of YMC formation bridges star/planet formation in the solar neighborhood to the oldest structures in the local universe.

  6. Feeding Blueberry Diets in Early Life Prevent Senescence of Osteoblasts and Bone Loss in Ovariectomized Adult Female Rats

    PubMed Central

    Zhang, Jian; Lazarenko, Oxana P.; Blackburn, Michael L.; Shankar, Kartik; Badger, Thomas M.; Ronis, Martin J. J.; Chen, Jin-Ran

    2011-01-01

    Background Appropriate nutrition during early development is essential for maximal bone mass accretion; however, linkage between early nutrition, childhood bone mass, peak bone mass in adulthood, and prevention of bone loss later in life has not been studied. Methodology and Principal Findings In this report, we show that feeding a high quality diet supplemented with blueberries (BB) to pre-pubertal rats throughout development or only between postnatal day 20 (PND20) and PND34 prevented ovariectomy (OVX)-induced bone loss in adult life. This protective effect of BB is due to suppression of osteoblastic cell senescence associated with acute loss of myosin expression after OVX. Early exposure of pre-osteoblasts to serum from BB-fed rats was found to consistently increase myosin expression. This led to maintenance osteoblastic cell development and differentiation and delay of cellular entrance into senescence through regulation of the Runx2 gene. High bone turnover after OVX results in insufficient collagenous matrix support for new osteoblasts and their precursors to express myosin and other cytoskeletal elements required for osteoblast activity and differentiation. Conclusions/Significance These results indicate: 1) a significant prevention of OVX-induced bone loss from adult rats can occur with only 14 days consumption of a BB-containing diet immediately prior to puberty; and 2) the molecular mechanisms underlying these effects involves increased myosin production which stimulates osteoblast differentiation and reduces mesenchymal stromal cell senescence. PMID:21912699

  7. Growth hormone mitigates loss of periosteal bone formation and muscle mass in disuse osteopenic rats.

    PubMed

    Grubbe, M-C; Thomsen, J S; Nyengaard, J R; Duruox, M; Brüel, A

    2014-12-01

    Growth hormone (GH) is a potent anabolic agent capable of increasing both bone and muscle mass. The aim was to investigate whether GH could counteract disuse-induced loss of bone and muscle mass in a rat model. Paralysis was induced by injecting 4 IU Botox (BTX) into the muscles of the right hind limb. Sixty female Wistar rats, 14 weeks old, were divided into the following groups: baseline, controls, BTX, BTX+GH, and GH. GH was given at a dosage of 5 mg/kg/d for 4 weeks. Compared with controls, BTX resulted in lower periosteal bone formation rate (BFR/BS,-79%, P<0.001), bone mineral density (aBMD, -13%, P<0.001), trabecular bone volume (BV/TV, -26%, P<0.05), and mid-femoral bone strength (-12%, P<0.05). In addition, BTX reduced rectus femoris muscle mass (-69%, P<0.001) and muscle cell cross sectional area (CSA) (-73%, P<0.001) compared with controls. GH counteracted disuse-induced losses of periosteal BFR/BS (2-fold increase vs. BTX, P<0.001), whereas no effect on aBMD, trabecular BV/TV, or bone strength was found. In addition, GH partly prevented loss of muscle mass (+29% vs. BTX, P<0.001), and tended to prevent loss of muscle CSA (+11%, P=0.064). In conclusion, GH mitigates disuse-induced loss of periosteal BFR/BS at the mid-femur and rectus femoris muscle mass. PMID:25524973

  8. Use of mesenchymal stem cells to enhance bone formation around revision hip replacements.

    PubMed

    Korda, Michelle; Blunn, Gordon; Goodship, Allen; Hua, Jia

    2008-06-01

    Tissue engineering approaches to regenerate bone stock in revision total hip replacements could enhance the longevity of the implant and benefit the quality of the patient's life. This study investigated the impaction of allograft with mesenchymal stem cells in an ovine hip hemiarthroplasty model. In total, 10 sheep were divided into two groups with 5 sheep in each group. The groups were: 1) mesenchymal stem cells mixed with allograft; 2) allograft only as a control. Ground reaction force was assessed for limb function and showed that there was no significant difference in the recovery for animals in different groups. The amount of bone regenerated around the hip replacement was assessed using un-decalcified histology. The results showed that the stem cell group generated significantly more new bone at the implant-allograft interface and within the graft than the control group. The results from this study indicate that the use of stem cells on an allograft scaffold increases bone formation indicating that the use of stem cells for revision hip arthroplasty may be beneficial for patients undergoing revision surgery where the bone stock is compromised. PMID:18271017

  9. Regulation of bone formation using rapamycin-induced BMP2 expression system: influence of implanted cell number

    Microsoft Academic Search

    Dong-Jin Lim; Bae Keun Park; Won Gu Jang; Kkot-Nim Lee; Renny Franceschi; Sun-Hun Kim; Shee-Eun Lee; Jeong-Tae Koh

    2010-01-01

    A rapamycin (RPM)-inducible fibroblast cell line expressing BMP2, BLK-RapBMP2, was previously developed using a stringent\\u000a dimerizer-regulated transcription system to achieve more kinetic control of bone morphogenetic protein (BMP) expression for\\u000a exogenous bone regeneration. This study examined the precise control of BMP2 synthesis and the induction of bone formation\\u000a using various amounts of cells and rapamycin. The response to the rapamycin

  10. The effects of prostaglandin E 2 in growing rats: Increased metaphyseal hard tissue and cortico-endosteal bone formation

    Microsoft Academic Search

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

    1985-01-01

    Summary  To assess the efficacy of PGE2 in inducingin vivo bone formation, graded doses of prostaglandins E2 were administered to 255 g rats. Histomorphometric analyses of selected sequential fluorescent-labeled bones of rats treated\\u000a with 0,0.3, 1.0, 3, or 6 mg PGE2\\/kg\\/d for 21 days showed that the doses of PGE2 depressed longitudinal bone growth, increased growth cartilage thickness slightly, decreased degenerative

  11. Serum Bone Alkaline Phosphatase Isoenzyme Levels in Normal Children and Children with Growth Hormone (GH) Deficiency: A Potential Marker for Bone Formation and Response to GH Therapy

    Microsoft Academic Search

    HITOSHI TOBIUME; SUSUMU KANZAKI; SHIGEKI HIDA; TAEKO ONO; TADASHI MORIWAKE; SHIGEKI YAMAUCHI; HIROYUKI TANAKA; YOSHIKI SEINO

    Serum bone alkaline phosphatase (B-ALP) has been considered to be a good marker for bone formation. Recently, a specific immuno- radiometric assay for serum B-ALP has been developed. Using this system, we measured the serum levels of B-ALP in 363 normal chil- dren (207 males and 156 females, age 0 -18 yr) and in 20 GH-deficient children (age 5-13 yr)

  12. Enzyme replacement therapy in newborn mucopolysaccharidosis IVA mice: Early treatment rescues bone lesions?

    PubMed

    Tomatsu, Shunji; Montaño, Adriana M; Oikawa, Hirotaka; Dung, Vu Chi; Hashimoto, Amiko; Oguma, Toshihiro; Gutiérrez, Monica L; Takahashi, Tatsuo; Shimada, Tsutomu; Orii, Tadao; Sly, William S

    2015-02-01

    We treated mucopolysaccharidosis IVA (MPS IVA) mice to assess the effects of long-term enzyme replacement therapy (ERT) initiated at birth, since adult mice treated by ERT showed little improvement in bone pathology [1]. To conduct ERT in newborn mice, we used recombinant human N-acetylgalactosamine-6-sulfate sulfatase (GALNS) produced in a CHO cell line. First, to observe the tissue distribution pattern, a dose of 250units/g body weight was administered intravenously in MPS IVA mice at day 2 or 3. The infused enzyme was primarily recovered in the liver and spleen, with detectable activity in the bone and brain. Second, newborn ERT was conducted after a tissue distribution study. The first injection of newborn ERT was performed intravenously, the second to fourth weekly injections were intraperitoneal, and the remaining injections from 5th to 14th weeks were intravenous into the tail vein. MPS IVA mice treated with GALNS showed clearance of lysosomal storage in the liver and spleen, and sinus lining cells in bone marrow. The column structure of the growth plate was organized better than that in adult mice treated with ERT; however, hyaline and fibrous cartilage cells in the femur, spine, ligaments, discs, synovium, and periosteum still had storage materials to some extent. Heart valves were refractory to the treatment. Levels of serum keratan sulfate were kept normal in newborn ERT mice. In conclusion, the enzyme, which enters the cartilage before the cartilage cell layer becomes mature, prevents disorganization of column structure. Early treatment from birth leads to partial remission of bone pathology in MPS IVA mice. PMID:24953405

  13. Developments in parathyroid hormone and related peptides as bone-formation agents

    Microsoft Academic Search

    John Fox

    2002-01-01

    Osteoporosis is a major and growing healthcare concern. When administered by daily injection, parathyroid hormone (PTH) and its N-terminal fragments and analogs are potent bone-formation agents. Teriparatide, recombinant human PTH(1–34), is likely to be the first anabolic agent approved for treating osteoporosis, despite inducing osteosarcomas in rats. Native PTH and other PTH fragments and analogs are also in development. N-terminal

  14. Species Differences in Growth Requirements for Bone Marrow Stromal Fibroblast Colony Formation In Vitro

    Microsoft Academic Search

    S. Kuznetsov; P. Gehron Robey

    1996-01-01

    .   The marrow stromal fibroblast (MSF) population has been shown to include precursor cells for at least five types of connective\\u000a tissue: bone, cartilage, adipose tissue, fibrous tissue, and hematopoiesis-supporting reticular stroma. In this study, growth\\u000a requirements for MSF colony formation were studied in vitro. In order to exclude the influence of nonadherent cells, after a period of initial adhesion

  15. Glycation of Human Cortical and Cancellous Bone Captures Differences in the Formation of Maillard Reaction Products between Glucose and Ribose

    PubMed Central

    Sroga, Gra?yna E.; Siddula, Alankrita; Vashishth, Deepak

    2015-01-01

    To better understand some aspects of bone matrix glycation, we used an in vitro glycation approach. Within two weeks, our glycation procedures led to the formation of advanced glycation end products (AGEs) at the levels that corresponded to approx. 25–30 years of the natural in vivo glycation. Cortical and cancellous bones from human tibias were glycated in vitro using either glucose (glucosylation) or ribose (ribosylation). Both glucosylation and ribosylation led to the formation of higher levels of AGEs and pentosidine (PEN) in cancellous than cortical bone dissected from all tested donors (young, middle-age and elderly men and women). More efficient glycation of bone matrix proteins in cancellous bone most likely depended on the higher porosity of this tissue, which facilitated better accessibility of the sugars to the matrix proteins. Notably, glycation of cortical bone from older donors led to much higher AGEs levels as compared to young donors. Such efficient in vitro glycation of older cortical bone could result from aging-related increase in porosity caused by the loss of mineral content. In addition, more pronounced glycation in vivo would be driven by elevated oxidation processes. Interestingly, the levels of PEN formation differed pronouncedly between glucosylation and ribosylation. Ribosylation generated very high levels of PEN (approx. 6- vs. 2.5-fold higher PEN level than in glucosylated samples). Kinetic studies of AGEs and PEN formation in human cortical and cancellous bone matrix confirmed higher accumulation of fluorescent crosslinks for ribosylation. Our results suggest that in vitro glycation of bone using glucose leads to the formation of lower levels of AGEs including PEN, whereas ribosylation appears to support a pathway toward PEN formation. Our studies may help to understand differences in the progression of bone pathologies related to protein glycation by different sugars, and raise awareness for excessive sugar supplementation in food and drinks. PMID:25679213

  16. Radiation-blocking shields to localize periarticular radiation precisely for prevention of heterotopic bone formation around uncemented total hip arthroplasties

    Microsoft Academic Search

    MURALI JASTY; STEVEN SCHUTZER; JOEL TEPPER; CHRISTOPHER WILLETT; MICHAEL A. STRACHER; WILLIAM H. HARRIS

    1990-01-01

    Sixteen patients (18 hips) were treated with localized radiation therapy limited to periarticular regions surrounding the femoral neck by shielding the prosthesis and the adjacent regions to prevent heterotopic bone formation around the uncemented prosthesis. All hips received 1500 rads. Eight of these hips were irradiated after excising severe heterotopic bone, five because they developed extensive heterotopic ossification in the

  17. Ethanolic extract of Actaea racemosa (black cohosh) potentiates bone nodule formation in MC3T3-E1 preosteoblast cells

    Microsoft Academic Search

    B. Y. Chan; K. S. Lau; B. Jiang; E. J. Kennelly; F. Kronenberg; A. W. C. Kung

    2008-01-01

    Aceaea racemosa (formerly Cimicifuga racemosa, black cohosh, AR) extracts have been widely used as an alternative to hormonal replacement therapy for menopausal symptoms. Recent evidences suggest AR extracts are also effective in protecting against postmenopausal bone loss. To determine whether AR has any direct anabolic effect on osteoblasts, we investigated the ethanolic extract of AR on bone nodule formation in

  18. The early phases of bone healing can be differentiated in a rat osteotomy model by focused transverse-transmission ultrasound.

    PubMed

    Rohrbach, Daniel; Preininger, Bernd; Hesse, Bernhard; Gerigk, Hinnerk; Perka, Carsten; Raum, Kay

    2013-09-01

    Here we describe the use of a 5-MHz focused transmission system to image the bone repair region and to distinguish the early healing phases in a rat osteotomy (OT) model. Twelve-month-old female rats underwent a 2-mm OT. After 6 wk of consolidation, 2-D projection images of time-of-flight, speed of sound, and ultrasound attenuation were measured in vitro. The tissue types in the OT gap region were assessed by site-matched histology sections and micro-computed tomography (?CT). In the cases investigated, OT gap regions containing fibrous tissue (group A) were found to have similar properties compared with adjacent muscle tissue, whereas regions filled with cartilage and mineralized callus tissues (group B) differed significantly. Analysis of variance revealed that the healing group had a stronger effect on acoustic parameters (F < 35) than on ?CT-based parameters (F < 22). This pilot study reports the feasibility of transverse transmission quantitative ultrasound in assessment of the onset of cartilage formation during callus formation. PMID:23830097

  19. Hydroxyapatite bioactivated bacterial cellulose promotes osteoblast growth and the formation of bone nodules

    PubMed Central

    2012-01-01

    The goal of this study was to investigate the feasibility of bacterial cellulose (BC) scaffold to support osteoblast growth and bone formation. BC was produced by culturing Acetobacter xylinum supplemented with hydroxyapatite (HA) to form BC membranes (without HA) and BC/HA membranes. Membranes were subjected to X-ray photoelectron spectroscopy (XPS) analysis to determine surface element composition. The membranes were further used to evaluate osteoblast growth, alkaline phosphatase activity and bone nodule formation. BC was free of calcium and phosphate. However, XPS analysis revealed the presence of both calcium (10%) and phosphate (10%) at the surface of the BC/HA membrane. Osteoblast culture showed that BC alone was non-toxic and could sustain osteoblast adhesion. Furthermore, osteoblast adhesion and growth were significantly (p ?0.05) increased on BC/HA membranes as compared to BC alone. Both BC and BC/HA membranes improved osteoconductivity, as confirmed by the level of alkaline phosphatase (ALP) activity that increased from 2.5 mM with BC alone to 5.3 mM with BC/HA. BC/HA membranes also showed greater nodule formation and mineralization than the BC membrane alone. This was confirmed by Alizarin red staining (ARS) and energy dispersive X-ray spectroscopy (EDX). This work demonstrates that both BC and BC/HA may be useful in bone tissue engineering. PMID:23174338

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

    PubMed

    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

    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

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

    PubMed Central

    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

    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

  2. Exercise maintains bone density at spine and hip EFOPS: a 3-year longitudinal study in early postmenopausal women

    Microsoft Academic Search

    K. Engelke; W. Kemmler; D. Lauber; C. Beeskow; R. Pintag; W. A. Kalender

    2006-01-01

    It is an important aim in the prevention of osteoporosis to stop or decelerate bone loss during the early postmenopausal years. Here we report on results of the 3-year EFOPS exercise trial in osteopenic women. The exercise strategy emphasized low-volume high-resistance strength training and high-impact aerobics. Forty-eight fully compliant women (55.1±3.3 years) with no medication or illness affecting bone metabolism participated

  3. Serum concentrations of formation (PINP) and resorption (Ctx) bone turnover markers in rheumatoid arthritis.

    PubMed

    Wis?owska, Margaret; Jakubicz, Danuta; Stepie?, Krystyna; Cicha, Ma?gorzata

    2009-10-01

    Joint inflammation in rheumatoid arthritis (RA) induces local periarticular osteoporosis. Generalised bone mineral density (BMD) decrease concerns approximately 50% of rheumatic patients. Both types of bone mass depletion can issue from cytokine-induced (TNF-alpha, IL-1, IL-6) osteoclasts' activation, osteoprotegerin and its ligand's (RANKL) function disorders, patients' immobilisation and glucocorticosteroid (GCS) intake, as well as from hormonal alterations in postmenopausal women, predominate among RA individuals. The aim of the study was to compare serum concentrations of marker of bone formation--serum aminoterminal propeptide of type I collagen (PINP), and bone resorption, carboxy (C) terminal telopeptide (Ctx), bone turnover markers in RA and osteoarthritis (OA) patients and in RA groups of different disease activity, different degree of joint damage and the history of GCS intake. A total of 50 RA female patients and 50 women with knee OA were included in the study. Blood for morphology and biochemistry laboratory tests was taken. Joint X-rays to establish OA and RA diagnosis and the degree of RA progression, as well as DEXA BMD measurements were performed. PINP and Ctx concentrations were assessed. In RA patients the number of swollen and painful joints, the duration of morning stiffness, visual analogue scale values and Waaler-Rose's test activity were recorded. The Disease Activity Index (DAS 28) was counted from the appropriate formula. No differences in bone turnover markers' concentrations were noted neither between RA and OA patients nor between the RA group when compared to the one without the history of GCS use. Bone turnover markers' concentrations in RA were proportional to the number of swollen and painful joints. However, no correlation was found between the markers' concentrations and RA activity assessed by DAS 28 or by laboratory means. Ctx concentrations were higher in patients at II degree joint damage according to Larsen and Dale's than at more advanced stages. Ctx concentrations decreased with the disease duration. Serum morphogenesis and resorption markers' concentrations change in course of RA indicating the decrease in bone metabolic activity with the disease duration and progression. High RA activity and severity correlate with increased markers' levels-the resorption one. The influence of GCS on bone metabolism in RA requires further study. PMID:19219607

  4. Early changes in bone density, microarchitecture, bone resorption, and inflammation predict the clinical outcome 12 weeks after conservatively treated distal radius fractures: an exploratory study.

    PubMed

    Meyer, Ursina; de Jong, Joost J; Bours, Sandrine G P; Keszei, András P; Arts, Jacobus J; Brink, Peter R G; Menheere, Paul; van Geel, Tineke A C M; van Rietbergen, Bert; van den Bergh, Joop P W; Geusens, Piet P; Willems, Paul C

    2014-09-01

    Fracture healing is an active process with early changes in bone and inflammation. We performed an exploratory study evaluating the association between early changes in densitometric, structural, biomechanical, and biochemical bone parameters during the first weeks of fracture healing and wrist-specific pain and disability at 12 weeks in postmenopausal women with a conservatively treated distal radius fracture. Eighteen patients (aged 64?±?8 years) were evaluated at 1 to 2 and 3 to 4 weeks postfracture, using high-resolution peripheral quantitative computed tomography (HR-pQCT), micro-finite element analysis, serum procollagen type-I N-terminal propeptide (P1NP), carboxy-terminal telopeptide of type I collagen (ICTP), and high-sensitive C-reactive protein (hsCRP). After 12 weeks, patients rated their pain and disability using Patient Rated Wrist Evaluation (PRWE) questionnaire. Additionally, Quick Disability of the Arm Shoulder and Hand (QuickDASH) questionnaire and active wrist range of motion was evaluated. Linear regression models were used to study the relationship between changes in bone parameters and in hsCRP from visit 1 to 2 and PRWE score after 12 weeks. A lower PRWE outcome, indicating better outcome, was significantly related to an early increase in trabecular bone mineral density (BMD) (? -0.96 [95% CI -1.75 to -0.16], R(2) ?=?0.37), in torsional stiffness (-0.14 [-0.28 to -0.004], R(2) ?=?0.31), and to an early decrease in trabecular separation (209 [15 to 402], R(2) ?=?0.33) and in ICTP (12.1 [0.0 to 24.1], R(2) ?=?0.34). Similar results were found for QuickDASH. Higher total dorsal and palmar flexion range of motion was significantly related to early increase in hsCRP (9.62 [3.90 to 15.34], R(2) ?=?0.52). This exploratory study indicates that the assessment of early changes in trabecular BMD, trabecular separation, calculated torsional stiffness, bone resorption marker ICTP, and hsCRP after a distal radius fracture provides valuable information regarding the 12-week clinical outcome in terms of pain, disability, and range of motion and validates its use in studies on the process of early fracture healing. © 2014 American Society for Bone and Mineral Research. PMID:24644096

  5. Bone formation on the apatite-coated zirconia porous scaffolds within a rabbit calvarial defect.

    PubMed

    Kim, Hae-Won; Shin, Seung-Yun; Kim, Hyoun-Ee; Lee, Yong-Moo; Chung, Chong-Pyoung; Lee, Hae-Hyoung; Rhyu, In-Chul

    2008-05-01

    Previously, a strong and bioactive ceramic scaffold consisting of a porous zirconia body coated with apatite double layers (fluorapatite (FA) as an inner layer and hydroxyapatite (HA) as an outer layer) was successfully fabricated. In this contribution, the authors investigate the in vivo performance of the engineered bioceramic scaffolds using a rabbit calvarial defect model. In particular, the porosity and pore size of the scaffolds are varied in order to observe the geometrical effects of the scaffolds on their bone formation behaviors. The scaffolds supported on a zirconia framework can be produced with an extremely high porosity (approximately 84-87%), while retaining excellent compressive strength (approximately 7-8 MPa), which has been unachievable in the case of pure apatite scaffolds (approximately 74% porosity with approximately 2 MPa strength). The experimental groups used in this study include three types of zirconia scaffolds coated with apatite; high porosity (approximately 87%) with large pore size (approximately 500- 700 microm): AZ-HL, high porosity (approximately 84%) with small pore size (approximately 150-200 microm): AZ-HS, and low porosity (approximately 75%) with large pore size (approximately 500-700 microm): AZ-LL, as well as one type of HA porous scaffold: low porosity (approximately 74%) with a large pore size (approximately 500-700 microm) for the purpose of comparison. The scaffolds prepared with dimensions of approximately 10 mm (diameter) x 1.2 mm (thickness) are grafted in rabbit calvaria defects. The histological sections are made at 4 and 12 weeks after surgery and immunohistochemical analyses are performed on the samples. All of the specimens show a good healing response without adverse tissue reactions. Good healing is shown at 4 weeks post-surgery with the ingrowth of new bone into the macropore-channels of the scaffolds. The newly formed bone amounts to approximately 19.9-24.2% of the initial defect area, depending on the scaffold type, but there is no statistical significance between the scaffold groups. However, the defects without the scaffolds (control group) show a significantly lower bone formation ratio (approximately 4.3%). At twelve weeks after surgery, the extent of new bone formation is more pronounced in all of the scaffold groups. All of the scaffold groups show significantly higher bone formation ratios (26.7-46.9%) with respect to the control without the graft. In the comparison between the scaffold groups, those with high porosities (AZ-HL and AZ-HS) exhibit significantly higher bone formation as compared to the scaffold with low porosity (AZ-LL). Based on the present in vivo test performed within a rabbit calvaria defect model, it is concluded that the apatite-coated zirconia scaffolds show good bone forming ability and are considered to be a promising scaffolding material for bone regeneration since they possess a high level of both mechanical and biological properties. PMID:17494967

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

    NASA Technical Reports Server (NTRS)

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

    1993-01-01

    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.

  7. Microstructural investigation of the early external callus after diaphyseal fractures of human long bone.

    PubMed

    Wen, H B; Cui, F Z; Feng, Q L; Li, H D; Zhu, X D

    1995-01-01

    Microstructures of the early external callus after diaphyseal fractures of human long bone were investigated by using scanning electron microscopy, X-ray diffraction, and transmission electron microscopy. It was found that the main structural framework of the human early callus consists of disordered, mineralized collagen fibrils with a small fraction of regions of ordered collagen fibrils. X-ray diffraction analyses show that hydroxyapatite containing some carbonate impurity has been the dominant crystalline phase in the human early callus. In addition, a small amount of brushite phase was detected. Selected area diffraction analyses indicated that hydroxyapatite microcrystals were embedded in microfibrils with a diameter of 4.5 nm and well-banded fibrils, whereas brushite particles of 15-20 nm in an irregular shape were located in the noncollagenous organic matter around the nonmineralized, ordered collagen fibrils. The spatial distribution of the brushite particles in the human early callus was for the first time determined. The brushite particles probably serve as the reservoir of calcium and phosphate ions for subsequent mineralized periods rather than the precursor of hydroxyapatite. PMID:7612396

  8. Differential gene expression of bone marrow CD34+ cells in early and advanced myelodysplastic syndrome.

    PubMed

    Vasikova, A; Budinska, E; Belickova, M; Cermak, J; Bruchova, H

    2009-01-01

    Myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder characterized by ineffective hematopoiesis and dysplasia in one or more blood cell lines. Because it often progress to poor outcome stages or acute leukemia we searched for candidate genes associated with disease progression. Using microarrays we performed gene expression profiling in CD34+ cells of 4 early and 4 advanced MDS patients and identified 286 significantly differentially expressed genes between these two categories. Out of these, 136 genes were up-regulated and 150 down-regulated in early MDS compared to advanced MDS. Using clustering analysis those two patient categories were clearly differentiated. Further, we selected three genes (ADAM8, BIRC5, MPL) for gene expression validation by qRT-PCR in an additional set of 29 MDS and sAML patients. We confirmed decreasing trend for BIRC5 expression from early to advanced stages of MDS, with the lowest levels in sAML patients. On the contrary, higher ADAM8 and MPL expression was observed in most advanced MDS patients compared to the early MDS patients. Association between gene expression levels and bone marrow blast proportion was tested, but only BIRC5 expression showed negative correlation (r=-0.83 at p<0.001). This study demonstrates stage-specific expression of some genes that may have potential prognostic significance. PMID:19469654

  9. E3 ubiquitin ligase-mediated regulation of bone formation and tumorigenesis

    PubMed Central

    Sévère, N; Dieudonné, F-X; Marie, P J

    2013-01-01

    The ubiquitination–proteasome and degradation system is an essential process that regulates protein homeostasis. This system is involved in the regulation of cell proliferation, differentiation and survival, and dysregulations in this system lead to pathologies including cancers. The ubiquitination system is an enzymatic cascade that mediates the marking of target proteins by an ubiquitin label and thereby directs their degradation through the proteasome pathway. The ubiquitination of proteins occurs through a three-step process involving ubiquitin activation by the E1 enzyme, allowing for the transfer to a ubiquitin-conjugated enzyme E2 and to the targeted protein via ubiquitin-protein ligases (E3), the most abundant group of enzymes involved in ubiquitination. Significant advances have been made in our understanding of the role of E3 ubiquitin ligases in the control of bone turnover and tumorigenesis. These ligases are implicated in the regulation of bone cells through the degradation of receptor tyrosine kinases, signaling molecules and transcription factors. Initial studies showed that the E3 ubiquitin ligase c-Cbl, a multi-domain scaffold protein, regulates bone resorption by interacting with several molecules in osteoclasts. Further studies showed that c-Cbl controls the ubiquitination of signaling molecules in osteoblasts and in turn regulates osteoblast proliferation, differentiation and survival. Recent data indicate that c-Cbl expression is decreased in primary bone tumors, resulting in excessive receptor tyrosine kinase signaling. Consistently, c-Cbl ectopic expression reduces bone tumorigenesis by promoting tyrosine kinase receptor degradation. Here, we review the mechanisms of action of E3 ubiquitin ligases in the regulation of normal and pathologic bone formation, and we discuss how targeting the interactions of c-Cbl with some substrates may be a potential therapeutic strategy to promote osteogenesis and to reduce tumorigenesis. PMID:23328670

  10. EPO Promotes Bone Repair through Enhanced Cartilaginous Callus Formation and Angiogenesis

    PubMed Central

    Wan, Lin; Zhang, Fengjie; He, Qiling; Tsang, Wing Pui; Lu, Li; Li, Qingnan; Wu, Zhihong; Qiu, Guixing; Zhou, Guangqian; Wan, Chao

    2014-01-01

    Erythropoietin (EPO)/erythropoietin receptor (EPOR) signaling is involved in the development and regeneration of several non-hematopoietic tissues including the skeleton. EPO is identified as a downstream target of the hypoxia inducible factor-? (HIF-?) pathway. It is shown that EPO exerts a positive role in bone repair, however, the underlying cellular and molecular mechanisms remain unclear. In the present study we show that EPO and EPOR are expressed in the proliferating, pre-hypertrophic and hypertrophic zone of the developing mouse growth plates as well as in the cartilaginous callus of the healing bone. The proliferation rate of chondrocytes is increased under EPO treatment, while this effect is decreased following siRNA mediated knockdown of EPOR in chondrocytes. EPO treatment increases biosynthesis of proteoglycan, accompanied by up-regulation of chondrogenic marker genes including SOX9, SOX5, SOX6, collagen type 2, and aggrecan. The effects are inhibited by knockdown of EPOR. Blockage of the endogenous EPO in chondrocytes also impaired the chondrogenic differentiation. In addition, EPO promotes metatarsal endothelial sprouting in vitro. This coincides with the in vivo data that local delivery of EPO increases vascularity at the mid-stage of bone healing (day 14). In a mouse femoral fracture model, EPO promotes cartilaginous callus formation at days 7 and 14, and enhances bone healing at day 28 indexed by improved X-ray score and micro-CT analysis of microstructure of new bone regenerates, which results in improved biomechanical properties. Our results indicate that EPO enhances chondrogenic and angiogenic responses during bone repair. EPO's function on chondrocyte proliferation and differentiation is at least partially mediated by its receptor EPOR. EPO may serve as a therapeutic agent to facilitate skeletal regeneration. PMID:25003898

  11. Lipoic acid increases the expression of genes involved in bone formation in mice fed a high-fat diet.

    PubMed

    Xiao, Ying; Cui, Jue; Shi, Yonghui; Le, Guowei

    2011-04-01

    Antioxidant lipoic acid (LA) has been reported to have a potential prophylactic effect on bone loss induced by high-fat diet (HFD). The aim of this work was to examine the hypothesis that LA decreases bone resorption-related gene expression and increases bone formation-related gene expression in HFD-fed mice, preventing a shift in the bone metabolism balance toward resorption. Male C57BL/6 mice were fed a normal diet, HFD, or HFD plus 0.1% LA for 12 weeks. The bone metabolism-related genes differentially expressed between mice fed HFD and those fed HFD supplemented with LA were identified through complementary DNA microarray. The supplemental LA significantly increased bone mineral density and bone antioxidant capacity in mice fed HFD (P < .05). Compared with the HFD-fed mice, LA induced the decreased expression of genes associated with bone resorption, such as Mmp9 (1.9-fold) and Ctsk (2.3-fold), and increased those genes associated with bone formation, such as Col1a1 (1.3-fold) and Alp1 (1.5-fold). Furthermore, LA upregulated many genes involved in the Igf signaling pathway, such as Igf-1 (increased 1.7-fold), and downregulated genes involved in the p53 apoptotic pathway, such as p53 (decreased 2.3-fold), thus attenuating the HFD-induced inhibition of bone formation. Lipoic acid induced upregulation of Il12a (2.1-fold) and downregulation of Tgfbr1 (4.3-fold) and Il17a (11.3-fold), which may reduce bone resorption. In summary, LA supplementation during HFD could affect bone density, altering gene expression. PMID:21530805

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

    PubMed

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

    2013-09-01

    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

  13. A reversal phase arrest uncoupling the bone formation and resorption contributes to the bone loss in glucocorticoid treated ovariectomised aged sheep.

    PubMed

    Andreasen, Christina M; Ding, Ming; Overgaard, Søren; Bollen, Peter; Andersen, Thomas L

    2015-06-01

    Large animals as sheep are often used as models for human osteoporosis. Our aim was therefore to determine how glucocorticoid treatment of ovariectomised sheep affects the cancellous bone, determining the cellular events within the bone remodelling process that contributes to their bone loss. Twenty female sheep were assigned for two groups; an untreated control group and an ovariectomised group treated with glucocorticoids (0.6mg/kg/day, 5 times weekly) for 7months. At 7months the glucocorticoid-treated ovariectomised sheep showed a significant change in the bone microstructure revealed by a decreased trabecular bone volume and thickness compared to the control sheep. The treatment led to a temporary elevation of the bone resorption marker CTX (c-terminal collagen telopeptide), while the bone formation marker osteocalcin remained suppressed all 7months. Histomorphometrically, the treated sheep had a complete absence of osteoid surfaces, and a 5-fold increase in the extent of eroded/reversal surfaces after 7months. Most of these reversal surfaces were actually arrested reversal surfaces, defined as reversal surfaces without the presence of neighbouring osteoid surfaces or osteoclasts, which is classically observed next to active reversal surfaces. As in humans, these arrested reversal surfaces had compared to active reversal surfaces a reduced canopy coverage, a significantly decreased cell density, and a decreased immunoreactivity for the osteoblastic markers osterix, runx2 and smooth muscle actin in the mononuclear reversal cells colonising the surfaces. In conclusion, glucocorticoid treatment of ovariectomised sheep induced a significant bone loss, caused by an arrest of the reversal phase, resulting in an uncoupling of the bone formation and resorption during the reversal phase, as recently demonstrated in postmenopausal women with glucocorticoid-induced osteoporosis. This supports the relevance of the sheep model to the pathophysiology of glucocorticoid-induced osteoporosis in postmenopausal women, making it a relevant preclinical model for orthopaedic implant and biomaterial research. PMID:25689083

  14. Widespread formation of cherts during the early Eocene climate optimum

    NASA Astrophysics Data System (ADS)

    Muttoni, G.; Kent, D. V.

    2007-12-01

    Radiolarian cherts in the Tethyan realm of Jurassic age were recently interpreted as resulting from high biosiliceous productivity along upwelling zones in subequatorial paleolatitudes the locations of which were confirmed by revised paleomagnetic estimates. However, the widespread occurrence of cherts in the Eocene suggests that cherts may not always be reliable proxies of latitude and upwelling zones. In a new survey of the global spatiotemporal distribution of Cenozoic cherts in Deep Sea Drilling Project (DSDP) and Ocean Drilling Program (ODP) sediment cores, we found that cherts occur most frequently in the Paleocene and early Eocene, with a peak in occurrences at ~50 Ma that is coincident with the time of highest bottom water temperatures of the early Eocene climatic optimum (EECO) when the global ocean was presumably characterized by reduced upwelling efficiency and biosiliceous productivity. Cherts occur less commonly during the subsequent Eocene global cooling trend. Primary paleoclimatic factors rather than secondary diagenetic processes seem therefore to control chert formation. This timing of peak Eocene chert occurrence, which is supported by detailed stratigraphic correlations, contradicts currently accepted models that involve an initial loading of large amounts of dissolved silica from enhanced weathering and/or volcanism in a supposedly sluggish ocean of the EECO, followed during the subsequent middle Eocene global cooling by more vigorous oceanic circulation and consequent upwelling that made this silica reservoir available for enhanced biosilicification, with the formation of chert as a result of biosilica transformation during diagenesis. Instead, we suggest that basin-basin fractionation by deep-sea circulation could have raised the concentration of EECO dissolved silica especially in the North Atlantic, where an alternative mode of silica burial involving widespread direct precipitation and/or absorption of silica by clay minerals could have been operative in order to maintain balance between silica input and output during the upwelling-deficient conditions of the EECO. Cherts may therefore not always be proxies of biosiliceous productivity associated with latitudinally focused upwelling zones.

  15. INSECT TRACE FOSSILS ON DINOSAUR BONES FROM THE UPPER JURASSIC MORRISON FORMATION, NORTHEASTERN WYOMING, AND THEIR USE IN VERTEBRATE TAPHONOMY

    E-print Network

    Bader, Kenneth Stephen

    2008-08-21

    INSECT TRACE FOSSILS ON DINOSAUR BONES FROM THE UPPER JURASSIC MORRISON FORMATION, NORTHEASTERN WYOMING, AND THEIR USE IN VERTEBRATE TAPHONOMY by ? 2008 Kenneth Stephen Bader B.S., University of Kansas, 2003 Submitted.... Bader certifies that this is the approved version of the following thesis: INSECT TRACE FOSSILS ON DINOSAUR BONES FROM THE UPPER JURASSIC MORRISON FORMATION, NORTHEASTERN WYOMING, AND THEIR USE IN VERTEBRATE TAPHONOMY...

  16. Dual growth factor delivery and controlled scaffold degradation enhance in vivo bone formation by transplanted bone marrow stromal cells

    Microsoft Academic Search

    Craig A. Simmons; Eben Alsberg; Susan Hsiong; Woo J. Kim; David J. Mooneya

    2004-01-01

    Supraphysiological concentrations of exogenous growth factors are typically required to obtain bone regeneration, and it is unclear why lower levels are not effective. We hypothesized that delivery of bone progenitor cells along with appropriate combinations of growth factors and scaffold characteristics would allow physiological doses of proteins to be used for therapeutic bone regeneration. We tested this hypothesis by measuring

  17. Assessing the osteoblast transcriptome in a model of enhanced bone formation due to constitutive Gs-G protein signaling in osteoblasts.

    PubMed

    Wattanachanya, Lalita; Wang, Liping; Millard, Susan M; Lu, Wei-Dar; O'Carroll, Dylan; Hsiao, Edward C; Conklin, Bruce R; Nissenson, Robert A

    2015-05-01

    G protein-coupled receptor (GPCR) signaling in osteoblasts (OBs) is an important regulator of bone formation. We previously described a mouse model expressing Rs1, an engineered constitutively active Gs-coupled GPCR, under the control of the 2.3 kb Col I promoter. These mice showed a dramatic age-dependent increase in trabecular bone of femurs. Here, we further evaluated the effects of enhanced Gs signaling in OBs on intramembranous bone formation by examining calvariae of 1- and 9-week-old Col1(2.3)/Rs1 mice and characterized the in vivo gene expression specifically occurring in osteoblasts with activated Gs G protein-coupled receptor signaling, at the cellular level rather than in a whole bone. Rs1 calvariae displayed a dramatic increase in bone volume with partial loss of cortical structure. By immunohistochemistry, Osterix was detected in cells throughout the inter-trabecular space while Osteocalcin was expressed predominantly in cells along bone surfaces, suggesting the role of paracrine mediators secreted from OBs driven by 2.3 kb Col I promoter could influence early OB commitment, differentiation, and/or proliferation. Gene expression analysis of calvarial OBs revealed that genes affected by Rs1 signaling include those encoding proteins important for cell differentiation, cytokines and growth factors, angiogenesis, coagulation, and energy metabolism. The set of Gs-GPCRs and other GPCRs that may contribute to the observed skeletal phenotype and candidate paracrine mediators of the effect of Gs signaling in OBs were also determined. Our results identify novel detailed in vivo cellular changes of the anabolic response of the skeleton to Gs signaling in mature OBs. PMID:25704759

  18. Suppression of the immune system as a critical step for bone formation from allogeneic osteoprogenitors implanted in rats

    PubMed Central

    Chatterjea, Anindita; LaPointe, Vanessa LS; Alblas, Jacqueline; Chatterjea, Supriyo; Blitterswijk, Clemens A; Boer, Jan

    2014-01-01

    The surface marker profile of mesenchymal stromal cells (MSCs) suggests that they can escape detection by the immune system of an allogeneic host. This could be an optimal strategy for bone regeneration applications, where off-the-shelf cells could be implanted to heal bone defects. However, it is unknown how pre-differentiation of MSCs to an osteogenic lineage, a means of improving bone formation, affects their immunogenicity. Using immunohistological techniques in a rat ectopic implantation model, we demonstrate that allogeneic osteoprogenitors mount a T cell- and B cell-mediated immune response resulting in an absence of in vivo bone formation. Suppression of the host immune response with daily administration of an immunosuppressant, FK506, is effective in preventing the immune attack on the allogeneic osteoprogenitors. In the immunosuppressed environment, the allogeneic osteoprogenitors are capable of generating bone in amounts similar to those of syngeneic cells. However, using osteoprogenitors from one of the allogeneic donors led to newly deposited bone that was attacked by the host immune system, despite the continued administration of the immunosuppressant. This suggests that, although using an immunosuppressant can potentially suppress the immune attack on the allogeneic cells, optimizing the dose of the immunosuppressant may be crucial to ensure bone formation within the allogeneic environment. Overall, allografts comprising osteoprogenitors derived from allogeneic MSCs have the potential to be used in bone regeneration applications. PMID:24237965

  19. Magnetic fields during the early phase of massive star formation

    NASA Astrophysics Data System (ADS)

    Seifried, Daniel Jürgen

    2013-01-01

    The goal of this work is to improve our current understanding of the formation process of massive stars in the presence of magnetic fields by means of numerical simulations. In particular, I focus on protostellar accretion rates, the evolution and the properties of protostellar discs and their associated outflows, and the interplay of turbulence and magnetic fields and its impact on protostellar disc formation. In a systematic parameter study I show that the accretion rates are remarkably constant over a wide range of initial conditions. Furthermore, I show that in the absence of turbulence for strong initial magnetic fields only sub-Keplerian discs can form which is attributed to the strong magnetic braking effect. This result seems to be in contrast to observational results. The morphology of the outflows, which shows a strong dependence on the initial conditions, can ultimately be linked to the structure of the underlying disc. Well-collimated outflows with high outflows velocities only develop if a Keplerian protostellar disc is present, otherwise slowly expanding, sphere-like outflows develop. Furthermore, I analyse the driving mechanism of outflows with an analytical criterion derived in the course of this work. When including supersonic, turbulent motions in the simulations, Keplerian protostellar discs form in contrast to the non-turbulent simulations. This result is in agreement with observations of early-type protostellar objects.

  20. Early-type galaxy star formation histories in different environments

    NASA Astrophysics Data System (ADS)

    Fitzpatrick, Patrick J.; Graves, Genevieve J.

    2015-02-01

    We use very high signal-to-noise ratio stacked spectra of ˜29 000 nearby quiescent early-type galaxies (ETGs) from the Sloan Digital Sky Survey to investigate variations in their star formation histories (SFHs) with environment at fixed position along and perpendicular to the Fundamental Plane. We define three classifications of local group environment based on the `identities' of galaxies within their dark matter haloes: central `Brightest Group Galaxies' (BGGs); Satellites; and Isolateds (those `most massive' in a dark matter halo with no Satellites). We find that the SFHs of quiescent ETGs are almost entirely determined by their structural parameters ? and ?Ie. Any variation with local group environment at fixed structure is only slight: Satellites have the oldest stellar populations, 0.02 dex older than BGGs and 0.04 dex older than Isolateds; differences in Fe enrichment with local group environment are consistent with zero (<2?); there are no differences in Mg enhancement between BGGs, Isolateds, and Satellites. Our observation that, to zeroth-order, the SFHs of quiescent ETGs are fully captured by their structures places important qualitative constraints on the degree to which late-time evolutionary processes (those which occur after a galaxy's initial formation and main star-forming lifetime) can alter their SFHs/structures.

  1. In vitro assessment of biomaterial-induced remodeling of subchondral and cancellous bone for the early intervention of joint degeneration with focus on the spinal disc

    NASA Astrophysics Data System (ADS)

    McCanless, Jonathan D.

    Osteoarthritis-associated pain of the spinal disc, knee, and hip derives from degeneration of cartilagenous tissues in these joints. Traditional therapies have focused on these cartilage (and disc specific nucleus pulposus) changes as a means of treatment through tissue grafting, regenerative synthetic implants, non-regenerative space filling implants, arthroplasty, and arthrodesis. Although such approaches may seem apparent upon initial consideration of joint degeneration, tissue pathology has shown changes in the underlying bone and vascular bed precede the onset of cartilaginous changes. It is hypothesized that these changes precedent joint degeneration and as such may provide a route for early prevention. The current work proposes an injectable biomaterial-based therapy within these subchondral and cancellous bone regions as a means of preventing or reversing osteoarthritis. Two human concentrated platelet releasate-containing alginate hydrogel/beta-tricalcium phosphate composites have been developed for this potential biomaterial application. The undertaking of assessing these materials through bench-, in vitro, and ex vivo work is described herein. These studies showed the capability of the biomaterials to initiate a wound healing response in monocytes, angiogenic and differentiation behavior in immature endothelial cells, and early osteochondral differentiation in mesenchymal stem cells. These cellular activities are associated with fracture healing and endochondral bone formation, demonstrating the potential of the biomaterials to induce osseous and vascular tissue remodeling underlying osteoarthritic joints as a novel therapy for a disease with rapidly growing healthcare costs.

  2. Radiation-blocking shields to localize periarticular radiation precisely for prevention of heterotopic bone formation around uncemented total hip arthroplasties

    SciTech Connect

    Jasty, M.; Schutzer, S.; Tepper, J.; Willett, C.; Stracher, M.A.; Harris, W.H. (Massachusetts General Hospital (USA))

    1990-08-01

    Sixteen patients (18 hips) were treated with localized radiation therapy limited to periarticular regions surrounding the femoral neck by shielding the prosthesis and the adjacent regions to prevent heterotopic bone formation around the uncemented prosthesis. All hips received 1500 rads. Eight of these hips were irradiated after excising severe heterotopic bone, five because they developed extensive heterotopic ossification in the opposite hip, and five others because they were considered to be at high risk for developing heterotopic ossification. Only two of the 18 hips developed a small amount of heterotopic bone after localized periarticular radiation. All wounds healed primarily. No progressive radiolucencies developed at the bone-prosthesis interface. There was only one trochanteric nonunion of six trochanteric osteotomies. Localized periarticular radiation therapy with precision shielding of the prosthetic components and adjacent skeletal structures is an effective means to prevent heterotopic bone formation around cementless total hip arthroplasties. It also has the advantage of not adversely affecting the healing of the trochanteric osteotomy.

  3. 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

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

    2014-11-01

    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

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

    PubMed Central

    Zhang, Jianying; Wang, James H-C

    2014-01-01

    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. PMID:25419468

  5. Mesenchymal Stem Cells Systemically Injected into Femoral Marrow of Dogs Home to Mandibular Defects to Enhance New Bone Formation

    PubMed Central

    Liu, Xian; Liao, Xuejuan; Luo, En; Chen, Wenchuan; Xu, Hockin H.K.

    2014-01-01

    Musculoskeletal diseases cost the U.S. $849 billion annually. To date, there has been no proof that remote long bone mesenchymal stem cells (BMSC) can home to craniofacial defects for bone regeneration. There has been no report that systemic BMSC injection can increase new bone formation in large animals. The objectives of this study were to use a sex-mismatched canine model for systemic BMSC injection and homing to mandibular defects and to investigate appendicular BMSC migration to craniofacial defects to increase new bone formation. Male beagle dog BMSC were injected into the femoral marrow cavity of female dogs upon which mandibular defects were created. The dogs were sacrificed at 6 weeks. Cells with Y chromosome markers were detected in defects of female dogs with systemic male BMSC injection, indicating the homing of the transplanted BMSC from femoral marrow to the mandibular defect. New bone formation in dogs with systemic BMSC injection was 20–40% higher than control without BMSC injection (p<0.05). Mineralized new bone percentage was increased by 20–40% due to systemic BMSC injection (p<0.05). In conclusion, this study proved that (1) allogeneic BMSC injected into long bone marrow are capable of homing to both appendicular and craniofacial bone in large animals and (2) systemically injected BMSC can significantly increase new bone formation in dog's mandibular defects. These results may help advance the understanding of stem cell homing and present a therapy to enhance bone repair, which may have a wide applicability to the regenerative medicine field. PMID:24125551

  6. A novel therapeutic approach with Caviunin-based isoflavonoid that en routes bone marrow cells to bone formation via BMP2/Wnt-?-catenin signaling.

    PubMed

    Kushwaha, P; Khedgikar, V; Gautam, J; Dixit, P; Chillara, R; Verma, A; Thakur, R; Mishra, D P; Singh, D; Maurya, R; Chattopadhyay, N; Mishra, P R; Trivedi, R

    2014-01-01

    Recently, we reported that extract of Dalbergia sissoo made from leaves and pods have antiresorptive and bone-forming effects. The positive skeletal effect attributed because of active molecules present in the extract of Dalbergia sissoo. Caviunin 7-O-[?-D-apiofuranosyl-(1-6)-?-D-glucopyranoside] (CAFG), a novel isoflavonoid show higher percentage present in the extract. Here, we show the osteogenic potential of CAFG as an alternative for anabolic therapy for the treatment of osteoporosis by stimulating bone morphogenetic protein 2 (BMP2) and Wnt/?-catenin mechanism. CAFG supplementation improved trabecular micro-architecture of the long bones, increased biomechanical strength parameters of the vertebra and femur and decreased bone turnover markers better than genistein. Oral administration of CAFG to osteopenic ovariectomized mice increased osteoprogenitor cells in the bone marrow and increased the expression of osteogenic genes in femur and show new bone formation without uterine hyperplasia. CAFG increased mRNA expression of osteoprotegerin in bone and inhibited osteoclast activation by inhibiting the expression of skeletal osteoclastogenic genes. CAFG is also an effective accelerant for chondrogenesis and has stimulatory effect on the repair of cortical bone after drill-hole injury at the tissue, cell and gene level in mouse femur. At cellular levels, CAFG stimulated osteoblast proliferation, survival and differentiation. Signal transduction inhibitors in osteoblast demonstrated involvement of p-38 mitogen-activated protein kinase pathway stimulated by BMP2 to initiate Wnt/?-catenin signaling to reduce phosphorylation of GSK3-? and subsequent nuclear accumulation of ?-catenin. Osteogenic effects were abrogated by Dkk1, Wnt-receptor blocker and FH535, inhibitor of TCF-complex by reduction in ?-catenin levels. CAFG modulated MSC responsiveness to BMP2, which promoted osteoblast differentiation via Wnt/?-catenin mechanism. CAFG at 1?mg/kg(/)day dose in ovariectomy mice (human dose ?0.081?mg/kg) led to enhanced bone formation, reduced bone resorption and bone turnover better than well-known phytoestrogen genistein. Owing to CAFG's inherent properties for bone, it could be positioned as a potential drug, food supplement, for postmenopausal osteoporosis and fracture repair. PMID:25232676

  7. Platelets govern pre-metastatic tumor communication to bone

    PubMed Central

    Kerr, Bethany A.; McCabe, N. Patrick; Feng, Weiyi; Byzova, Tatiana V.

    2013-01-01

    While the survival rate for early detected cancers is high, once a cancer metastasizes to bone, it is incurable. Interestingly, patients without visible metastases display abnormal bone formation and resorption suggesting a link between primary cancers and the bone microenvironment prior to metastasis and this link likely facilitates preparation of the pre-metastatic niche. We hypothesized that communication from the primary tumor would result in bone remodeling alterations and that platelets could facilitate this communication. Using three tumor models, we demonstrate that primary tumor growth stimulates bone formation measured by microcomputed tomography (microCT). Further, platelet depletion prevented tumor-induced bone formation highlighting the importance of platelets in the communication between tumors and the bone microenvironment. Finally, we determine that platelets sequester a variety of tumor-derived proteins, TGF-?1 and MMP-1 in particular, which regulate bone formation. Thus, our data reveals that platelets function as mediators of tumor-bone communication prior to metastasis. PMID:23069656

  8. Clonal distribution of osteoprogenitor cells in cultured chick periostea: Functional relationship to bone formation

    SciTech Connect

    McCulloch, C.A.; Fair, C.A.; Tenenbaum, H.C.; Limeback, H.; Homareau, R. (Univ. of Toronto, Ontario (Canada))

    1990-08-01

    Folded explants of periosteum from embryonic chick calvaria form bone-like tissue when grown in the presence of ascorbic acid, organic phosphate, and dexamethasone. All osteoblast-like cells in these cultures arise de novo by differentiation of osteoprogenitor cells present in the periosteum. To study the spatial and functional relationships between bone formation and osteoprogenitor cells, cultures were continuously labeled with (3H)thymidine for periods of 1-5 days. Radioautographs of serial 2-microns plastic sections stained for alkaline phosphatase (AP) showed maximal labeling of 30% of fibroblastic (AP-negative) cells by 3 days while osteogenic cells (AP-positive) exhibited over 95% labeling by 5 days. No differential shifts in labeling indices, grain count histograms of fibroblastic and osteogenic cells or numbers of AP-positive cells were observed, indicating no significant recruitment of cells from the fibroblastic to the osteogenic compartment. Despite the continuous presence of (3H)thymidine, less than 35% of both osteoblasts and osteocytes were labeled at 5 days, indicating that only one-third of the osteoprogenitor cells had cycled prior to differentiation. Spatial clustering of (3H)thymidine-labeled cells was measured by computer-assisted morphometry and application of the Poisson distribution to assess contagion. Cluster size and number of labeled cells per cluster did not vary between 1-3 days, but the number of clusters increased 20-fold between Day 1 and Day 3. Three-dimensional reconstruction from serial sections showed that clusters formed long, tubular arrays of osteogenic cells up to eight cells in length and located within 2-3 cell layers from the bone surface. Selective killing of S-phase cells with two pulse labels of high specific activity (3H)thymidine at 1 and 2 days of culture completely blocked bone formation.

  9. Early and late bone-marrow changes after irradiation: MR evaluation

    SciTech Connect

    Stevens, S.K.; Moore, S.G.; Kaplan, I.D. (Stanford Univ. Medical Center, CA (USA))

    1990-04-01

    Knowledge of the chronologic evolution of bone-marrow changes during and after radiation therapy is essential in differentiating normal postradiation changes from other marrow abnormalities. The appearance of the lumbar vertebral bone marrow was studied on 55 serial spin-echo and short-T1 inversion-recovery (STIR) MR images obtained in 14 patients receiving radiation therapy for Hodgkin disease, seminoma, or prostate carcinoma. Images were obtained before, at weekly intervals during, and at various monthly intervals up to 14 months after a 3- to 6-week course of fractionated paravertebral lymph-node irradiation of 1500-5000 rad (15-50 Gy). During the first 2 weeks of therapy, there was no definite change in the appearance of the marrow on spin-echo images; however, there was an increase in signal intensity on the STIR images, apparently reflecting early marrow edema and necrosis. Between weeks 3 and 6, the marrow showed an increasingly heterogenous signal and prominence of the signal from central marrow fat, shown best on T1-weighted images. Late marrow patterns (6 weeks to 14 months after therapy) varied and consisted of either homogenous fatty replacement or a band pattern of peripheral intermediate signal intensity, possibly representing hematopoietic marrow surrounding the central marrow fat. No focal marrow lesions or soft-tissue edema were identified during the course of radiation therapy; their presence should raise the possibility of the presence of a pathologic process other than radiation change. These data suggest that MR can detect radiation-induced marrow changes as early as 2 weeks after starting therapy, and that there are at least two distinct types of late marrow MR patterns.

  10. Multivariate analysis of the sexual dimorphism of the hip bone in a modern human population and in early hominids.

    PubMed

    Arsuaga, J L; Carretero, J M

    1994-02-01

    A large sample of hip bones of known sex coming from one modern population is studied morphologically and by multivariate analysis to investigate sexual dimorphism patterns. A principal component analysis of raw data shows that a large amount of the hip bone sexual dimorphism is accounted for by size differences, but that sex-linked shape variation is also very conspicuous and cannot be considered an allometric consequence of differences in body size between the sexes. The PCA of transformed ("shape") variables indicates that the female hip bones are different in those traits associated with a relatively larger pelvic inlet (longer pubic bones, a greater degree of curvature of the iliopectineal line, and more posterior position of the auricular surface), as well as a broader sciatic notch. The analysis of nonmetric traits also shows marked sexual dimorphism in the position of the sacroiliac joint in the iliac bone, in the shape of the sciatic notch, in pubic morphology, and in the presence of the pre-auricular sulcus in females. When the australopithecine AL 288-1 and Sts 14 hip bones are included in the multivariate analysis, they appear as "ultra-females." In particular these early hominids exhibit extraordinarily long pubic bones and iliopectineal lines, which cannot be explained by allometry. PMID:8147439

  11. Cold Accretion in Early Galaxy Formation and Its Ly? Signatures

    NASA Astrophysics Data System (ADS)

    Yajima, Hidenobu; Li, Yuexing; Zhu, Qirong; Abel, Tom

    2015-03-01

    Ly? emission has played an important role in detecting high-redshift galaxies, including recently distant ones at redshifts z\\gt 7. It may also contain important information concerning the origin of these galaxies. Here, we investigate the formation of a typical L* galaxy and its observational signatures at the earliest stage by combining a cosmological hydrodynamic simulation with three-dimensional radiative transfer (RT) calculations using the newly improved AR{{T}2} code. Our cosmological simulation uses the Aquila initial condition, which zooms in on a Milky-Way-like halo with high resolutions, and our RT couples multi-wavelength continuum, Ly? line, and ionization of hydrogen. We find that the modeled galaxy starts to form at redshift z ? 24 through the efficient accretion of cold gas, which produces a strong Ly? line with a luminosity of {{L}Ly? }? {{10}42} erg {{s}-1} as early as z ? 14. The Ly? emission appears to trace the cold, dense gas. The lines exhibit asymmetric, single-peak profiles, and are shifted to the blue wing, a characteristic feature of gas inflow. Moreover, the contribution to the total Ly? luminosity from excitation cooling increases with redshift and becomes dominant at z ? 6. We predict that L* galaxies such as the modeled one may be detected at z ? 8 by the James Webb Space Telescope and Atacama Large Millimeter Array with a reasonable integration time. Beyond redshift 12, however, the Ly? line may only be observable by spectroscopic surveys. Our results suggest that the Ly? line is one of the most powerful tools to detect the first generation of galaxies and decipher their formation mechanism.

  12. Early-Type Galaxy Star Formation Histories in Different Environments

    NASA Astrophysics Data System (ADS)

    Fitzpatrick, Patrick; Graves, G.

    2014-01-01

    We use very high-S/N stacked spectra of ˜29,000 nearby quiescent early-type galaxies (ETGs) from the Sloan Digital Sky Survey (SDSS) to investigate variations in their star formation histories (SFHs) with environment at fixed position along and perpendicular to the Fundamental Plane (FP). We separate galaxies in the three-dimensional FP space defined by galaxy effective radius Re, central stellar velocity dispersion ?, and surface brightness residual from the FP, ?Ie. We use the SDSS group catalogue of Yang et al. to further separate galaxies into three categories by their “identities” within their respective dark matter halos: central “Brightest Group Galaxies” (BGGs); Satellites; and Isolateds (those which are “most massive” in a dark matter halo with no Satellites). Within each category, we construct high-S/N mean stacked spectra to determine mean singleburst ages, [Fe/H], and [Mg/Fe] based on the stellar population synthesis models of R. Schiavon. This allows us to study variations in the stellar population properties (SPPs) with local group environment at fixed structure (i.e., fixed position in FP-space). We find that the SFHs of quiescent ETGs are almost entirely determined by their structural parameters ? and ?Ie. Any variation with local group environment at fixed structure is only slight: Satellites have the oldest stellar populations, 0.02 dex older than BGGs and 0.04 dex older than Isolateds; BGGs have the highest Fe-enrichments, 0.01 dex higher than Isolateds and 0.02 dex higher than Satellites; there are no differences in Mg-enhancement between BGGs, Isolateds, and Satellites. Our observation that, to zeroth-order, the SFHs of quiescent ETGs are fully captured by their structures places important qualitative constraints on the degree to which late-time evolutionary processes (those which occur after a galaxy’s initial formation and main star-forming lifetime) can alter their SFHs/structures.

  13. Rictor Is Required for Early B Cell Development in Bone Marrow

    PubMed Central

    Gu, Jie; Zhang, Liyan; Hao, Sha; Liang, Haoyue; Wang, Xiaomin; Wang, Weili; Xu, Jing; Liu, Hanzhi; Liu, Bin; Cheng, Tao; Yuan, Weiping

    2014-01-01

    The development of early B cells, which are generated from hematopoietic stem cells (HSCs) in a series of well-characterized stages in bone marrow (BM), represents a paradigm for terminal differentiation processes. Akt is primarily regulated by phosphorylation at Thr308 by PDK1 and at Ser473 by mTORC2, and Akt signaling plays a key role in hematopoiesis. However, the role of mTORC2 in the development of early B cells remains poorly understood. In this study, we investigated the functional role of mTORC2 by specifically deleting an integral component, Rictor, in a hematopoietic system. We demonstrated that the deletion of Rictor induced an aberrant increase in the FoxO1 and Rag-1 proteins in BM B cells and that this increase was accompanied by a significant decrease in the abundance of B cells in the peripheral blood (PB) and the spleen, suggesting impaired development of early B cells in adult mouse BM. A BM transplantation assay revealed that the B cell differentiation defect induced by Rictor deletion was not affected by the BM microenvironment, thus indicating a cell-intrinsic mechanism. Furthermore, the knockdown of FoxO1 in Rictor-deleted HSCs and hematopoietic progenitor cells (HPCs) promoted the maturation of B cells in the BM of recipient mice. In addition, we revealed that treatment with rapamycin (an mTORC1 inhibitor) aggravated the deficiency in B cell development in the PB and BM. Taken together, our results provide further evidence that Rictor regulates the development of early B cells in a cell-intrinsic manner by modifying the expression of FoxO1 and Rag-1. PMID:25084011

  14. Additive Effects of Mechanical Marrow Ablation and PTH Treatment on de Novo Bone Formation in Mature Adult Rats.

    PubMed

    Zhang, Qing; Miller, Christopher; Bible, Jesse; Li, Jiliang; Xu, Xiaoqing; Mehta, Nozer; Gilligan, James; Vignery, Agnès; Scholz, Jodi A Carlson

    2012-01-01

    Mechanical ablation of bone marrow in young rats induces rapid but transient bone growth, which can be enhanced and maintained for three weeks by the administration of parathyroid hormone (PTH). Additionally, marrow ablation, followed by PTH treatment for three months leads to increased cortical thickness. In this study, we sought to determine whether PTH enhances bone formation after marrow ablation in aged rats. Aged rats underwent unilateral femoral marrow ablation and treatment with PTH or vehicle for four weeks. Both femurs from each rat were analyzed by X-ray and pQCT, then analyzed either by microCT, histology or biomechanical testing. Marrow ablation alone induced transient bone formation of low abundance that persisted over four weeks, while marrow ablation followed by PTH induced bone formation of high abundance that also persisted over four weeks. Our data confirms that the osteo-inducive effect of marrow ablation and the additive effect of marrow ablation, followed by PTH, occurs in aged rats. Our observations open new avenues of investigations in the field of tissue regeneration. Local marrow ablation, in conjunction with an anabolic agent, might provide a new platform for rapid site-directed bone growth in areas of high bone loss, such as in the hip and wrist, which are subject to fracture. PMID:24710549

  15. Additive Effects of Mechanical Marrow Ablation and PTH Treatment on de Novo Bone Formation in Mature Adult Rats

    PubMed Central

    Zhang, Qing; Miller, Christopher; Bible, Jesse; Li, Jiliang; Xu, Xiaoqing; Mehta, Nozer; Gilligan, James; Vignery, Agnès; Scholz, Jodi A Carlson

    2012-01-01

    Mechanical ablation of bone marrow in young rats induces rapid but transient bone growth, which can be enhanced and maintained for three weeks by the administration of parathyroid hormone (PTH). Additionally, marrow ablation, followed by PTH treatment for three months leads to increased cortical thickness. In this study, we sought to determine whether PTH enhances bone formation after marrow ablation in aged rats. Aged rats underwent unilateral femoral marrow ablation and treatment with PTH or vehicle for four weeks. Both femurs from each rat were analyzed by X-ray and pQCT, then analyzed either by microCT, histology or biomechanical testing. Marrow ablation alone induced transient bone formation of low abundance that persisted over four weeks, while marrow ablation followed by PTH induced bone formation of high abundance that also persisted over four weeks. Our data confirms that the osteo-inducive effect of marrow ablation and the additive effect of marrow ablation, followed by PTH, occurs in aged rats. Our observations open new avenues of investigations in the field of tissue regeneration. Local marrow ablation, in conjunction with an anabolic agent, might provide a new platform for rapid site-directed bone growth in areas of high bone loss, such as in the hip and wrist, which are subject to fracture. PMID:24710549

  16. Bone Response to Surface-Modified Titanium Implants: Studies on the Early Tissue Response to Implants with Different Surface Characteristics

    PubMed Central

    Larsson Wexell, C.; Thomsen, P.; Aronsson, B.-O.; Tengvall, P.; Rodahl, M.; Lausmaa, J.; Kasemo, B.; Ericson, L. E.

    2013-01-01

    In a series of experimental studies, the bone formation around systematically modified titanium implants is analyzed. In the present study, three different surface modifications were prepared and evaluated. Glow-discharge cleaning and oxidizing resulted in a highly stoichiometric TiO2 surface, while a glow-discharge treatment in nitrogen gas resulted in implants with essentially a surface of titanium nitride, covered with a very thin titanium oxide. Finally, hydrogen peroxide treatment of implants resulted in an almost stoichiometric TiO2, rich in hydroxyl groups on the surface. Machined commercially pure titanium implants served as controls. Scanning Auger Electron Spectroscopy, Scanning Electron Microscopy, and Atomic Force Microscopy revealed no significant differences in oxide thickness or surface roughness parameters, but differences in the surface chemical composition and apparent topography were observed. After surface preparation, the implants were inserted in cortical bone of rabbits and evaluated after 1, 3, and 6 weeks. Light microscopic evaluation of the tissue response showed that all implants were in contact with bone and had a large proportion of newly formed bone within the threads after 6 weeks. There were no morphological differences between the four groups. Our study shows that a high degree of bone contact and bone formation can be achieved with titanium implants of different surface composition and topography. PMID:24174936

  17. Early consumption of blueberry diet protects against sex steroid deficiency-induced bone loss in adult female rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We studied the effects of blueberry consumption in early development on bone loss in ovariectomized (OVX) female rats later in life. Weanling female rats were fed AIN-93G semi-purified diets supplemented with 10% whole blueberry powder from PND 21 to PND34 (short-term group), or PND21 to PND81 (chro...

  18. Changes in micro-CT 3D bone parameters reflect effects of a potent cathepsin K inhibitor (SB-553484) on bone resorption and cortical bone formation in ovariectomized mice.

    PubMed

    Xiang, Anbo; Kanematsu, Masahiro; Kumar, Sanjay; Yamashita, Dennis; Kaise, Toshihiko; Kikkawa, Hideo; Asano, Satoshi; Kinoshita, Mine

    2007-05-01

    Cathepsin K is a cysteine proteinase that is highly expressed by osteoclasts and is being pursued as a potential drug target for the treatment of osteoporosis. We have reported that microcomputed tomography (micro-CT) analysis of bone microarchitecture may serve as a valuable tool for evaluating both antiresorptive and anabolic agents in ovariectomized (OVX) mice. The purpose of this study was to evaluate the effect of SB-553484, a novel cathepsin K inhibitor (human Ki,app=0.14 nM, mouse Ki,app=26 nM), on the OVX mice by micro-CT bone morphometric analysis. Seven weeks female BALB/c mice were OVX or sham-operated. OVX animals were treated with SB-553484 (30 mg/kg, sc) or Rolipram (10 mg/kg, po), a phosphodiesterase 4 inhibitor used as a positive bone anabolic agent, twice a day for 2 weeks. Both SB-553484 and Rolipram significantly prevented the decrease of trabecular bone volume as well as the deterioration of trabecular architecture in OVX mice. Interestingly, SB-553484 demonstrated a more pronounced effect in improvement of trabecular separation, number and connectivity, and a weaker effect in improvement of trabecular thickness compared to that of Rolipram. These differences indicate that SB-553484 mainly acted as an antiresorptive agent in OVX-induced loss of trabecular bone. On the other hand, SB-553484 significantly increased cortical bone volume and cortical thickness as well as Rolipram in OVX mice indicating an unexpected stimulatory effect of SB-553484 on cortical bone formation. These data suggest that targeting cathepsin K may prove therapeutically beneficial in the treatment of diseases with accelerated bone loss such as postmenopausal osteoporosis not only by inhibiting bone resorption but also by potentially stimulating cortical bone formation. PMID:17347064

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

    NASA Technical Reports Server (NTRS)

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

    1983-01-01

    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.

  20. Antagonizing the ?v?3 Integrin Inhibits Angiogenesis and Impairs Woven but Not Lamellar Bone Formation Induced by Mechanical Loading

    PubMed Central

    Tomlinson, Ryan E.; Schmieder, Anne H.; Quirk, James D.; Lanza, Gregory M.; Silva, Matthew J.

    2015-01-01

    Angiogenesis and osteogenesis are critically linked, though the role of angiogenesis is not well understood in osteogenic mechanical loading. In this study, either damaging or non-damaging cyclic axial compression was used to generate woven bone formation (WBF) or lamellar bone formation (LBF), respectively, at the mid-diaphysis of the adult rat forelimb. ?v?3 integrin targeted nanoparticles or vehicle was injected intravenously following mechanical loading. ?3 integrin subunit expression on vasculature was maximal 7 days after damaging mechanical loading, but was still robustly expressed 14 days after loading. Accordingly, targeted nanoparticle delivery in WBF loaded limbs was increased compared to non-loaded limbs. Vascularity was dramatically increased after WBF loading (+700% on day 14) and modestly increased after LBF loading (+50% on day 14). This increase in vascularity was inhibited by nanoparticle treatment in both WBF and LBF loaded limbs at days 7 and 14 after loading. Decreased vascularity led to diminished woven, but not lamellar, bone formation. Decreased woven bone formation resulted in impaired structural properties of the skeletal repair, particularly in post-yield behavior. These results demonstrate that ?v?3 integrin mediated angiogenesis is critical for recovering fracture resistance following bone injury, but is not required for bone modeling after modest mechanical strain. PMID:24644077

  1. Diagnostic role of 99Tcm-MDP SPECT/CT combined SPECT/MRI Multi modality imaging for early and atypical bone metastases

    PubMed Central

    Chen, Xiao-Liang; Li, Qian; Cao, Lin; Jiang, Shi-Xi

    2014-01-01

    The bone metastasis appeared early before the bone imaging for most of the above patients. 99Tcm-MDP (99Tcm marked methylene diphosphonate) bone imaging could diagnosis the bone metastasis with highly sensitivity, but with lower specificity. The aim of this study is to explore the diagnostic value of 99Tcm-MDP SPECT/CT combined SPECT/MRI Multi modality imaging for the early period atypical bone metastases. 15 to 30 mCi 99Tcm-MDP was intravenously injected to the 34 malignant patients diagnosed as doubtful early bone metastases. SPECT, CT and SPECT/CT images were captured and analyzed consequently. For the patients diagnosed as early period atypical bone metastases by SPECT/CT, combining the SPECT/CT and MRI together as the SPECT/MRI integrated image. The obtained SPECT/MRI image was analyzed and compared with the pathogenic results of patients. The results indicated that 34 early period doubtful metastatic focus, including 34 SPECT positive focus, 17 focus without special changes by using CT method, 11 bone metastases focus by using SPECT/CT method, 23 doubtful bone metastases focus, 8 doubtful bone metastases focus, 14 doubtful bone metastases focus and 2 focus without clear image. Totally, SPECT/CT combined with SPECT/MRI method diagnosed 30 bone metastatic focus and 4 doubtfully metastatic focus. In conclusion, 99Tcm-MDP SPECT/CT combined SPECT/MRI Multi modality imaging shows a higher diagnostic value for the early period bone metastases, which also enhances the diagnostic accuracy rate. PMID:25664040

  2. 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 Central

    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

    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

  3. Complexation and Sequestration of BMP-2 from an ECM Mimetic Hyaluronan Gel for Improved Bone Formation

    PubMed Central

    Kisiel, Marta; Klar, Agnieszka S.; Ventura, Manuela; Buijs, Jos; Mafina, Marc-Krystelle; Cool, Simon M.; Hilborn, Jöns

    2013-01-01

    Bone morphogenetic protein-2 (BMP-2) is considered a promising adjuvant for the treatment of skeletal non-union and spinal fusion. However, BMP-2 delivery in a conventional collagen scaffold necessitates a high dose to achieve an efficacious outcome. To lower its effective dose, we precomplexed BMP-2 with the glycosaminoglycans (GAGs) dermatan sulfate (DS) or heparin (HP), prior to loading it into a hyaluronic acid (HA) hydrogel. In vitro release studies showed that BMP-2 precomplexed with DS or HP had a prolonged delivery compared to without GAG. BMP-2-DS complexes achieved a slightly faster release in the first 24 h than HP; however, both delivered BMP-2 for an equal duration. Analysis of the kinetic interaction between BMP-2 and DS or HP showed that HP had approximately 10 times higher affinity for BMP-2 than DS, yet it equally stabilized the protein, as determined by alkaline phosphatase activity. Ectopic bone formation assays at subcutaneous sites in rats demonstrated that HA hydrogel-delivered BMP-2 precomplexed with GAG induced twice the volume of bone compared with BMP-2 delivered uncomplexed to GAG. PMID:24167632

  4. Unusual bone formation in the anterior rim of foramen magnum: cause, effect and treatment

    PubMed Central

    Shah, Abhidha

    2009-01-01

    A rare case of proatlas segmental abnormality resulting in a bony mass in the anterior rim of the foramen magnum is studied. Case report of a 19-year-old female showed a progressive weakness of all four limbs for about 3 years. When admitted she could not perform any useful activities by herself. Investigations revealed an unusual bone growth in the region of the anterior rim of foramen magnum that resulted in severe cord compression. The abnormal bone formation involved the lower end of clivus, the tip of the odontoid process and the posterior arch of the atlas. Dynamic imaging did not reveal any clear evidence of instability. Following transoral decompression and posterior fixation, the patient showed dramatic and lasting clinical recovery. Conclusions were drawn as follows. Anomalies of the most caudal part of the occipital sclerotomes due to the failure of proatlas segmentation can be the cause of an abnormal bone mass in the anterior rim of foramen magnum. Transoral decompression, followed by posterior atlantoaxial fixation, results in neurological recovery and provides lasting cure from the problem. PMID:20033741

  5. Developments in parathyroid hormone and related peptides as bone-formation agents.

    PubMed

    Fox, John

    2002-06-01

    Osteoporosis is a major and growing healthcare concern. When administered by daily injection, parathyroid hormone (PTH) and its N-terminal fragments and analogs are potent bone-formation agents. Teriparatide, recombinant human PTH(1-34), is likely to be the first anabolic agent approved for treating osteoporosis, despite inducing osteosarcomas in rats. Native PTH and other PTH fragments and analogs are also in development. N-terminal fragments sometimes differ in activity from the native hormone, however, and the C-terminal region of PTH, acting through a receptor different from the classical PTH-1 receptor, initiates a variety of distinct biological activities. In particular, the C-terminal region of PTH, by promoting bone-cell apoptosis, may be important in opposing the anti-apoptotic effects of teriparatide in these cells, thereby maintaining normal bone-cell turnover. Because of these differences, care must be taken to consider the effects of native PTH and N-terminal PTH fragments and analogs separately. PMID:12020480

  6. Hypoxia Modulates the Phenotype of Osteoblasts Isolated From Knee Osteoarthritis Patients, Leading to Undermineralized Bone Nodule Formation

    PubMed Central

    Chang, Joan; Jackson, Sonya G; Wardale, John; Jones, Simon W

    2014-01-01

    Objective To investigate the role of hypoxia in the pathology of osteoarthritic (OA) bone by exploring its effect on the phenotype of isolated primary osteoblasts from patients with knee OA. Methods OA bone samples were collected at the time of elective joint replacement surgery for knee or hip OA. Normal bone samples were collected postmortem from cadaver donors. Primary osteoblasts were isolated from knee OA bone chips and cultured under normoxic or hypoxic (2% O2) conditions. Alkaline phosphatase activity was quantified using an enzymatic assay, and osteopontin and prostaglandin E2 (PGE2) production was assayed by enzyme-linked immunosorbent assay. Total RNA was extracted from bone and osteoblasts, and gene expression was profiled by quantitative reverse transcription–polymerase chain reaction. Results Human OA bone tissue sections stained positively for carbonic anhydrase IX, a biomarker of hypoxia, and exhibited differential expression of genes that mediate the vasculature and blood coagulation as compared to those found in normal bone. Culture of primary osteoblasts isolated from knee OA bone under hypoxic conditions profoundly affected the osteoblast phenotype, including the expression of genes that mediate bone matrix, bone remodeling, and bone vasculature. Hypoxia also increased the expression of cyclooxygenase 2 and the production of PGE2 by OA osteoblasts. Osteoblast expression of type II collagen ?1 chain, angiopoietin-like 4, and insulin-like growth factor binding protein 1 was shown to be mediated by hypoxia-inducible factor 1?. Chronic hypoxia reduced osteoblast- mineralized bone nodule formation. Conclusion These findings demonstrate that hypoxia can induce pathologic changes in osteoblast functionality consistent with an OA phenotype, providing evidence that hypoxia is a key driver of OA pathology. PMID:24574272

  7. Relative bone mass decreased in mice fed high dietary fat despite an increase in body mass and bone formation markers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Osteoporosis and obesity are interrelated health disorders. Osteoblasts and adipocytes are derived from common mesenchymal stem cells and age-related osteoporosis is associated with increased bone marrow adipogenesis. To determine whether bone mass and osteoblast number and activity are affected by ...

  8. Effects of growth hormone and testosterone on cortical bone formation and bone density in aged orchiectomized rats

    Microsoft Academic Search

    G Prakasam; J. K Yeh; M.-M Chen; M Castro-Magana; C. T Liang; J. F Aloia

    1999-01-01

    Osteoporosis in men is a disease that is increasing in incidence, and with an increasing elderly population it poses a serious health problem. Since both testosterone (T) and growth hormone (GH) have an anabolic effect on bone and both decrease with aging, we were prompted to test whether the administration of these hormones in combination would increase bone mass in

  9. Anabolic activity of ursolic acid in bone: Stimulating osteoblast differentiation in vitro and inducing new bone formation in vivo

    Microsoft Academic Search

    Su-Ui Lee; Sang-Joon Park; Han Bok Kwak; Jaemin Oh; Yong Ki Min; Seong Hwan Kim

    2008-01-01

    In the field of osteoporosis, there has been growing interest in anabolic agents that enhance bone mass and improve bone architecture. In this study, we demonstrated that the ubiquitous plant triterpenoid, ursolic acid, enhances differentiation and mineralization of osteoblasts in vitro. We found that ursolic acid induced the expression of osteoblast-specific genes with the activation of mitogen-activated protein kinases, nuclear

  10. Stimulation of Chondrocyte Hypertrophy by Chemokine Stromal Cell-Derived Factor 1 in the Chondro-osseous Junction during Endochondral Bone Formation

    PubMed Central

    Wei, Lei; Kanbe, Katsuaki; Lee, Mark; Wei, Xiaochun; Pei, Ming; Sun, Xiaojuan; Terek, Richard; Chen, Qian

    2010-01-01

    During endochondral bone formation, chondrocytes undergo differentiation toward hypertrophy before they are replaced by bone and bone marrow. In this study, we found that a G-protein coupled receptor CXCR4 is predominantly expressed in hypertrophic chondrocytes, while its ligand, chemokine stromal cell derived factor 1 (SDF-1) is expressed in the bone marrow adjacent to hypertrophic chondrocytes. Thus, they are expressed in a complementary pattern in the chondro-osseous junction of the growth plate. Transfection of a CXCR4 cDNA into pre-hypertrophic chondrocytes results in a dose-dependent increase of hypertrophic markers including Runx2, Col X, and MMP-13 in response to SDF-1 treatment. In organ culture SDF-1 infiltrates cartilage and accelerates growth plate hypertrophy. Furthermore, a continuous infusion SDF-1 into the rabbit proximal tibial physis results in early physeal closure, which is accompanied by a transient elevation of type X collagen expression. Blocking SDF-1/CXCR4 interaction suppresses the expression of Runx2. Thus, interaction of SDF-1 and CXCR4 is required for Runx2 expression. Interestingly, knocking down Runx2 gene expression results in a decrease of CXCR4 mRNA levels in hypertrophic chondrocytes. This suggests a positive feedback loop of stimulation of chondrocyte hypertrophy by SDF-1/CXCR4, which is mediated by Runx2. PMID:20206617

  11. BMP signaling mediated by constitutively active Activin type 1 receptor (ACVR1) results in ectopic bone formation localized to distal extremity joints.

    PubMed

    Agarwal, Shailesh; Loder, Shawn J; Brownley, Cameron; Eboda, Oluwatobi; Peterson, Jonathan R; Hayano, Satoru; Wu, Bingrou; Zhao, Bin; Kaartinen, Vesa; Wong, Victor C; Mishina, Yuji; Levi, Benjamin

    2015-04-15

    BMP signaling mediated by ACVR1 plays a critical role for development of multiple structures including the cardiovascular and skeletal systems. While deficient ACVR1 signaling impairs normal embryonic development, hyperactive ACVR1 function (R206H in humans and Q207D mutation in mice, ca-ACVR1) results in formation of heterotopic ossification (HO). We developed a mouse line, which conditionally expresses ca-ACVR1 with Nfatc1-Cre(+) transgene. Mutant mice developed ectopic cartilage and bone at the distal joints of the extremities including the interphalangeal joints and hind limb ankles as early as P4 in the absence of trauma or exogenous bone morphogenetic protein (BMP) administration. Micro-CT showed that even at later time points (up to P40), cartilage and bone development persisted at the affected joints most prominently in the ankle. Interestingly, this phenotype was not present in areas of bone outside of the joints - tibia are normal in mutants and littermate controls away from the ankle. These findings demonstrate that this model may allow for further studies of heterotopic ossification, which does not require the use of stem cells, direct trauma or activation with exogenous Cre gene administration. PMID:25722188

  12. Formation and Processing of Organics in the Early Solar System

    NASA Astrophysics Data System (ADS)

    Kerridge, John F.

    1999-10-01

    Until pristine samples can be returned from cometary nuclei, primitive meteorites represent our best source of information about organic chemistry in the early solar system. However, this material has been affected by secondary processing on asteroidal parent bodies which probably did not affect the material now present in cometary nuclei. Production of meteoritic organic matter apparently involved the following sequence of events: Molecule formation by a variety of reaction pathways in dense interstellar clouds; Condensation of those molecules onto refractory interstellar grains; Irradiation of organic-rich interstellar-grain mantles producing a range of molecular fragments and free radicals; Inclusion of those interstellar grains into the protosolar nebula with probable heating of at least some grain mantles during passage through the shock wave bounding the solar accretion disc; Agglomeration of residual interstellar grains and locally produced nebular condensates into asteroid-sized planetesimals; Heating of planetesimals by decay of extinct radionuclides; Melting of ice to produce liquid water within asteroidal bodies; Reaction of interstellar molecules, fragments and radicals with each other and with the aqueous environment, possibly catalysed by mineral grains; Loss of water and other volatiles to space yielding a partially hydrated lithology containing a complex suite of organic molecules; Heating of some of this organic matter to generate a kerogen-like complex; Mixing of heated and unheated material to yield the meteoritic material now observed. Properties of meteoritic organic matter believed to be consistent with this scenario include: Systematic decrease of abundance with increasing C number in homologous series of characterisable molecules; Complete structural diversity within homologous series; Predominance of branched-chain isomers; Considerable isotopic variability among characterisable molecules and within kerogen-like material; Substantial deuterium enrichment in all organic fractions; Some fractions significantly enriched in nitrogen-15; Modest excesses of L-enantiomers in some racemisation-resistant molecules but no general enantiomeric preference. Despite much speculation about the possible role of Fischer-Tropsch catalytic hydrogenation of CO in production of organic molecules in the solar nebula, no convincing evidence for such material has been found in meteorites. A similarity between some meteoritic organics and those produced by Miller-Urey discharge synthesis may reflect involvement of common intermediates rather than the operation of electric discharges in the early solar system. Meteoritic organic matter constitutes a useful, but not exact, guide to what we shall find with in situ analytical and sample-return missions to cometary nuclei.

  13. Formation and processing of organics in the early solar system.

    PubMed

    Kerridge, J F

    1999-01-01

    Until pristine samples can be returned from cometary nuclei, primitive meteorites represent our best source of information about organic chemistry in the early solar system. However, this material has been affected by secondary processing on asteroidal parent bodies which probably did not affect the material now present in cometary nuclei. Production of meteoritic organic matter apparently involved the following sequence of events: Molecule formation by a variety of reaction pathways in dense interstellar clouds; Condensation of those molecules onto refractory interstellar grains; Irradiation of organic-rich interstellar-grain mantles producing a range of molecular fragments and free radicals; Inclusion of those interstellar grains into the protosolar nebula with probable heating of at least some grain mantles during passage through the shock wave bounding the solar accretion disc; Agglomeration of residual interstellar grains and locally produced nebular condensates into asteroid-sized planetesimals; Heating of planetesimals by decay of extinct radionuclides; Melting of ice to produce liquid water within asteroidal bodies; Reaction of interstellar molecules, fragments and radicals with each other and with the aqueous environment, possibly catalysed by mineral grains; Loss of water and other volatiles to space yielding a partially hydrated lithology containing a complex suite of organic molecules; Heating of some of this organic matter to generate a kerogen-like complex; Mixing of heated and unheated material to yield the meteoritic material now observed. Properties of meteoritic organic matter believed to be consistent with this scenario include: Systematic decrease of abundance with increasing C number in homologous series of characterisable molecules; Complete structural diversity within homologous series; Predominance of branched-chain isomers; Considerable isotopic variability among characterisable molecules and within kerogen-like material; Substantial deuterium enrichment in all organic fractions; Some fractions significantly enriched in nitrogen-15; Modest excesses of L-enantiomers in some racemisation-resistant molecules but no general enantiomeric preference. Despite much speculation about the possible role of Fischer-Tropsch catalytic hydrogenation of CO in production of organic molecules in the solar nebula, no convincing evidence for such material has been found in meteorites. A similarity between some meteoritic organics and those produced by Miller-Urey discharge synthesis may reflect involvement of common intermediates rather than the operation of electric discharges in the early solar system. Meteoritic organic matter constitutes a useful, but not exact, guide to what we shall find with in situ analytical and sample-return missions to cometary nuclei. PMID:11543289

  14. Evaluating apatite formation and osteogenic activity of electrospun composites for bone tissue engineering.

    PubMed

    Patlolla, Ajitha; Arinzeh, Treena Livingston

    2014-05-01

    Significant interest has been in examining calcium phosphate ceramics, specifically ?-tricalcium phosphate (?-TCP) (Ca3 (PO4)2 ) and synthetic hydroxyapatite (HA) (Ca10 (PO4)6 (OH)2 ), in composites and more recently, in fibrous composites formed using the electrospinning technique for bone tissue engineering applications. Calcium phosphate ceramics are sought because they can be bone bioactive, which means an apatite forms on their surface that facilitates bonding to bone tissue, and are osteoconductive. However, studies examining the bioactivity of electrospun composites containing calcium phosphates and their corresponding osteogenic activity have been limited. In this study, electrospun composites consisting of (20/80) HA/TCP nanoceramics and poly (?-caprolactone) (PCL) were fabricated. Solvent and solvent combinations were evaluated to form scaffolds with a maximum concentration and dispersion of ceramic and pore sizes large enough for cell infiltration and tissue growth. PCL was dissolved in either methylene chloride (Composite-MC) or a combination of methylene chloride (80%) and dimethylformamide (20%; Composite-MC?+?DMF). Composites were evaluated in vitro for degradation, apatite formation, and osteogenic differentiation of human mesenchymal stem cells (MSCs) with an emphasis on temporal gene expression of osteogenic markers and the pluripotent gene Sox-2. Apatite formation and the osteogenic differentiation was the greatest for Composite-MC as determined by gene expression, protein production and biochemical markers, even without the presence of osteoinductive factors in the media, in comparison to Composite-MC?+?DMF and unfilled PCL mats. Sox-2 levels also reduced over time. The results of this study demonstrate that the solvent or solvent combination used in preparing the electrospun composite mats plays a critical role in determining their bioactivity which may, in turn, affect cell behavior. PMID:24264603

  15. Efficacy of a small cell-binding peptide coated hydroxyapatite substitute on bone formation and implant fixation in sheep.

    PubMed

    Ding, Ming; Andreasen, Christina M; Dencker, Mads L; Jensen, Anders E; Theilgaard, Naseem; Overgaard, Søren

    2015-04-01

    Cylindrical critical size defects were created at the distal femoral condyles bilaterally of eight female adult sheep. Titanium implants with 2-mm concentric gaps were inserted and the gaps were filled with one of the four materials: allograft; a synthetic 15-amino acid cell-binding peptide coated hydroxyapatite (ABM/P-15); hydroxyapatite + ?tricalciumphosphate+ Poly-Lactic-Acid (HA/?TCP-PDLLA); or ABM/P-15+HA/?TCP-PDLLA. After nine weeks, bone-implant blocks were harvested and sectioned for micro-CT scanning, push-out test, and histomorphometry. Significant bone formation and implant fixation could be observed in all four groups. Interestingly, the microarchitecture of the ABM/P-15 group was significantly different from the control group. Tissue volume fraction and thickness were significantly greater in the ABM/P-15 group than in the allograft group. Bone formation and bone ingrowth to porous titanium implant were not significantly different among the four groups. The ABM/P-15 group had similar shear mechanical properties on implant fixation as the allograft group. Adding HA/?TCP-PDLLA to ABM/P-15 did not significantly change these parameters. This study revealed that ABM/P-15 had significantly bone formation in concentric gap, and its enhancements on bone formation and implant fixation were at least as good as allograft. It is suggested that ABM/P-15 might be a good alternative biomaterial for bone implant fixation in this well-validated critical-size defect gap model in sheep. Nevertheless, future clinical researches should focus on prospective, randomized, controlled trials in order to fully elucidate whether ABM/P-15 could be a feasible candidate for bone substitute material in orthopedic practices. PMID:25045068

  16. Synergistic Effect of Parathyroid Hormone and Growth Hormone on Trabecular and Cortical Bone Formation in Hypophysectomized Rats

    Microsoft Academic Search

    Maria Sarah N. Guevarra; James K. Yeh; Mariano Castro Magana; John F. Aloia

    2010-01-01

    Background\\/Aims: Growth hormone (GH) deficiency in pediatric patients results in short stature and osteopenia. We postulated that the GH and parathyroid hormone (PTH) combination would result in improvement in bone growth and bone formation. Methods: Forty hypophysectomized female rats at age 8 weeks were divided into hypophysectomy (HX), HX + PTH (62.5 ?g\\/kg, s.c. daily), HX + GH (3.33 mg\\/kg,

  17. Microarray analysis of gene expression during the inflammation and endochondral bone formation stages of rat femur fracture repair

    Microsoft Academic Search

    Charles H. Rundle; Hali Wang; Hongrun Yu; Robert B. Chadwick; Emile I. Davis; Jon E. Wergedal; K.-H. William Lau; Subburaman Mohan; James T. Ryaby; David J. Baylink

    2006-01-01

    Microarray analysis of gene expression was performed in the healing femur fractures of 13-week-old male rats during the inflammatory stage of repair, at 3 days post-fracture, and the endochondral bone formation stage of repair, at 11 days post-fracture. Multiple replicate pairs of fracture tissues paired with unfractured tissues, and unfractured control bones that had the stabilizing K-wire were introduced. This

  18. Early star formation and the evolution of the stellar initial mass function in Richard B. Larson*

    E-print Network

    Larson, Richard B.

    Early star formation and the evolution of the stellar initial mass function in galaxies Richard B function, mass function ­ galaxies: evolution ­ galaxies: formation ­ galaxies: stellar content ­ dark in the literature that the stellar IMF in galaxies was top-heavy at early times. This would be plausible physically

  19. Mechanism by which MLO-A5 Late Osteoblasts/Early Osteocytes Mineralize in Culture: Similarities with Mineralization of Lamellar Bone

    PubMed Central

    Barragan-Adjemian, C.; Nicolella, D.; Dusevich, V.; Dallas, M. R.; Eick, J. D.; Bonewald, L. F.

    2007-01-01

    The mechanisms whereby bone mineralizes are unclear. To study this process, we used a cell line, MLO-A5, which has highly elevated expression of markers of the late osteoblast such as alkaline phosphatase, bone sialoprotein, parathyroid hormone type 1 receptor, and osteocalcin and will mineralize in sheets, not nodules. In culture, markers of osteocytes and dendricity increase with time, features of differentiation from a late osteoblast to an early osteocyte. Mineral formation was examined using transmission electron microscopy, scanning electron microscopy with energy-dispersive X-ray analysis, and atomic force microscopy. At 3–4 days of culture, spheres of approximately 20–50 nm containing calcium and phosphorus were observed budding from and associated with developing cellular projections. By 5–6 days, these calcified spheres were associated with collagen fibrils, where over time they continued to enlarge and to engulf the collagen network. Coalescence of these mineralized spheres and collagen-mediated mineralization were responsible for the mineralization of the matrix. Similar calcified spheres were observed in cultured fetal rat calvarial cells and in murine lamellar bone. We propose that osteoidosteocytes generate spherical structures that calcify during the budding process and are fully mineralized on their developing cellular processes. As the cellular process narrows in diameter, these mineralized structures become associated with and initiate collagen-mediated mineralization. PMID:17115241

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

    PubMed Central

    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

    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

  1. miR-124 Negatively Regulates Osteogenic Differentiation and In vivo Bone Formation of Mesenchymal Stem Cells.

    PubMed

    Qadir, Abdul S; Um, Soyoun; Lee, Heesu; Baek, Kyunghwa; Seo, Byoung Moo; Lee, Gene; Kim, Gwan-Shik; Woo, Kyung Mi; Ryoo, Hyun-Mo; Baek, Jeong-Hwa

    2015-05-01

    MicroRNAs are novel key regulators of cellular differentiation. Dlx transcription factors play an important role in osteoblast differentiation, and Dlx5 and Dlx2 are known targets of miR-124. Therefore, in the present study, we investigated the regulatory effects of miR-124 on the osteogenic differentiation and in vivo bone formation of mesenchymal stem cells (MSCs). During osteogenic induction by BMP2, the expression levels of miR-124 were inversely correlated with those of osteogenic differentiation marker genes in human and mouse bone marrow-derived MSCs, MC3T3-E1 cells and C2C12 cells. The overexpression of a miR-124 mimic significantly decreased the expression levels of Dlx5, Dlx3, and Dlx2, whereas the silencing of miR-124 with hairpin inhibitors significantly increased the expression of these Dlx genes. Luciferase reporter assays demonstrated that miR-124 directly targets the 3'UTRs of Dlx3, Dlx5, and Dlx2. The overexpression of a miR-124 mimic suppressed the osteogenic marker gene expression levels, alkaline phosphatase activity and matrix mineralization, which were all significantly increased by the overexpression of a miR-124 inhibitor. When ectopic bone formation was induced by the subcutaneous transplantation of human bone marrow-derived MSCs in nude mice, MSCs overexpressing a miR-124 inhibitor significantly enhanced woven bone formation compared with control MSCs. However, MSCs overexpressing a miR-124 mimic exhibited increased adipocyte differentiation at the expense of ectopic bone formation. These results suggest that miR-124 is a negative regulator of osteogenic differentiation and in vivo bone formation and that the targeting of Dlx5, Dlx3, and Dlx2 genes partly contributes to this inhibitory effect exerted by miR-124. J. Cell. Biochem. 116: 730-742, 2015. © 2014 Wiley Periodicals, Inc. PMID:25424317

  2. The effects of disorders of cartilage formation and bone resorption on bone shape: a study with chondrodystrophic and osteopetrotic mouse mutants.

    PubMed Central

    Johnson, D R; O'Higgins, P; McAndrew, T J

    1991-01-01

    The shapes of scapulae and basi-occipital bones from three genetically distinct achondroplastic mutants and one osteopetrotic mutant in the mouse (achondroplasia, brachymorphic, stumpy and grey lethal), and appropriate controls, have been compared using Fourier analysis and multivariate statistical techniques. Normal littermates were generally similar in shape, but mutants were significantly different from these controls and from each other. The pattern of morphological differences between the mutants and between the mutants and normal controls is examined. These differences are discussed in relation to the different effects of the four genes on bone morphogenesis, and the significance of these findings in relation to the contributions of cartilage formation and bone resorption to skeletal morphogenesis is considered. PMID:1917676

  3. Formation of the early atmosphere from late-accreting planetesimals Sujoy Mukhopadhyay*

    E-print Network

    Mukhopadhyay, Sujoy

    1 Formation of the early atmosphere from late-accreting planetesimals Sujoy Mukhopadhyay* , Rita, Cambridge MA 02138, USA. * Corresponding author Abstract The composition of Earth's early atmosphere strongly influenced chemical reactions on our planet's surface. For example, an early reducing atmosphere

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

    NASA Technical Reports Server (NTRS)

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

    1992-01-01

    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).

  5. Bone tissue formation with human mesenchymal stem cells and biphasic calcium phosphate ceramics: the local implication of osteoclasts and macrophages.

    PubMed

    Gamblin, Anne-Laure; Brennan, Meadhbh A; Renaud, Audrey; Yagita, Hideo; Lézot, Frédéric; Heymann, Dominique; Trichet, Valérie; Layrolle, Pierre

    2014-12-01

    Human mesenchymal stem cells (hMSC) have immunomodulative properties and, associated with calcium phosphate (CaP) ceramics, induce bone tissue repair. However, the mechanisms of osteoinduction by hMSC with CaP are not clearly established, in particular the role of osteoclasts and macrophages. Biphasic calcium phosphate (BCP) particles were implanted with or without hMSC in the paratibial muscles of nude mice. hMSC increased osteoblastic gene expression at 1 week, the presence of macrophages at 2 and 4 weeks, osteoclastogenesis at 4 and 8 weeks, and osteogenesis at 4 and 8 weeks. hMSC disappeared from the implantation site after 2 weeks, indicating that hMSC were inducers rather than effectors of bone formation. Induced blockage of osteoclastogenesis by anti-Rankl treatment significantly impaired bone formation, revealing the pivotal role of osteoclasts in bone formation. In summary, hMSC positively influence the body foreign reaction by attracting circulating haematopoietic stem cells and inducing their differentiation into macrophages M1 and osteoclasts, thus favouring bone formation. PMID:25176068

  6. Effects of AISI 316L corrosion products in in vitro bone formation.

    PubMed

    Morais, S; Sousa, J P; Fernandes, M H; Carvalho, G S; de Bruijn, J D; van Blitterswijk, C A

    1998-06-01

    Rat bone marrow cells were cultured in experimental conditions that favour the proliferation and differentiation of osteoblastic cells (i.e., 2.52 x 10(-4) mol l(-1) ascorbic acid, 10(-2) mol l(-1) beta-glycerophosphate and 10(-8) mol l(-1) dexamethasone) in the absence and in the presence of stainless-steel corrosion products, for a period of 18 days. An AISI 316L stainless-steel slurry (SS) was obtained by electrochemical means and the concentrations of the major metal ions, determined by atomic absorption spectrometry, were 8.78 x 10(-3) mol l(-1) of Fe, 4.31 x 10(-3) mol l(-1) of Cr and 2.56 x 10(-3) mol l(-1) of Ni. Bone marrow cells were exposed to 0.01, 0.1 and 1% of the SS and at the end of the incubation period, control and treated cultures were evaluated by histochemical assays for the identification of the presence of alkaline phosphatase and also calcium and phosphate deposition. Cultures were further observed by scanning electron microscopy. Levels of total and ionised calcium and phosphorus in the culture media collected from control and metal exposed cell cultures were also quantified. Histochemical staining showed that control cultures presented a strong reaction for the presence of alkaline phosphatase and exhibited formation of calcium and phosphates deposits. The presence of 0.01% SS caused no detectable biological effects in these cultures, 0.1% SS impaired osteoblastic behaviour and, 1% SS resulted in cell death. In the absence of bone cells, levels of total and ionised calcium and phosphorus in the control and metal added culture medium were similar throughout the incubation period. A significant decrease in the levels of ionised calcium and phosphorus were observed in the culture medium of control cultures and also in cultures exposed to 0.01% SS after two weeks of incubation, an event related with the formation of mineral calcium phosphate deposits in these cultures. In cultures grown in the presence of 0.1 and 1% SS corrosion products, levels of calcium and phosphorus were similar to those observed in the absence of cells. Results showed that stainless-steel corrosion products above certain concentrations may disturb the normal behaviour of osteoblast-like rat bone marrow cell cultures. PMID:9692798

  7. The effects of rhBMP-2 released from biodegradable polyurethane\\/microsphere composite scaffolds on new bone formation in rat femora

    Microsoft Academic Search

    Bing Li; Toshitaka Yoshii; Andrea E. Hafeman; Jeffry S. Nyman; Joseph C. Wenke; Scott A. Guelcher

    2009-01-01

    Scaffolds prepared from biodegradable polyurethanes (PUR) have been investigated as a supportive matrix and delivery system for skin, cardiovascular, and bone tissue engineering. While previous studies have suggested that PUR scaffolds are biocompatible and moderately osteoconductive, the effects of encapsulated osteoinductive molecules, such as recombinant human bone morphogenetic protein (rhBMP-2), on new bone formation have not been investigated for this

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

    PubMed Central

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

    2014-01-01

    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

  9. TRAF Family Member-associated NF-?B Activator (TANK) Is a Negative Regulator of Osteoclastogenesis and Bone Formation*

    PubMed Central

    Maruyama, Kenta; Kawagoe, Tatsukata; Kondo, Takeshi; Akira, Shizuo; Takeuchi, Osamu

    2012-01-01

    The differentiation of bone-resorbing osteoclasts is induced by RANKL signaling, and leads to the activation of NF-?B via TRAF6 activation. TRAF family member-associated NF-?B activator (TANK) acts as a negative regulator of Toll-like receptors (TLRs) and B-cell receptor (BCR) signaling by inhibiting TRAF6 activation. Tank?/? mice spontaneously develop autoimmune glomerular nephritis in an IL-6-dependent manner. Despite its importance in the TCRs and BCR-activated TRAF6 inhibition, the involvement of TANK in RANKL signaling is poorly understood. Here, we report that TANK is a negative regulator of osteoclast differentiation. The expression levels of TANK mRNA and protein were up-regulated during RANKL-induced osteoclastogenesis, and overexpression of TANK in vitro led to a decrease in osteoclast formation. The in vitro osteoclastogenesis of Tank?/? cells was significantly increased, accompanied by increased ubiquitination of TRAF6 and enhanced canonical NF-?B activation in response to RANKL stimulation. Tank?/? mice showed severe trabecular bone loss, but increased cortical bone mineral density, because of enhanced bone erosion and formation. TANK mRNA expression was induced during osteoblast differentiation and Tank?/? osteoblasts exhibited enhaced NF-?B activation, IL-11 expression, and bone nodule formation than wild-type control cells. Finally, wild-type mice transplanted with bone marrow cells from Tank?/? mice showed trabecular bone loss analogous to that in Tank?/? mice. These findings demonstrate that TANK is critical for osteoclastogenesis by regulating NF-?B, and is also important for proper bone remodeling. PMID:22773835

  10. An experimental study on the application of radionuclide imaging in repair of the bone defect

    PubMed Central

    Zhu, Weimin; Wang, Daping; Zhang, Xiaojun; Lu, Wei; Liu, Jianquan; Peng, Liangquan; Li, Hao; Han, Yun; Zeng, Yanjun

    2011-01-01

    The aim of our study was to validate the effect of radionuclide imaging in early monitoring of the bone’s reconstruction, the animal model of bone defect was made on the rabbits repaired with HA artificial bone. The ability of bone defect repair was evaluated by using radionuclide bone imaging at 2, 4, 8 and 12 weeks postoperatively. The results indicate that the experimental group stimulated more bone formation than that of the control group. The differences of the bone reconstruction ability were statistically significant (p<0.05). The nano-HA artificial has good bone conduction, and it can be used for the treatment of bone defects. Radionuclide imaging may be an effective and first choice method for the early monitoring of the bone’s reconstruction. PMID:21875418

  11. Bone Morphogenetic Protein 15 (BMP15) Acts as a BMP and Wnt Inhibitor during Early Embryogenesis*

    PubMed Central

    Di Pasquale, Elisa; Brivanlou, Ali H.

    2009-01-01

    Bone morphogenetic protein 15 (BMP15) belongs to an unusual subgroup of the transforming growth factor ? (TGF?) superfamily of signaling ligands as it lacks a key cysteine residue in the mature region required for proper intermolecular dimerization. Naturally occurring BMP15 mutation leads to early ovarian failure in humans, and BMP15 has been shown to activate the Smad1/5/8 pathway in that context. Despite its important role in germ cell specification, the embryological function of BMP15 remains unknown. Surprisingly, we find that during early Xenopus embryogenesis BMP15 acts solely as an inhibitor of the Smad1/5/8 pathway and the Wnt pathway. BMP15 gain-of-function leads to embryos with secondary ectopic heads and to direct neural induction in intact explants. BMP15 inhibits BMP4-mediated epidermal induction in dissociated explants. BMP15 strongly inhibits BRE response induced by BMP4 and blocks phosphorylation and activation of Smad1/5/8 MH2-domain. Mechanistically, BMP15 protein specifically interacts with BMP4 protein, suggesting inhibition upstream of receptor binding. Loss-of-function experiments using morpholinos or a naturally occurring human BMP15 dominant-negative mutant (BMP15-Y235C) leads to embryos lacking head. BMP15-Y235C also eliminates the inhibitory activity of BMP15 on BRE (BMP-responsive element). Finally, we show that BMP15 inhibits the canonical branch of the Wnt pathway, upstream of ?-catenin. We, thus, demonstrate that BMP15 is necessary and sufficient for the specification of dorso-anterior structures and highlight novel mechanisms of BMP15 function that strongly suggest a reinterpretation of its function in ovaries specially for ovarian failure. PMID:19553676

  12. Macrophage function in murine allogeneic bone marrow radiation chimeras in the early phase after transplantation

    SciTech Connect

    Roesler, J.; Baccarini, M.; Vogt, B.; Lohmann-Matthes, M.L. (Fraunhofer-Institute for Toxicology and Aerosol Research, Hannover (Germany, F.R.))

    1989-08-01

    We tested several of the functions of macrophages (M phi) in the early phase after allogeneic bone marrow transfer to get information about this important aspect of the nonspecific immune system in the T-cell-deficient recipient. On days 3-5 after transfer, the number of M phi was reduced in the spleen, liver, lungs, and peritoneal cavity (Pe). The phagocytosis of sheep red blood cells (SRBC) by these M phi was normal or even enhanced, as in the case of Pe-M phi. Already on days 8-12 after transfer, the number of M phi in spleen and liver exceeded that of controls, whereas the number was still reduced in lungs and Pe. We examined their ability to kill P815 tumor cells, to produce tumor necrosis factor-alpha (TNF alpha), to phagocytose SRBC, to produce reactive oxygen intermediates (ROI) in vitro and to kill Listeria monocytogenes in vivo. Most functions were normal and often even enhanced, depending on the organ origin, but the ability of Pe-M phi to produce ROI was reduced. Proliferative response to macrophage colony-stimulating factor (M-CSF) and killing of YAC-1 tumor cells revealed a high frequency of macrophage precursor cells in the spleen and liver and a high natural killer (NK) activity in the liver. Altogether, enhanced nonspecific immune function, especially preactivated M phi, may enable chimeras to survive attacks by opportunistic pathogens.

  13. Bone Metabolism on ISS Missions

    NASA Technical Reports Server (NTRS)

    Smith, S. M.; Heer, M. A.; Shackelford, L. C.; Zwart, S. R.

    2014-01-01

    Spaceflight-induced bone loss is associated with increased bone resorption (1, 2), and either unchanged or decreased rates of bone formation. Resistive exercise had been proposed as a countermeasure, and data from bed rest supported this concept (3). An interim resistive exercise device (iRED) was flown for early ISS crews. Unfortunately, the iRED provided no greater bone protection than on missions where only aerobic and muscular endurance exercises were available (4, 5). In 2008, the Advanced Resistive Exercise Device (ARED), a more robust device with much greater resistance capability, (6, 7) was launched to the ISS. Astronauts who had access to ARED, coupled with adequate energy intake and vitamin D status, returned from ISS missions with bone mineral densities virtually unchanged from preflight (7). Bone biochemical markers showed that while the resistive exercise and adequate energy consumption did not mitigate the increased bone resorption, bone formation was increased (7, 8). The typical drop in circulating parathyroid hormone did not occur in ARED crewmembers. In 2014, an updated look at the densitometry data was published. This study confirmed the initial findings with a much larger set of data. In 42 astronauts (33 male, 9 female), the bone mineral density response to flight was the same for men and women (9), and those with access to the ARED did not have the typical decrease in bone mineral density that was observed in early ISS crewmembers with access to the iRED (Figure 1) (7). Biochemical markers of bone formation and resorption responded similarly in men and women. These data are encouraging, and represent the first in-flight evidence in the history of human space flight that diet and exercise can maintain bone mineral density on long-duration missions. However, the maintenance of bone mineral density through bone remodeling, that is, increases in both resorption and formation, may yield a bone with strength characteristics different from those that existed before space flight. Studies to assess bone strength after flight are underway at NASA, to better understand the results of bone remodeling. Studies are also underway to evaluate optimized exercise protocols and nutritional countermeasures. Regardless, there is clear evidence of progress being made to protect bone during spaceflight.

  14. Assessing Early Learning through Formative Assessment: Key Issues and Considerations

    ERIC Educational Resources Information Center

    Dunphy, Elizabeth

    2010-01-01

    At all levels of education the assessment of learning is generally regarded as an integral part of teachers' work. For early childhood teachers, i.e., those who work with children in the age-range birth to six years, there are very particular considerations arising from the characteristics of young learners and the nature of early learning. This…

  15. 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)

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

    2007-05-01

    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.

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

    PubMed Central

    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

    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

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

    PubMed

    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

    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

  18. Inhibition of bone marrow colony formation by human natural killer cells and by natural killer cell-derived colony-inhibiting activity

    PubMed Central

    1985-01-01

    Incubation of human peripheral blood lymphocytes with bone marrow cells resulted in significant inhibition of colony formation by committed myeloid and erythroid cells. Using positively selected homogeneous natural killer (NK) cell preparations and lymphocyte subpopulations depleted of or enriched for NK cells, we definitively characterize as NK cells the cells in normal peripheral blood that are responsible for inhibition of bone marrow colony growth. The inhibitory effect of NK cells on hematopoiesis can be mediated by a soluble factor that is produced only by NK cells upon culture with HLA-DR+ hematopoietic cells and with NK-sensitive cell lines. Both NK cells and the NK-produced, colony-inhibiting activity (NK-CIA) are suppressive for allogeneic and autologous bone marrow CFU-GEMM (colony-forming units, granulocyte, erythroid, monocyte, megakaryocyte), CFU-E (CFU, erythroid), and early CFU-GM (CFU, granulocyte, monocyte), but not for either BFU-E (burst- forming units, erythroid) or late CFU-GM. [3H]Thymidine incorporation was inhibited by NK-CIA-containing supernatants in HLA-DR+ but not HLA- DR- bone marrow cell populations stimulated to proliferative by colony- stimulating factor (CSF). These data suggest that the NK cell-mediated inhibitory effect on proliferation and differentiation of hematopoietic precursor cells is mediated in part or completely by the secreted NK- CIA. The concentration of NK-CIA reached in the supernatant of the mixture of NK cell-containing lymphocyte populations with bone marrow cells is sufficient to account for the inhibitory effect mediated by NK cells. Our data support the hypothesis that human NK cells play a major role in the control of hematopoiesis, down-regulating it under conditions in which the NK cells are functionally activated. PMID:3838767

  19. Demonstration of early functional compromise of bone marrow derived hematopoietic progenitor cells during bovine neonatal pancytopenia through in vitro culture of bone marrow biopsies

    PubMed Central

    2012-01-01

    Background Bovine neonatal pancytopenia (BNP) is a syndrome characterised by thrombocytopenia associated with marked bone marrow destruction in calves, widely reported since 2007 in several European countries and since 2011 in New Zealand. The disease is epidemiologically associated with the use of an inactivated bovine virus diarrhoea (BVD) vaccine and is currently considered to be caused by absorption of colostral antibody produced by some vaccinated cows (“BNP dams”). Alloantibodies capable of binding to the leukocyte surface have been detected in BNP dams and antibodies recognising bovine MHC class I and ?-2-microglobulin have been detected in vaccinated cattle. In this study, calves were challenged with pooled colostrum collected from BNP dams or from non-BNP dams and their bone marrow hematopoietic progenitor cells (HPC) cultured in vitro from sternal biopsies taken at 24 hours and 6 days post-challenge. Results Clonogenic assay demonstrated that CFU-GEMM (colony forming unit-granulocyte/erythroid/macrophage/megakaryocyte; pluripotential progenitor cell) colony development was compromised from HPCs harvested as early as 24 hour post-challenge. By 6 days post challenge, HPCs harvested from challenged calves failed to develop CFU-E (erythroid) colonies and the development of both CFU-GEMM and CFU-GM (granulocyte/macrophage) was markedly reduced. Conclusion This study suggests that the bone marrow pathology and clinical signs associated with BNP are related to an insult which compromises the pluripotential progenitor cell within the first 24 hours of life but that this does not initially include all cell types. PMID:23110710

  20. A rare incident of Paget's disease of bone in early adult life

    PubMed Central

    Rai, Harishchandra; Pai, Shaila M; Dayakar, Anitha; Javagal, Vivek

    2014-01-01

    Paget's disease of bone (PDB) is characterized by a focal alteration of bone remodeling, which leads to bone with anomalous structure and altered mechanical properties associated with pain and complications. It is more common in Western Europe where as rare in Africa and Asia. The disease is more common in men of older adults and mean age of occurrence is 59 ± 14 years. But it is rarely encountered in patients younger than 40 years of age. PMID:25364167

  1. A rare incident of Paget's disease of bone in early adult life.

    PubMed

    Rai, Harishchandra; Pai, Shaila M; Dayakar, Anitha; Javagal, Vivek

    2014-09-01

    Paget's disease of bone (PDB) is characterized by a focal alteration of bone remodeling, which leads to bone with anomalous structure and altered mechanical properties associated with pain and complications. It is more common in Western Europe where as rare in Africa and Asia. The disease is more common in men of older adults and mean age of occurrence is 59 ± 14 years. But it is rarely encountered in patients younger than 40 years of age. PMID:25364167

  2. Evaluation of radionuclide bone-imaging for the early detection of sepsis in a model of equine neonatal osteomyelitis

    E-print Network

    Taylor, James Rutledge

    1986-01-01

    abscesses. It is well documented today, however, that regions of osteomyelitis can appear as areas of decreased uptake, or "cold spots". ' ' Most likely in the early phase of osteomyelitis, 11, 12, 14 acute inflammation of the bone and marrow causes... osteomyelitis. CHAPTER III INDIUM-111-OXINE LABELED LEUKOCYTE IMAGING Literature Review The localization of an abscess is often a difficult clinical problem. Since an abscess is a focal accumulation of leukocytes, a patient's leukocytes labeled with gamma...

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

    PubMed

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

    2014-04-01

    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

  4. Detecting early bone changes using in vivo micro-CT in ovariectomized, zoledronic acid-treated, and sham-operated rats

    Microsoft Academic Search

    E. Perilli; V. Le; B. Ma; P. Salmon; K. Reynolds; N. L. Fazzalari

    2010-01-01

    Summary  This study monitored in vivo the effect on bone microarchitecture of initiating antiresorptive treatment with zoledronic acid\\u000a in rats at 2 weeks following ovariectomy, an early phase at which major degenerative bone changes have been found to occur.\\u000a The treatment still facilitated the full reversal of cancellous bone loss in rat tibia, highlighting the importance of the\\u000a time point of initiation

  5. Unusual presentation of glomus tympanicum tumour: New bone formation in the middle ear

    PubMed Central

    Kumar, Gaurav; Andreou, Zenon; Virk, Jagdeep Singh; Owa, Anthony

    2014-01-01

    The objective of this study is to increase awareness of the rare presentation, diagnostic difficulties and management of glomus tympanicum of the middle ear. A 49 years old male, with a background of hypertension and epilepsy, presented with a two month history of left sided conductive hearing loss, pulsatile tinnitus and headache. Clinically and radiologically a diagnosis of glomus tympanicum was made. Intraoperatively, extensive osteogenesis of the middle ear resulting in ossicular fixation and erosion was found. This patient required a two stage operation for full clearance of disease. A stapedectomy drill was used to drill off the bony overgrowth surrounding the ossicles resulting in improved hearing thresholds and full clearance of the disease at two year follow up. Glomus tympanicum can result in new bone formation in the middle ear with resultant ossicular fixation and conductive hearing loss. This can be effectively treated surgically with restoration of hearing. PMID:25232551

  6. JMJD3 promotes chondrocyte proliferation and hypertrophy during endochondral bone formation in mice

    PubMed Central

    Zhang, Feng; Xu, Longyong; Xu, Longxia; Xu, Qing; Li, Dangsheng; Yang, Yingzi; Karsenty, Gerard; Chen, Charlie Degui

    2015-01-01

    JMJD3 (KDM6B) is an H3K27me3 demethylase and counteracts polycomb-mediated transcription repression. However, the function of JMJD3 in vivo is not well understood. Here we show that JMJD3 is highly expressed in cells of the chondrocyte lineage, especially in prehypertrophic and hypertrophic chondrocytes, during endochondral ossification. Homozygous deletion of Jmjd3 results in severely decreased proliferation and delayed hypertrophy of chondrocytes, and thereby marked retardation of endochondral ossification in mice. Genetically, JMJD3 associates with RUNX2 to promote proliferation and hypertrophy of chondrocytes. Biochemically, JMJD3 associates with and enhances RUNX2 activity by derepression of Runx2 and Ihh transcription through its H3K27me3 demethylase activity. These results demonstrate that JMJD3 is a key epigenetic regulator in the process of cartilage maturation during endochondral bone formation. PMID:25587042

  7. The comparative effectiveness of demineralized bone matrix, beta-tricalcium phosphate, and bovine-derived anorganic bone matrix on inflammation and bone formation using a paired calvarial defect model in rats

    PubMed Central

    Khoshzaban, Ahad; Mehrzad, Shahram; Tavakoli, Vida; Keshel, Saeed Heidari; Behrouzi, Gholam Reza; Bashtar, Maryam

    2011-01-01

    Background In this study, the effectiveness of Iranian Tissue Bank–produced demineralized bone matrix (ITB-DBM), beta-tricalcium phosphate (?TCP), and Bio-Oss® (Geistlich Pharma AG, Wolhusen, Switzerland) were evaluated and compared with double controls. The main goal was to measure the amount of new bone formation in the center of defects created in rat calvaria. Another goal was to compare the controls and evaluate the effects of each treatment material on their adjacent untreated (control) defects. Methods In this study, 40 male Wistar rats were selected and divided into four groups, In each group, there were ten rats with two defects in their calvarias; one of them is considered as control and the other one was treated with ITB-DBM (group 1), BIO-OSS (group2), and ?TCP (group 3), respectively. But in group 4, both defects were considered as control. The amount of inflammation and new bone formation were evaluated at 4 and 10 weeks. In the first group, one defect was filled with ITB-DBM; in the second group, one defect was filled with Bio-Oss; in the third group, one defect was filled with ?TCP; and in the fourth group, both defects were left unfilled. Zeiss microscope (Carl Zeiss AG, Oberkochen, Germany) and Image Tool® (version 3.0; University of Texas Health Science Center at San Antonio, San Antonio, TX) software were used for evaluation. SPSS Statistics (IBM Corp, Somers, NY) was used for statistical analysis. Results Maximum bone formation at 4 and 10 weeks were observed in the ITB-DBM group (46.960% ± 4.366%, 94.970% ± 0.323%), which had significant difference compared with the other groups (P < 0.001). Ranking second was the Bio-Oss group and third, the ?TCP group. Bone formation in the group with two unfilled defects was much more significant than in the other controls beside the Bio-Oss and ?TCP after 10 weeks (29.1 ± 2.065, 29.05 ± 1.649), while this group had the least bone formation compared with the other controls at week 4 (2.100% ± 0.758%, 1.630% ± 0.668%, P < 0.001). Conclusion Overall, the ITB-DBM group showed the best results, although the results for other experimental groups were unfavorable. The authors conclude that human DBM (ITB-DBM) should be offered as an alternative for bone regeneration in animals, such as horses, as well as in humans, especially for jaw reconstruction. In relation to bone regeneration in control defects, the effect of experimental material on controls was apparent during the initial weeks. PMID:23674917

  8. Mutation in Osteoactivin Decreases Bone Formation in Vivo and Osteoblast Differentiation in Vitro

    PubMed Central

    Abdelmagid, Samir M.; Belcher, Joyce Y.; Moussa, Fouad M.; Lababidi, Suzanne L.; Sondag, Gregory R.; Novak, Kimberly M.; Sanyurah, Afif S.; Frara, Nagat A.; Razmpour, Roshanak; Del Carpio-Cano, Fabiola E.; Safadi, Fayez F.

    2015-01-01

    We have previously identified osteoactivin (OA), encoded by Gpnmb, as an osteogenic factor that stimulates osteoblast differentiation in vitro. To elucidate the importance of OA in osteogenesis, we characterized the skeletal phenotype of a mouse model, DBA/2J (D2J) with a loss-of-function mutation in Gpnmb. Microtomography of D2J mice showed decreased trabecular mass, compared to that in wild-type mice [DBA/2J-Gpnmb+/SjJ (D2J/Gpnmb+)]. Serum analysis showed decreases in OA and the bone-formation markers alkaline phosphatase and osteocalcin in D2J mice. Although D2J mice showed decreased osteoid and mineralization surfaces, their osteoblasts were increased in number, compared to D2J/Gpnmb+ mice. We then examined the ability of D2J osteoblasts to differentiate in culture, where their differentiation and function were decreased, as evidenced by low alkaline phosphatase activity and matrix mineralization. Quantitative RT-PCR analyses confirmed the decreased expression of differentiation markers in D2J osteoblasts. In vitro, D2J osteoblasts proliferated and survived significantly less, compared to D2J/Gpnmb+ osteoblasts. Next, we investigated whether mutant OA protein induces endoplasmic reticulum stress in D2J osteoblasts. Neither endoplasmic reticulum stress markers nor endoplasmic reticulum ultrastructure were altered in D2J osteoblasts. Finally, we assessed underlying mechanisms that might alter proliferation of D2J osteoblasts. Interestingly, TGF-? receptors and Smad-2/3 phosphorylation were up-regulated in D2J osteoblasts, suggesting that OA contributes to TGF-? signaling. These data confirm the anabolic role of OA in postnatal bone formation. PMID:24462663

  9. Circulating Fibroblast Growth Factor23 Increases Following Intermittent Parathyroid Hormone (1–34) in Postmenopausal Osteoporosis: Association with Biomarker of Bone Formation

    Microsoft Academic Search

    M. Sridharan; J. Cheung; A. E. Moore; M. L. Frost; W. D. Fraser; I. Fogelman; G. Hampson

    2010-01-01

    Uncertainties exist regarding whether FGF-23 production is influenced by PTH and its involvement in bone formation. We evaluated\\u000a FGF-23 response and its relation to changes in biomarkers of bone formation following intermittent PTH treatment. Twenty-seven\\u000a women with a mean [SD] age of 75.8 [5.4] years with postmenopausal osteoporosis were treated with PTH(1–34) for 18 months.\\u000a Bone mineral density (BMD) was measured

  10. Mandibular Bone Formation Rates in Aged Ovariectomized Rats Treated with Anti-resorptive Agents Alone and in Combination with Intermittent Parathyroid Hormone

    Microsoft Academic Search

    J. Hunziker; TJ Wronski; S. C. Miller

    2000-01-01

    Anti-resorptive agents-including estrogen (E), calcitonin (CT), and bisphosphonates-are established in the treatment of osteoporosis. Intermittent administration of parathyroid hormone (PTH) stimulates bone formation and is a possible therapeutic agent for the restoration of bone mass. The purpose was to determine the effects of the anti-resorptive agents alone and in combination with intermittent PTH on bone formation in the mandible and

  11. A Novel Low-Molecular-Weight Compound Enhances Ectopic Bone Formation and Fracture Repair

    PubMed Central

    Wong, Eugene; Sangadala, Sreedhara; Boden, Scott D.; Yoshioka, Katsuhito; Hutton, William C.; Oliver, Colleen; Titus, Louisa

    2013-01-01

    Background: Use of recombinant human bone morphogenetic protein-2 (rhBMP-2) is expensive and may cause local side effects. A small synthetic molecule, SVAK-12, has recently been shown in vitro to potentiate rhBMP-2-induced transdifferentiation of myoblasts into the osteoblastic phenotype. The aims of this study were to test the ability of SVAK-12 to enhance bone formation in a rodent ectopic model and to test whether a single percutaneous injection of SVAK-12 can accelerate callus formation in a rodent femoral fracture model. Methods: Collagen disks with rhBMP-2 alone or with rhBMP-2 and SVAK-12 were implanted in a standard athymic rat chest ectopic model, and radiographic analysis was performed at four weeks. In a second set of rats (Sprague-Dawley), SVAK-12 was percutaneously injected into the site of a closed femoral fracture. The fractures were analyzed radiographically and biomechanically (with torsional testing) five weeks after surgery. Results: In the ectopic model, there was dose-dependent enhancement of rhBMP-2 activity with use of SVAK-12 at doses of 100 to 500 ?g. In the fracture model, the SVAK-12-treated group had significantly higher radiographic healing scores than the untreated group (p = 0.028). Biomechanical testing revealed that the fractured femora in the 200 to 250-?g SVAK-12 group were 43% stronger (p = 0.008) and 93% stiffer (p = 0.014) than those in the control group. In summary, at five weeks the femoral fracture group injected with SVAK-12 showed significantly improved radiographic and biomechanical evidence of healing compared with the controls. Conclusions: A single local dose of a low-molecular-weight compound, SVAK-12, enhanced bone-healing in the presence of low-dose exogenous rhBMP-2 (in the ectopic model) and endogenous rhBMPs (in the femoral fracture model). Clinical Relevance: This study demonstrates that rhBMP-2 responsiveness can be enhanced by a novel small molecule, SVAK-12. Local application of anabolic small molecules has the potential for potentiating and accelerating fracture-healing. Use of this small molecule to lower required doses of rhBMPs might both decrease their cost and improve their safety profile. PMID:23467869

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

    PubMed Central

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

    2014-01-01

    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

  13. Balancing the Rates of New Bone Formation and Polymer Degradation Enhances Healing of Weight-Bearing Allograft/Polyurethane Composites in Rabbit Femoral Defects

    PubMed Central

    Dumas, Jerald E.; Prieto, Edna M.; Zienkiewicz, Katarzyna J.; Guda, Teja; Wenke, Joseph C.; Bible, Jesse; Holt, Ginger E.

    2014-01-01

    There is a compelling clinical need for bone grafts with initial bone-like mechanical properties that actively remodel for repair of weight-bearing bone defects, such as fractures of the tibial plateau and vertebrae. However, there is a paucity of studies investigating remodeling of weight-bearing bone grafts in preclinical models, and consequently there is limited understanding of the mechanisms by which these grafts remodel in vivo. In this study, we investigated the effects of the rates of new bone formation, matrix resorption, and polymer degradation on healing of settable weight-bearing polyurethane/allograft composites in a rabbit femoral condyle defect model. The grafts induced progressive healing in vivo, as evidenced by an increase in new bone formation, as well as a decrease in residual allograft and polymer from 6 to 12 weeks. However, the mismatch between the rates of autocatalytic polymer degradation and zero-order (independent of time) new bone formation resulted in incomplete healing in the interior of the composite. Augmentation of the grafts with recombinant human bone morphogenetic protein-2 not only increased the rate of new bone formation, but also altered the degradation mechanism of the polymer to approximate a zero-order process. The consequent matching of the rates of new bone formation and polymer degradation resulted in more extensive healing at later time points in all regions of the graft. These observations underscore the importance of balancing the rates of new bone formation and degradation to promote healing of settable weight-bearing bone grafts that maintain bone-like strength, while actively remodeling. PMID:23941405

  14. An automatic early stage alveolar-bone-resorption evaluation method on digital dental panoramic radiographs

    NASA Astrophysics Data System (ADS)

    Zhang, Min; Katsumata, Akitoshi; Muramatsu, Chisako; Hara, Takeshi; Suzuki, Hiroki; Fujita, Hiroshi

    2014-03-01

    Periodontal disease is a kind of typical dental diseases, which affects many adults. The presence of alveolar bone resorption, which can be observed from dental panoramic radiographs, is one of the most important signs of the progression of periodontal disease. Automatically evaluating alveolar-bone resorption is of important clinic meaning in dental radiology. The purpose of this study was to propose a novel system for automated alveolar-bone-resorption evaluation from digital dental panoramic radiographs for the first time. The proposed system enables visualization and quantitative evaluation of alveolar bone resorption degree surrounding the teeth. It has the following procedures: (1) pre-processing for a test image; (2) detection of tooth root apices with Gabor filter and curve fitting for the root apex line; (3) detection of features related with alveolar bone by using image phase congruency map and template matching and curving fitting for the alveolar line; (4) detection of occlusion line with selected Gabor filter; (5) finally, evaluation of the quantitative alveolar-bone-resorption degree in the area surrounding teeth by simply computing the average ratio of the height of the alveolar bone and the height of the teeth. The proposed scheme was applied to 30 patient cases of digital panoramic radiographs, with alveolar bone resorption of different stages. Our initial trial on these test cases indicates that the quantitative evaluation results are correlated with the alveolar-boneresorption degree, although the performance still needs further improvement. Therefore it has potential clinical practicability.

  15. Bone scanning in patients with early breast carcinoma: should it be a routine staging procedure

    Microsoft Academic Search

    Yeu-Tsu N. Lee

    1981-01-01

    Bone scanning is a sensitive test for the detection of metastatic breast cancer, but not all abnormal findings on bone scan are diagnostic of skeletal metastasis. Recent studies have found a relatively low rate (less than or equal to 5%) of abnormal scans in patients with Stage I and II breast cancers, and only half of those with positive scans

  16. Licochalcone A up-regulates of FasL in mesenchymal stem cells to strengthen bone formation and increase bone mass

    PubMed Central

    Ming, Leiguo; Jin, Fang; Huang, Ping; Luo, Hailang; Liu, Wenjia; Zhang, Leilei; Yuan, Wei; Zhang, Yongjie; Jin, Yan

    2014-01-01

    The role of bone marrow-derived mesenchymal stem cells(BMSCs)in the pathogenesis and therapy of osteoporosis has drawn increasing attention in recent years. In the development of osteoporosis, it has been demonstrated that many changes occurred in the behavior of BMSCs. For example, the biological system of FasL pathways mediated differentiation of ERK and GSK-3?-catenin pathway was damaged. Here we found that 0.35?mg/L Licochalcone A (L-A) had a strong effect in increasing the osteogenic differentiation and mineralization of BMSCs both in vivo and in vitro by up-regulating FasL and further playing a role in regulating the ERK and GSK-3?-catenin systems. It has also demonstrated that the administration of L-A could restore the biological function of the damaged BMSCs differentiation by recovering or protecting bone mass in a disease state through activating the endosteal bone formation and partially inhibiting bone resorption in acute estrogen deficiency model. Results of our study suggested that careful titration of MSC was response to L-A and up-regulated FasL pathways mediating differentiation of ERK and GSK-3?-catenin biological systems under disease state in vivo, restore the impaired function, is one of the ways of L-A relieve or treatment osteoporosis. PMID:25428397

  17. Anabolic bone formation via a site-specific bone-targeting delivery system by interfering with semaphorin 4D expression.

    PubMed

    Zhang, Yufeng; Wei, Lingfei; Miron, Richard J; Shi, Bin; Bian, Zhuan

    2015-02-01

    Semaphorins have been recently targeted as new molecules directly implicated in the cell-cell communication that occurs between osteoclasts and osteoblasts. Overexpression of certain semaphorins, such as semaphorin4D (sema4D), is found in an osteoporotic phenotype and plays a key role in osteoclast activity by suppressing osteoblast maturation, thus significantly altering the bone modeling cycle. In the present study, we fabricate a site-specific bone-targeting drug-delivery system from polymeric nanoparticles with the incorporation of siRNA interference molecule for sema4D and demonstrate their cellular uptake and intracellular trafficking within osteoclasts, thus preventing the suppression of osteoblast activity. We then demonstrate in an osteoporotic animal model induced by ovariectomy that weekly intravenous injections led to a significantly greater number of active osteoblasts at the bone surface, resulting in higher bone volume in compromised animals. The findings from the present study demonstrate a novel and promising site-specific therapeutic option for the treatment of osteoporosis via interference of the sema4D-plexin cell communication pathway between osteoclasts and osteoblasts. PMID:25088728

  18. Early-Stage Primary Bone Lymphoma: A Retrospective, Multicenter Rare Cancer Network (RCN) Study

    SciTech Connect

    Cai Ling [Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, VD (Switzerland); Sun Yat-sen University Cancer Center, Guangzhou, Guangdong (China); Stauder, Michael C. [Mayo Clinic, Rochester, MN (United States); Zhang Yujing [Sun Yat-sen University Cancer Center, Guangzhou, Guangdong (China); Poortmans, Philip [Verbeeten Institute, Tilburg (Netherlands); Li Yexiong [Cancer Hospital, Chinese Academy of Medical Sciences, Beijing (China); Constantinou, Nicolaos [Theagenio Cancer Hospital, Thessaloniki, Macedonia (Greece); Thariat, Juliette [Centre Anti-Cancereux Antoine-Lacassagne, Nice, Cote d'Azur (France); Kadish, Sidney P. [University of Massachusetts Medical School, Worcester, MA (United States); Nguyen, Tan Dat [Institut Jean-Godinot, Reims, Champagne-Ardenne (France); Kirova, Youlia M. [Institut Curie, Paris (France); Ghadjar, Pirus [Inselspital, Bern University Hospital, and University of Bern (Switzerland); Weber, Damien C. [Hopitaux Universitaires de Geneve (Switzerland); Bertran, Victoria Tuset [Hospital Universitari Germans Trias i Pujol, Barcelona (Spain); Ozsahin, Mahmut [Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, VD (Switzerland); Mirimanoff, Rene-Olivier, E-mail: Rene-Olivier.Mirimanoff@chuv.ch [Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, VD (Switzerland)

    2012-05-01

    Purpose: Primary bone lymphoma (PBL) represents less than 1% of all malignant lymphomas. In this study, we assessed the disease profile, outcome, and prognostic factors in patients with Stages I and II PBL. Patients and Methods: Thirteen Rare Cancer Network (RCN) institutions enrolled 116 consecutive patients with PBL treated between 1987 and 2008 in this study. Eighty-seven patients underwent chemoradiotherapy (CXRT) without (78) or with (9) surgery, 15 radiotherapy (RT) without (13) or with (2) surgery, and 14 chemotherapy (CXT) without (9) or with (5) surgery. Median RT dose was 40 Gy (range, 4-60). The median number of CXT cycles was six (range, 2-8). Median follow-up was 41 months (range, 6-242). Results: The overall response rate at the end of treatment was 91% (complete response [CR] 74%, partial response [PR] 17%). Local recurrence or progression was observed in 12 (10%) patients and systemic recurrence in 17 (15%). The 5-year overall survival (OS), lymphoma-specific survival (LSS), and local control (LC) were 76%, 78%, and 92%, respectively. In univariate analyses (log-rank test), favorable prognostic factors for OS and LSS were International Prognostic Index (IPI) score {<=}1 (p = 0.009), high-grade histology (p = 0.04), CXRT (p = 0.05), CXT (p = 0.0004), CR (p < 0.0001), and RT dose >40 Gy (p = 0.005). For LC, only CR and Stage I were favorable factors. In multivariate analysis, IPI score, RT dose, CR, and CXT were independently influencing the outcome (OS and LSS). CR was the only predicting factor for LC. Conclusion: This large multicenter retrospective study confirms the good prognosis of early-stage PBL treated with combined CXRT. An adequate dose of RT and complete CXT regime were associated with better outcome.

  19. Early Formation of Training Programs for Cost Effectiveness Analysis.

    ERIC Educational Resources Information Center

    Jorgensen, C. C.; Hoffer, P. L.

    Developed for application in Air Force weapons systems training programs, a research project investigated the methods, procedures, and data available for conducting cost and training effectiveness analyses (CTEA). The primary objective of the project was to develop a user-oriented procedure for early formulation of training programs that can be…

  20. Formation and Processing of Organics in the Early Solar System

    Microsoft Academic Search

    John F. Kerridge

    1999-01-01

    Until pristine samples can be returned from cometary nuclei, primitive meteorites represent our best source of information about organic chemistry in the early solar system. However, this material has been affected by secondary processing on asteroidal parent bodies which probably did not affect the material now present in cometary nuclei. Production of meteoritic organic matter apparently involved the following sequence

  1. Early Oligocene initiation of North Atlantic Deep Water formation

    Microsoft Academic Search

    Richard Davies; Joseph Cartwright; Jennifer Pike; Charles Line

    2001-01-01

    Dating the onset of deep-water flow between the Arctic and North Atlantic oceans is critical for modelling climate change in the Northern Hemisphere and for explaining changes in global ocean circulation throughout the Cenozoic era (from about 65 million years ago to the present). In the early Cenozoic era, exchange between these two ocean basins was inhibited by the Greenland-Scotland

  2. Bone-like apatite layer formation on hydroxyapatite prepared by spark plasma sintering (SPS).

    PubMed

    Gu, Y W; Khor, K A; Cheang, P

    2004-08-01

    Hydroxyapatite (HA) compacts with high density and superior mechanical properties were fabricated by spark plasma sintering (SPS) using spray-dried HA powders as feedstock. The formation of bone-like apatite layer on SPS consolidated HA compacts were investigated by soaking the HA compacts in simulated body fluid (SBF) for various periods (maximum of 28 days). The structural changes in HA post-SBF were analyzed with scanning electron microscopy, grazing incidence X-ray diffraction and X-ray photoelectron spectroscopy. It was found that a layer consisting microcrystalline carbonate-containing hydroxyapatite was formed on the surface of HA compacts after soaking for 24h. The formation mechanism of apatite on the surface of HA compacts after soaking in SBF was attributed to the ion exchange between HA compacts and the SBF solution. The increase in ionic concentration of calcium and phosphorus as well as the increase in pH after SBF immersion resulted in an increase in ionic activity product of apatite in the solution, and provided a specific surface with a low interface energy that is conducive to the nucleation of apatite on the surface of HA compacts. PMID:15046903

  3. Autologous fat grafts placed around temporomandibular joint total joint prostheses to prevent heterotopic bone formation

    PubMed Central

    Morales-Ryan, Carlos A.; Morales, Patricia Garcia; Cassano, Daniel Serra

    2008-01-01

    This study evaluated 1) the efficacy of packing autologous fat grafts around temporomandibular joint (TMJ) total joint prosthetic reconstructions to prevent fibrosis and heterotopic bone formation and 2) the effects on postsurgical joint mobility and jaw function. One hundred fifteen patients (5 males and 110 females) underwent TMJ reconstruction with total joint prostheses and simultaneous fat grafts (88 bilateral and 27 unilateral) for a total of 203 joints. The abdominal fat grafts were packed around the articulating portion of the joint prostheses after the fossa and mandibular components were stabilized. Patients were divided into two groups: group 1 (n = 76 joints) received Christensen total joint prostheses, and group 2 (n = 127 joints) received TMJ Concepts total joint prostheses. Clinical and radiographic assessments were performed before surgery, immediately after surgery, and at long-term follow-up. In group 1, maximal incisal opening (MIO) increased 3.5 mm, lateral excursions (LE) decreased 0.2 mm, and jaw function improved 1.9 levels. In group 2, MIO increased 6.8 mm, LE decreased 1.4 mm, and jaw function improved 2.4 levels. The improvement for MIO and patient perception of jaw function in both groups was statistically significant; no significant difference was found for LE. There was no radiographic or clinical evidence of heterotopic calcifications or limitation of mobility secondary to fibrosis in either group. Twenty-five Christensen prostheses (33%) were removed because of device failure and/or metal hypersensitivity; no fibrosis or heterotopic bone formation was seen at surgical removal. Four TMJ Concepts prostheses (3%) were removed because of metal hypersensitivity. In all instances, removal of the prostheses was unrelated to the autologous fat grafting. Ten patients (8.7%) developed complications involving the fat donor site: two patients (1.8%) developed abdominal cysts requiring surgery, and eight patients (6.9%) developed seroma formation requiring aspiration. Autologous fat transplantation is a useful adjunct to prosthetic TMJ reconstruction to minimize the occurrence of excessive joint fibrosis and heterotopic calcification, consequently providing improved range of motion and jaw function. PMID:18628972

  4. Stimulating angiogenesis mitigates the unloading-induced reduction in osteogenesis in early-stage bone repair in rats

    PubMed Central

    Matsumoto, Takeshi; Sato, Shota

    2015-01-01

    Accelerating fracture healing during bed rest allows early mobilization and avoids prolonged fracture healing times. We tested the hypothesis that stimulating angiogenesis with deferoxamine (DFO) mitigates the unloading-induced reduction in early-stage bone repair. Rats aged 12 weeks were subjected to cortical drilling on their tibial diaphysis under anesthesia and treated with hindlimb unloading (HU), HU and DFO administration (DFOHU), or weight bearing (WB) for 5 or 10 days (HU5/10, DFOHU5/10, WB5/10; n = 8 per groups) until sacrifice for vascular casting with a zirconium dioxide-based contrast agent. Taking advantage of its absorption discontinuity at the K-absorption edge, vascular and bone images in the drill-hole defects were acquired by synchrotron radiation subtraction CT. Bone repair was reduced in HU rats. The bone volume fraction (B.Vf) was 88% smaller in HU5 and 42% smaller in HU10 than in WB5/10. The bone segment densities (B.Seg) were 97% smaller in HU5 and 141% larger in HU10 than in WB5/10, and bone thickness (B.Th) was 38% smaller in HU10 than in WB10. The vascular volume fraction (V.Vf) was 35% and the mean vessel diameter (V.D) was 13% smaller in HU10 than in WB10. When compared according to categorized vessel sizes, V.Vf in the diameter ranges 20–30, 30–40, and >40 ?m were smaller in HU10 than in WB10, and V.Seg in the diameter range >40 ?m was smaller in HU10 than in WB10. In contrast, there was no difference in B.Vf between DFOHU5/10 and WB5/10 and in V.Vf between DFOHU10 and WB10, though B.Seg remained 86% smaller in DFOHU5 and 94% larger in DFOHU10 than in WB5/10, and B.Th and V.D were 23% and 14% lower in DFOHU10 than in WB10. Vessel size-specific V.Vf in the diameter ranges 10–20 and 20–30 ?m was larger in DFOHU5 than in HU5. In conclusion, the enhanced angiogenic ingrowth mitigates the reduction in bone repair during mechanical unloading. PMID:25780087

  5. Stimulating angiogenesis mitigates the unloading-induced reduction in osteogenesis in early-stage bone repair in rats.

    PubMed

    Matsumoto, Takeshi; Sato, Shota

    2015-03-01

    Accelerating fracture healing during bed rest allows early mobilization and avoids prolonged fracture healing times. We tested the hypothesis that stimulating angiogenesis with deferoxamine (DFO) mitigates the unloading-induced reduction in early-stage bone repair. Rats aged 12 weeks were subjected to cortical drilling on their tibial diaphysis under anesthesia and treated with hindlimb unloading (HU), HU and DFO administration (DFOHU), or weight bearing (WB) for 5 or 10 days (HU5/10, DFOHU5/10, WB5/10; n = 8 per groups) until sacrifice for vascular casting with a zirconium dioxide-based contrast agent. Taking advantage of its absorption discontinuity at the K-absorption edge, vascular and bone images in the drill-hole defects were acquired by synchrotron radiation subtraction CT. Bone repair was reduced in HU rats. The bone volume fraction (B.Vf) was 88% smaller in HU5 and 42% smaller in HU10 than in WB5/10. The bone segment densities (B.Seg) were 97% smaller in HU5 and 141% larger in HU10 than in WB5/10, and bone thickness (B.Th) was 38% smaller in HU10 than in WB10. The vascular volume fraction (V.Vf) was 35% and the mean vessel diameter (V.D) was 13% smaller in HU10 than in WB10. When compared according to categorized vessel sizes, V.Vf in the diameter ranges 20-30, 30-40, and >40 ?m were smaller in HU10 than in WB10, and V.Seg in the diameter range >40 ?m was smaller in HU10 than in WB10. In contrast, there was no difference in B.Vf between DFOHU5/10 and WB5/10 and in V.Vf between DFOHU10 and WB10, though B.Seg remained 86% smaller in DFOHU5 and 94% larger in DFOHU10 than in WB5/10, and B.Th and V.D were 23% and 14% lower in DFOHU10 than in WB10. Vessel size-specific V.Vf in the diameter ranges 10-20 and 20-30 ?m was larger in DFOHU5 than in HU5. In conclusion, the enhanced angiogenic ingrowth mitigates the reduction in bone repair during mechanical unloading. PMID:25780087

  6. Numerical assessment of bone remodeling around conventionally and early loaded titanium and titanium-zirconium alloy dental implants.

    PubMed

    Akça, K?vanç; Eser, At?l?m; Çavu?o?lu, Yeliz; Sa??rkaya, Elçin; Çehreli, Murat Cavit

    2015-05-01

    The aim of this study was to investigate conventionally and early loaded titanium and titanium-zirconium alloy implants by three-dimensional finite element stress analysis. Three-dimensional model of a dental implant was created and a thread area was established as a region of interest in trabecular bone to study a localized part of the global model with a refined mesh. The peri-implant tissues around conventionally loaded (model 1) and early loaded (model 2) implants were implemented and were used to explore principal stresses, displacement values, and equivalent strains in the peri-implant region of titanium and titanium-zirconium implants under static load of 300 N with or without 30° inclination applied on top of the abutment surface. Under axial loading, principal stresses in both models were comparable for both implants and models. Under oblique loading, principal stresses around titanium-zirconium implants were slightly higher in both models. Comparable stress magnitudes were observed in both models. The displacement values and equivalent strain amplitudes around both implants and models were similar. Peri-implant bone around titanium and titanium-zirconium implants experiences similar stress magnitudes coupled with intraosseous implant displacement values under conventional loading and early loading simulations. Titanium-zirconium implants have biomechanical outcome comparable to conventional titanium implants under conventional loading and early loading. PMID:25725630

  7. Low Magnitude and High Frequency Mechanical Loading Prevents Decreased Bone Formation Responses of 2T3 Preosteoblasts

    PubMed Central

    Patel, Mamta J.; Chang, Kyungh Hwa; Sykes, Michelle C.; Talish, Roger; Rubin, Clinton; Jo, Hanjoong

    2009-01-01

    Bone loss due 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 loading has been shown to normalize and prevent bone loss. However, the underlying molecular changes and the target cells by which LMHF mechanical loading alleviate bone loss are not known. Here, we hypothesized that direct application of LMHF mechanical loading to osteoblasts alters their cell responses, preventing decreased bone formation induced by disuse or microgravity conditions. To test our hypothesis, preosteoblast 2T3 cells were exposed to a disuse condition using the Random Positioning Machine (RPM) and intervened with an LMHF mechanical load (0.1-0.4g at 30Hz for 10-60 min/day). Exposure of 2T3 cells to the RPM decreased bone formation responses as determined by alkaline phosphatase (ALP) activity and mineralization even in the presence of a submaximal dose of BMP4 (20ng/ml). However, LMHF mechanical loading prevented the RPM-induced decrease in ALP activity and mineralization. Mineralization induced by LMHF mechanical loading was enhanced by treatment with bone morphogenic protein 4 (BMP4) and blocked by the BMP antagonist noggin, suggesting a role for BMPs in this response. In addition, LMHF mechanical loading rescued the RPM-induced decrease in gene expression of ALP, runx2, osteomodulin, parathyroid hormone receptor 1, and osteoglycin. These findings suggest that preosteoblasts may directly respond to LMHF mechanical loading to induce differentiation responses. The mechanosensitive genes identified here provide potential targets for pharmaceutical treatments that may be used in combination with low level mechanical loading to better treat osteoporosis or disuse-induced bone loss. PMID:19125415

  8. Damaging fatigue loading stimulates increases in periosteal vascularity at sites of bone formation in the rat ulna.

    PubMed

    Matsuzaki, Hironori; Wohl, Gregory R; Novack, Deborah V; Lynch, Jennifer A; Silva, Matthew J

    2007-06-01

    Bone formation in a variety of contexts depends on angiogenesis; however, there are few reports of the vascular response to osteogenic skeletal loading. We used the rat forelimb compression model to characterize vascular changes after fatigue loading. The right forelimbs of 72 adult rats were loaded cyclically in vivo to one of four displacement levels, to produce four discrete levels of ulnar damage. Rats were killed 3-14 days after loading, and their vasculature was perfused with silicone rubber. Transverse histological sections were cut along the ulnar diaphysis. We quantified vessel number, average vessel area, total vessel area, and bone area. On day 3, we observed a dramatic periosteal expansion near the ulnar midshaft, with significant increases in periosteal vascularity; total vessel area was increased 250-450% (P < 0.001). Vascularity remained elevated on days 7 and 14. Vessel number and average vessel area were not correlated (P = 0.09) and contributed independently to total vascular increases. Bone area was not increased on day 3 but on days 7 and 14 was increased significantly in all displacement groups (P < 0.01) due to periosteal woven bone formation. Vascular and bone changes depended on longitudinal location (P < 0.001), with peak increases 2 mm distal to the midshaft. Vascular and bone changes also depended on displacement level (P < 0.005), with greater increases at higher levels of fatigue displacement. We conclude that skeletal fatigue loading induces a rapid increase in periosteal vascularity, followed by an increase in bone area. The angiogenic-osteogenic response is spatially coordinated and scaled to the level of the mechanical stimulus. PMID:17551770

  9. Quantitative computed tomography of vertebral spongiosa: a sensitive method for detecting early bone loss after oophorectomy

    SciTech Connect

    Genant, H.K.; Cann, C.E.; Ettinger, B.; Gordan, G.S.

    1982-11-01

    The bone mineral loss was assessed serially in 37 premenopausal women for 24 months after oophorectomy and the dose-response for conjugated estrogen therapy in preventing this loss was determined. Spinal cancellous bone was measured by quantitative computed tomography and measurement of appendicular cortical bone by radial photon absorptiometry and metacarpal radiogrammetry. For the placebo and low-dose treatment groups, the mean annual bone mineral losses were 7% to 9% from the vertebral spongiosum and 1% to 3% from the peripheral cortex. The correlation between axial and appendicular loss was weak, precluding a reliable estimate of spinal loss from peripheral measurements. For the maximal-dose group (0.6 mg/d), the mean annual bone mineral losses were less than 0.5% from the axial and appendicular sites, and were not significant. The results indicate that spinal quantitative computed tomography provides a highly sensitive measurement of bone mineral loss after oophorectomy, that bone mineral loss is five- to sevenfold greater from the spinal spongiosum than from the appendicular cortex, and that conjugated estrogen in doses of less than 0.6 mg/d are inadequate to prevent the vertebral mineral loss.

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

    PubMed Central

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

    2006-01-01

    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

  11. Adaptive bone formation in acellular vertebrae of sea bass (Dicentrarchus labrax L.)

    Microsoft Academic Search

    S. Kranenbarg; Cleynenbreugel van T; H. Schipper; Leeuwen van J. L

    2005-01-01

    Mammalian bone is an active tissue in which osteoblasts and osteoclasts balance bone mass. This process of adaptive modelling and remodelling is probably regulated by strain-sensing osteocytes. Bone of advanced teleosts is acellular yet, despite the lack of osteocytes, it is capable of an adaptive response to physical stimuli. Strenuous exercise is known to induce lordosis. Lordosis is a ventrad

  12. Formative Evaluation of the Understanding the Early Years Initiative. Final Report

    ERIC Educational Resources Information Center

    Human Resources and Skills Development Canada, 2009

    2009-01-01

    This report presents the findings of the formative evaluation of the Understanding the Early Years (UEY) Initiative. The evaluation was conducted to examine issues of implementation and design, early progress in achieving immediate objectives, and issues related to accountability. The evaluation team was also asked to provide preliminary guidance…

  13. "Conceptual Play": Foregrounding Imagination and Cognition during Concept Formation in Early Years Education

    ERIC Educational Resources Information Center

    Fleer, Marilyn

    2011-01-01

    The international trend to increase the cognitive achievement of early childhood children has generated a need for better understanding how concept formation occurs within play-based programs. Yet the theories of play for supporting early childhood professionals were originally not conceptualized with this need in mind. In this article, concepts…

  14. CO2-SO2 clathrate hydrate formation on early Mars1 Eric Chassefirea,b

    E-print Network

    Boyer, Edmond

    1 CO2-SO2 clathrate hydrate formation on early Mars1 2 Eric Chassefièrea,b , Emmanuel Dartoisc hal-00804822,version1-26Mar2013 Author manuscript, published in "Icarus 223, 2 (2013) 878-891" DOI atmosphere was necessary in order to keep28 early Mars warm and wet. However, current models have not been

  15. Eosinophils and Megakaryocytes Support the Early Growth of Murine MOPC315 Myeloma Cells in Their Bone Marrow Niches

    PubMed Central

    Wong, David; Winter, Oliver; Hartig, Christina; Siebels, Svenja; Szyska, Martin; Tiburzy, Benjamin; Meng, Lingzhang; Kulkarni, Upasana; Fähnrich, Anke; Bommert, Kurt; Bargou, Ralf; Berek, Claudia; Chu, Van Trung; Bogen, Bjarne; Jundt, Franziska; Manz, Rudolf Armin

    2014-01-01

    Multiple myeloma is a bone marrow plasma cell tumor which is supported by the external growth factors APRIL and IL-6, among others. Recently, we identified eosinophils and megakaryocytes to be functional components of the micro-environmental niches of benign bone marrow plasma cells and to be important local sources of these cytokines. Here, we investigated whether eosinophils and megakaryocytes also support the growth of tumor plasma cells in the MOPC315.BM model for multiple myeloma. As it was shown for benign plasma cells and multiple myeloma cells, IL-6 and APRIL also supported MOPC315.BM cell growth in vitro, IL-5 had no effect. Depletion of eosinophils in vivo by IL-5 blockade led to a reduction of the early myeloma load. Consistent with this, myeloma growth in early stages was retarded in eosinophil-deficient ?dblGATA-1 mice. Late myeloma stages were unaffected, possibly due to megakaryocytes compensating for the loss of eosinophils, since megakaryocytes were found to be in contact with myeloma cells in vivo and supported myeloma growth in vitro. We conclude that eosinophils and megakaryocytes in the niches for benign bone marrow plasma cells support the growth of malignant plasma cells. Further investigations are required to test whether perturbation of these niches represents a potential strategy for the treatment of multiple myeloma. PMID:25272036

  16. Bone formation by three-dimensional stromal osteoblast culture in biodegradable polymer scaffolds

    NASA Technical Reports Server (NTRS)

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

    1997-01-01

    Bone formation was investigated in vitro by culturing stromal osteoblasts in three-dimensional (3-D), biodegradable poly(DL-lactic-co-glycolic acid) foams. Three polymer foam pore sizes, ranging from 150-300, 300-500, and 500-710 microns, and two different cell seeding densities, 6.83 x 10(5) cells/cm2 and 22.1 x 10(5) cells/cm2, were examined over a 56-day culture period. The polymer foams supported the proliferation of seeded osteoblasts as well as their differentiated function, as demonstrated by high alkaline phosphatase activity and deposition of a mineralized matrix by the cells. Cell number, alkaline phosphatase activity, and mineral deposition increased significantly over time for all the polymer foams. Osteoblast foam constructs created by seeding 6.83 x 10(5) cells/cm2 on foams with 300-500 microns pores resulted in a cell density of 4.63 x 10(5) cells/cm2 after 1 day in culture; they had alkaline phosphatase activities of 4.28 x 10(-7) and 2.91 x 10(-6) mumol/cell/min on Days 7 and 28, respectively; and they had a cell density that increased to 18.7 x 10(5) cells/cm2 by Day 56. For the same constructs, the mineralized matrix reached a maximum penetration depth of 240 microns from the top surface of the foam and a value of 0.083 mm for mineralized tissue volume per unit of cross sectional area. Seeding density was an important parameter for the constructs, but pore size over the range tested did not affect cell proliferation or function. This study suggests the feasibility of using poly(alpha-hydroxy ester) foams as scaffolding materials for the transplantation of autogenous osteoblasts to regenerate bone tissue.

  17. Temporomandibular joint bone tissue resorption in patients with early rheumatoid arthritis can be predicted by joint crepitus and plasma glutamate level.

    PubMed

    Hajati, Anna-Kari; Näsström, Karin; Alstergren, Per; Bratt, Johan; Kopp, Sigvard

    2010-01-01

    The aim was to investigate whether bone tissue resorption in early RA is related to crepitus of the temporomandibular joint (TMJ) and systemic levels of inflammatory mediators and markers and sex steroid hormones. Twentynine women and 18 men with recently diagnosed RA were examined for TMJ bone erosions with computerized tomography and TMJ crepitus was assessed. Blood samples were analyzed for glutamate, 5-HT, TNF, IL-1beta, IL-6, VEGF, inflammatory markers, and estradiol, progesterone and testosterone. The TMJ erosion score was positively correlated to glutamate, and TMJ crepitus where crepitus, glutamate and ESR explained 40% of the variation in the bone erosion score. In the patients without crepitus, bone erosion score was positively correlated to glutamate, which was not the case in the patients with crepitus. In conclusion, the results of this study show that TMJ bone tissue resorption can be predicted by TMJ crepitus and glutamate in early RA. PMID:20671920

  18. Inhibition of osteoclast-like cell formation by bisphosphonates in long-term cultures of human bone marrow.

    PubMed Central

    Hughes, D E; MacDonald, B R; Russell, R G; Gowen, M

    1989-01-01

    Bisphosphonates inhibit bone resorption in vivo and in vitro by unknown mechanisms. The effect of bisphosphonates on the formation of osteoclasts from their mononuclear hematopoietic precursors was investigated using human long-term marrow cultures in which multinucleated cells form that express most of the known features of the osteoclast phenotype (e.g., bone resorption, tartrate-resistant acid phosphatase, calcitonin responsiveness, and reactivity with specific MAbs). The five bisphosphonates that were tested strongly inhibited 1,25-dihydroxyvitamin D3-stimulated formation of these cells with the same relative potencies as they inhibit bone resorption in vivo. Two representative compounds (3-amino-1-hydroxypropylidene-1,1-bisphosphonate and dichloromethylene bisphosphonate) failed to inhibit the proliferation of precursors of the osteoclast-like cells. However, these compounds decreased the proportion of mononuclear and multinucleated cells expressing an osteoclast antigen, thus suggesting a degree of specificity for cells of the osteoclast lineage. We conclude that bisphosphonates are potent inhibitors of osteoclast-like cell formation in long-term human marrow cultures, and that this may be related to their ability to inhibit bone resorption in vivo. Images PMID:2524504

  19. Locally injection of cell sheet fragments enhances new bone formation in mandibular distraction osteogenesis: a rabbit model.

    PubMed

    Ma, Dongyang; Ren, Liling; Yao, Hong; Tian, Wenyan; Chen, Fulin; Zhang, Junrui; Liu, Yanpu; Mao, Tianqiu

    2013-07-01

    Effective methods to shorten the treatment period of distraction osteogenesis (DO) are needed. To investigate whether injections of osteogenic bone marrow stromal cell (BMSC) sheet fragments could be used to facilitate new bone formation during DO, 30 rabbits underwent bilateral mandibular osteotomy and their mandibles were lengthened at a rate of 0.75?mm/12?h for 6 days after a 5-day latency period. There were three treatment groups (n?=?10 for each group): Serum-free medium, dissociated BMSCs, and BMSC sheet fragments. A local injection was conducted with a needle directly into the distracted areas immediately after distraction. Rabbits were sacrificed for examination at 3 and 6 weeks after injection. Gross examination, radiographic evaluation, and micro-CT scanning indicated a significant increase in bony union in the BMSC sheet fragment group, compared with the medium group and the dissociated cell group. The histomorphometric analysis showed more intensive bone formation in the sheet fragment group than the other two groups at each time point. Additionally, the peak load was significantly higher in the fragment group than those in the others. The results show that injection of BMSC sheet fragments promotes bone formation in DO and indicate a promising approach to shorten the treatment period of osteodistraction. PMID:23494761

  20. Formation and Processing of Organics in the Early Solar System

    Microsoft Academic Search

    John F. Kerridge

    1999-01-01

    Until pristine samples can be returned from cometary nuclei, primitive meteorites represent our best source of information\\u000a about organic chemistry in the early solar system. However, this material has been affected by secondary processing on asteroidal\\u000a parent bodies which probably did not affect the material now present in cometary nuclei. Production of meteoritic organic\\u000a matter apparently involved the following sequence

  1. The effects of rhBMP-2 released from biodegradable polyurethane/microsphere composite scaffolds on new bone formation in rat femora.

    PubMed

    Li, Bing; Yoshii, Toshitaka; Hafeman, Andrea E; Nyman, Jeffry S; Wenke, Joseph C; Guelcher, Scott A

    2009-12-01

    Scaffolds prepared from biodegradable polyurethanes (PUR) have been investigated as a supportive matrix and delivery system for skin, cardiovascular, and bone tissue engineering. While previous studies have suggested that PUR scaffolds are biocompatible and moderately osteoconductive, the effects of encapsulated osteoinductive molecules, such as recombinant human bone morphogenetic protein (rhBMP-2), on new bone formation have not been investigated for this class of biomaterials. The objective of this study was to investigate the effects of different rhBMP-2 release strategies on new bone formation in PUR scaffolds implanted in rat femoral plug defects. In the simplest approach, rhBMP-2 was added as a dry powder prior to the foaming reaction, which resulted in a burst release of 35% followed by a sustained release for 21 days. Encapsulation of rhBMP-2 in either 1.3-micron or 114-micron PLGA microspheres prior to the foaming reaction reduced the burst release. At 4 weeks post-implantation, all rhBMP-2 treatment groups enhanced new bone formation relative to the scaffolds without rhBMP-2. Scaffolds incorporating rhBMP-2 powder promoted the most extensive new bone formation, while scaffolds incorporating rhBMP-2 encapsulated in 1.3-micron microspheres, which exhibited the lowest burst release, promoted the least extensive new bone formation. Thus our observations suggest that an initial burst release followed by sustained release is better for promoting new bone formation. PMID:19762079

  2. The osteogenic niche promotes early-stage bone colonization of disseminated breast cancer cells.

    PubMed

    Wang, Hai; Yu, Cuijuan; Gao, Xia; Welte, Thomas; Muscarella, Aaron M; Tian, Lin; Zhao, Hong; Zhao, Zhen; Du, Shiyu; Tao, Jianning; Lee, Brendan; Westbrook, Thomas F; Wong, Stephen T C; Jin, Xin; Rosen, Jeffrey M; Osborne, C Kent; Zhang, Xiang H-F

    2015-02-01

    Breast cancer bone micrometastases can remain asymptomatic for years before progressing into overt lesions. The biology of this process, including the microenvironment niche and supporting pathways, is unclear. We find that bone micrometastases predominantly reside in a niche that exhibits features of osteogenesis. Niche interactions are mediated by heterotypic adherens junctions (hAJs) involving cancer-derived E-cadherin and osteogenic N-cadherin, the disruption of which abolishes niche-conferred advantages. We elucidate that hAJ activates the mTOR pathway in cancer cells, which drives the progression from single cells to micrometastases. Human data set analyses support the roles of AJ and the mTOR pathway in bone colonization. Our study illuminates the initiation of bone colonization, and provides potential therapeutic targets to block progression toward osteolytic metastases. PMID:25600338

  3. Lecture notes on the formation and early evolution of planetary systems

    E-print Network

    Philip J. Armitage

    2014-08-26

    These notes provide an introduction to the theory of the formation and early evolution of planetary systems. Topics covered include the structure, evolution and dispersal of protoplanetary disks; the formation of planetesimals, terrestrial and gas giant planets; and orbital evolution due to gas disk migration, planetesimal scattering, planet-planet interactions, and tides.

  4. Paleomagnetic results from the Late Carboniferous\\/Early Permian Casper Formation: implications for northern Appalachian tectonics

    Microsoft Academic Search

    Jimmy F. Diehl; Peter N. Shive

    1981-01-01

    Paleomagnetic samples were collected from 190 m of the Late Carboniferous\\/Early Permian Casper Formation in southeastern Wyoming. A total of 549 samples was drilled near the vicinity of Horse Creek Station at an average stratigraphic interval of 33 cm. All samples were reversely magnetized. Rock magnetic analyses indicate that the primary carrier of remanence in the formation is hematite. A

  5. Chondroitin sulfate and sulfated hyaluronan-containing collagen coatings of titanium implants influence peri-implant bone formation in a minipig model.

    PubMed

    Korn, P; Schulz, M C; Hintze, V; Range, U; Mai, R; Eckelt, U; Schnabelrauch, M; Möller, S; Becher, J; Scharnweber, D; Stadlinger, B

    2014-07-01

    An improved osseous integration of dental implants in patients with lower bone quality is of particular interest. The aim of this study was to evaluate the effect of artificial extracellular matrix implant coatings on early bone formation. The coatings contained collagen (coll) in conjunction with either chondroitin sulfate (CS) or sulfated hyaluronan (sHya). Thirty-six screw-type, grit-blasted, and acid-etched titanium implants were inserted in the mandible of 6 minipigs. Three surface states were tested: (1) uncoated control (2) coll/CS (3) coll/sHya. After healing periods of 4 and 8 weeks, bone implant contact (BIC), bone volume density (BVD) as well as osteoid related parameters were measured. After 4 weeks, control implants showed a BIC of 44% which was comparable to coll/CS coated implants (48%) and significantly higher compared to coll/sHya coatings (37%, p?=?0.012). This difference leveled out after 8 weeks. No significant differences could be detected for BVD values after 4 weeks and all surfaces showed reduced BVD values after 8 weeks. However, at that time, BVD around both, coll/CS (30%, p?=?0.029), and coll/sHya (32%, p?=?0.015), coatings was significantly higher compared to controls (22%). The osteoid implant contact (OIC) showed no significant differences after 4 weeks. After 8 weeks OIC for controls was comparable to coll/CS, the latter being significantly higher compared to coll/sHya (0.9% vs. 0.4%, p?=?0.012). There were no significant differences in osteoid volume density. In summary, implant surface coatings by the chosen organic components of the extracellular matrix showed a certain potential to influence osseointegration in vivo. PMID:23946280

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

    PubMed

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

    2014-04-01

    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

  7. Effect of acemannan, an extracted polysaccharide from Aloe vera, on BMSCs proliferation, differentiation, extracellular matrix synthesis, mineralization, and bone formation in a tooth extraction model.

    PubMed

    Boonyagul, Sani; Banlunara, Wijit; Sangvanich, Polkit; Thunyakitpisal, Pasutha

    2014-07-01

    Aloe vera is a traditional wound healing medicine. We hypothesized acemannan, a polysaccharide extracted from Aloe vera gel, could affect bone formation. Primary rat bone marrow stromal cells (BMSCs) were treated with various concentrations of acemannan. New DNA synthesis, VEGF, BMP-2, alkaline phosphatase activity, bone sialoprotein, osteopontin expression, and mineralization were determined by [(3)H] thymidine incorporation assay, ELISA, biochemical assay, western blotting, and Alizarin Red staining, respectively. In an animal study, mandibular right incisors of male Sprague-Dawley rats were extracted and an acemannan treated sponge was placed in the socket. After 1, 2, and 4 weeks, the mandibles were dissected. Bone formation was evaluated by dual-energy X-ray absorptiometry and histopathological examination. The in vitro results revealed acemannan significantly increased BMSC proliferation, VEGF, BMP-2, alkaline phosphatase activity, bone sialoprotein and osteopontin expression, and mineralization. In-vivo results showed acemannan-treated groups had higher bone mineral density and faster bone healing compared with untreated controls. A substantial ingrowth of bone trabeculae was observed in acemannan-treated groups. These data suggest acemannan could function as a bioactive molecule inducing bone formation by stimulating BMSCs proliferation, differentiation into osteoblasts, and extracellular matrix synthesis. Acemannan could be a candidate natural biomaterial for bone regeneration. PMID:23315202

  8. 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

    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

    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

  9. Impact of Seasonal Flux on 25-hydroxyvitamin D and Bone Turnover in Pre- and Early Pubertal Youth

    PubMed Central

    Rajakumar, Kumaravel; Holick, Michael F.; Moore, Charity G.; Cohen, Elan; Olabopo, Flora; Haralam, Mary Ann; Bogusz, Jaimee; Nucci, Anita; Greenspan, Susan L.

    2013-01-01

    Background Seasonal fluxes in 25-hydroxyvitamin D [25(OH)D] in children can impact bone turnover, and in turn potentially affect bone accrual and peak bone mass. Objective To examine the effect of seasonal flux on the association among 25(OH)D and parathyroid hormone (PTH) on markers of bone turnover in pre- and early pubertal black and white children. Design Data were collected during summer (June –September) and winter (December – March) in 6- to 12-yr-old children. Measurements included serum 25(OH)D, PTH, osteocalcin (OC), collagen type 1 cross-linked C-telopeptide (CTx), dietary intake of vitamin D and calcium, skin color, sunlight exposure, and body-mass-index (BMI). Results A total of 138 children (mean [±SD] age: 9.1±1.7 year, black: 94, male: 81) were studied. 25(OH)D (41.2±13 vs 34.5±11.1 ng/mL, p<0.001) were higher and CTx were lower (0.8±0.3 vs 0.9±0.5 ng/mL, p<0.001) in all participants during summer when compared to winter. Furthermore, seasonal differences in CTx were more pronounced in blacks (summer: 0.7±0.3 vs winter: 1.0±0.5 ng/mL, p<0.001). PTH was a significant predictor of serum CTx and OC after adjusting for race, season, Tanner stage, dietary calcium, skin color and BMI. Conclusion 25(OH)D declined significantly in both black and whites during winter. CTx significantly increased during winter in blacks than whites suggesting increased rates of resorption in blacks during winter. Benefits of enhancement of wintertime vitamin D status on bone health need further exploration. PMID:24003769

  10. Early magma ocean and core formation on Vesta

    NASA Astrophysics Data System (ADS)

    Neumann, Wladimir; Breuer, Doris; Spohn, Tilman

    2013-04-01

    The Dawn mission confirms predictions that the asteroid 4 Vesta is differentiated in an iron rich core, a silicate mantle and a basaltic crust, supports its identification as the parent body of the HEDs and provides revised values of e.g. the mass, the bulk density and the dimensions of the asteroid 4 Vesta. Although no distinct volcanic regions have been identified, resurfacing by igneous processes distinguishes Vesta from asteroids like Ceres with its primitive surface, or Lutetia, which retained its primordial surface composition (and may still be partially differentiated[1]). Vesta's core radius is estimated to be 107-113 km[2] (derived from the mass concentration towards the centre). We performed numerical calculations of the thermo-chemical evolution of Vesta adopting the new data obtained by the Dawn mission (mass, bulk density, radius). We have expanded the thermo-chemical evolution model of [3], which includes accretion, compaction, melting, associated changes of the material properties, advective heat transport and differentiation by porous flow, by considering convection and thus effective cooling in a magma ocean to analyse its formation and evolution on Vesta. For melt fractions below the rheologically critical melt fraction (RCMF) of ?50% the heat transport by melt segregation is modeled assuming melt flow in porous media and by supplementing the energy balance equation with additional advection terms. Above the RCMF the effective thermal conductivity keff is computed from the convective heat flux in the soft turbulence regime[4]. The parameter keff mimics the vigorous convection and heat flux of the magma ocean with a low viscosity. It amounts to O(106) W m-1K-1 and substitutes the thermal conductivity in the energy balance equation. We consider both instantaneous and continuous accretion (assuming late runaway material accumulation). In particular, we compare the evolution scenarios arising from the instantaneous accretion of Vesta at different formation times t0 (relative to the formation of the CAIs) with those for which the accretion durations ta is between 0.5 and 2.0 Ma. According to our results core formation is possible for formation times of up to 2.5 Ma after the CAIs. An important process for the formation and evolution of a magma ocean is the partitioning of 26Al and its relocation with the silicate melt. Previous models[5] suggest the formation of an internal magma ocean throughout the whole mantle beneath a solid crust. Thereby, the partitioning of 26Al is neglected. In contrast to that, if partitioning of 26Al into the melt is considered we obtain an about 1 km thick superficial magma ocean due to the enrichment of the radioactive nuclides in the liquid phase and redistribution towards the surface with the rising melt (for t0

  11. Early Oligocene initiation of North Atlantic Deep Water formation.

    PubMed

    Davies, R; Cartwright, J; Pike, J; Line, C

    2001-04-19

    Dating the onset of deep-water flow between the Arctic and North Atlantic oceans is critical for modelling climate change in the Northern Hemisphere and for explaining changes in global ocean circulation throughout the Cenozoic era (from about 65 million years ago to the present). In the early Cenozoic era, exchange between these two ocean basins was inhibited by the Greenland-Scotland ridge, but a gateway through the Faeroe-Shetland basin has been hypothesized. Previous estimates of the date marking the onset of deep-water circulation through this basin-on the basis of circumstantial evidence from neighbouring basins-have been contradictory, ranging from about 35 to 15 million years ago. Here we describe the newly discovered Southeast Faeroes drift, which extends for 120 km parallel to the basin axis. The onset of deposition in this drift has been dated to the early Oligocene epoch ( approximately 35 million years ago) from a petroleum exploration borehole. We show that the drift was deposited under a southerly flow regime, and conclude that the initiation of deep-water circulation from the Norwegian Sea into the North Atlantic Ocean took place much earlier than is currently assumed in most numerical models of ancient ocean circulation. PMID:11309613

  12. High Calcium Bioglass Enhances Differentiation and Survival of Endothelial Progenitor Cells, Inducing Early Vascularization in Critical Size Bone Defects

    PubMed Central

    Nguyen Ngoc, Christina; Meier, Simon; Nau, Christoph; Schaible, Alexander; Marzi, Ingo; Henrich, Dirk

    2013-01-01

    Early vascularization is a prerequisite for successful bone healing and endothelial progenitor cells (EPC), seeded on appropriate biomaterials, can improve vascularization. The type of biomaterial influences EPC function with bioglass evoking a vascularizing response. In this study the influence of a composite biomaterial based on polylactic acid (PLA) and either 20 or 40% bioglass, BG20 and BG40, respectively, on the differentiation and survival of EPCs in vitro was investigated. Subsequently, the effect of the composite material on early vascularization in a rat calvarial critical size defect model with or without EPCs was evaluated. Human EPCs were cultured with ?-TCP, PLA, BG20 or BG40, and seeding efficacy, cell viability, cell morphology and apoptosis were analysed in vitro. BG40 released the most calcium, and improved endothelial differentiation and vitality best. This effect was mimicked by adding an equivalent amount of calcium to the medium and was diminished in the presence of the calcium chelator, EGTA. To analyze the effect of BG40 and EPCs in vivo, a 6-mm diameter critical size calvarial defect was created in rats (n?=?12). Controls (n?=?6) received BG40 and the treatment group (n?=?6) received BG40 seeded with 5×105 rat EPCs. Vascularization after 1 week was significantly improved when EPCs were seeded onto BG40, compared to implanting BG40 alone. This indicates that Ca2+ release improves EPC differentiation and is useful for enhanced early vascularization in critical size bone defects. PMID:24244419

  13. Plant homeodomain finger protein 2 promotes bone formation by demethylating and activating Runx2 for osteoblast differentiation.

    PubMed

    Kim, Hye-Jin; Park, Jong-Wan; Lee, Kyoung-Hwa; Yoon, Haejin; Shin, Dong Hoon; Ju, Uk-Il; Seok, Seung Hyeok; Lim, Seung Hyeon; Lee, Zang Hee; Kim, Hong-Hee; Chun, Yang-Sook

    2014-10-01

    Plant homeodomain finger protein 2 (PHF2), which contains a plant homeodomain and a Jumonji-C domain, is an epigenetic regulator that demethylates lysine 9 in histone 3 (H3K9me2). On the other hand, runt-related transcription factor 2 (Runx2) plays essential roles in bone development and regeneration. Given previous reports that the PHF2 mutation can cause dwarfism in mice and that PHF2 expression is correlated with that of Runx2 in differentiating thymocytes, we investigated whether PHF2 regulates Runx2-mediated bone formation. Overexpression of PHF2 facilitated bone development in newborn mice, and viral shRNA-mediated knockdown of PHF2 delayed calvarial bone regeneration in adult rats. In primary osteoblasts and C2C12 precursor cells, PHF2 enhances osteoblast differentiation by demethylating Runx2, while suppressor of variegation 3-9 homolog 1 (SUV39H1) inhibits bone formation by methylating it. The PHF2-Runx2 interaction is mediated by the Jumonji-C and Runt domains of the two proteins, respectively. The interaction between Runx2 and osteocalcin promoter is regulated by the methylation status of Runx2, i.e., the interaction is augmented when Runx2 is demethylated. Our results suggest that SUV39H1 and PHF2 reciprocally regulate osteoblast differentiation by modulating Runx2-driven transcription at the post-translational level. This study may provide a theoretical basis for the development of new therapeutic modalities for patients with impaired bone development or delayed fracture healing. PMID:25257467

  14. Biogenicity of an Early Quaternary iron formation, Milos Island, Greece.

    PubMed

    Chi Fru, E; Ivarsson, M; Kilias, S P; Frings, P J; Hemmingsson, C; Broman, C; Bengtson, S; Chatzitheodoridis, E

    2015-05-01

    A ~2.0-million-year-old shallow-submarine sedimentary deposit on Milos Island, Greece, harbours an unmetamorphosed fossiliferous iron formation (IF) comparable to Precambrian banded iron formations (BIFs). This Milos IF holds the potential to provide clues to the origin of Precambrian BIFs, relative to biotic and abiotic processes. Here, we combine field stratigraphic observations, stable isotopes of C, S and Si, rock petrography and microfossil evidence from a ~5-m-thick outcrop to track potential biogeochemical processes that may have contributed to the formation of the BIF-type rocks and the abrupt transition to an overlying conglomerate-hosted IF (CIF). Bulk ?(13) C isotopic compositions lower than -25‰ provide evidence for biological contribution by the Calvin and reductive acetyl-CoA carbon fixation cycles to the origin of both the BIF-type and CIF strata. Low S levels of ~0.04 wt.% combined with ?(34) S estimates of up to ~18‰ point to a non-sulphidic depository. Positive ?(30) Si records of up to +0.53‰ in the finely laminated BIF-type rocks indicate chemical deposition on the seafloor during weak periods of arc magmatism. Negative ?(30) Si data are consistent with geological observations suggesting a sudden change to intense arc volcanism potentially terminated the deposition of the BIF-type layer. The typical Precambrian rhythmic rocks of alternating Fe- and Si-rich bands are associated with abundant and spatially distinct microbial fossil assemblages. Together with previously proposed anoxygenic photoferrotrophic iron cycling and low sedimentary N and C potentially connected to diagenetic denitrification, the Milos IF is a biogenic submarine volcano-sedimentary IF showing depositional conditions analogous to Archaean Algoma-type BIFs. PMID:25645266

  15. Bare Bones Pattern Formation: A Core Regulatory Network in Varying Geometries Reproduces Major Features of Vertebrate Limb Development and Evolution

    PubMed Central

    Zhu, Jianfeng; Zhang, Yong-Tao; Alber, Mark S.; Newman, Stuart A.

    2010-01-01

    Background Major unresolved questions regarding vertebrate limb development concern how the numbers of skeletal elements along the proximodistal (P-D) and anteroposterior (A-P) axes are determined and how the shape of a growing limb affects skeletal element formation. There is currently no generally accepted model for these patterning processes, but recent work on cartilage development (chondrogenesis) indicates that precartilage tissue self-organizes into nodular patterns by cell-molecular circuitry with local auto-activating and lateral inhibitory (LALI) properties. This process is played out in the developing limb in the context of a gradient of fibroblast growth factor (FGF) emanating from the apical ectodermal ridge (AER). Results We have simulated the behavior of the core chondrogenic mechanism of the developing limb in the presence of an FGF gradient using a novel computational environment that permits simulation of LALI systems in domains of varying shape and size. The model predicts the normal proximodistal pattern of skeletogenesis as well as distal truncations resulting from AER removal. Modifications of the model's parameters corresponding to plausible effects of Hox proteins and formins, and of the reshaping of the model limb, bud yielded simulated phenotypes resembling mutational and experimental variants of the limb. Hypothetical developmental scenarios reproduce skeletal morphologies with features of fossil limbs. Conclusions The limb chondrogenic regulatory system operating in the presence of a gradient has an inherent, robust propensity to form limb-like skeletal structures. The bare bones framework can accommodate ancillary gene regulatory networks controlling limb bud shaping and establishment of Hox expression domains. This mechanism accounts for major features of the normal limb pattern and, under variant geometries and different parameter values, those of experimentally manipulated, genetically aberrant and evolutionary early forms, with no requirement for an independent system of positional information. PMID:20531940

  16. Topics in Galaxy Evolution: Early Star Formation and Quenching

    NASA Astrophysics Data System (ADS)

    Goncalves, Thiago Signorini

    In this thesis, we present three projects designed to shed light on yet unanswered questions on galaxy formation and evolution. The first two concern a sample of UV-bright starburst galaxies in the local universe (z ˜0.2). These objects are remarkably similar to star-forming galaxies that were abundant at high redshifts (2 < z < 3)---the Lyman break galaxies---and can help explain the very distinctive properties observed at such epochs. Thus, these galaxies are denominated Lyman break analogs, or LBAs. First, we describe a survey of kinematics of the nebular gas in such objects, and how that can help explain the formation process, including gas assembly, in these starbursts. We show strong evidence that the gas kinematics resemble those observed at high redshifts. However, by artificially manipulating our observations to mimic our objects at greater distances, we show how low resolution and signal-to-noise ratios can lead to erroneous conclusions, in particular when attempting to diagnose mergers as the origin of the starburst. Then, we present results from a pilot survey to study the cold, molecular gas reservoir in such objects. Again, we show that the observed properties are analogous to those observed at high redshift, in particular with respect to baryonic gas fractions in the galaxy, higher than normally found in low-extinction objects in the local universe. Furthermore, we show how gas surface density and star-formation surface density follow the same relation as local galaxies, albeit at much higher values. Finally, we discuss an observational project designed to measure the mass flux density from the blue sequence to the red sequence across the so-called green valley. We obtain the deepest spectra ever observed of green valley galaxies at intermediate redshifts (z˜0.8) in order to measure spectral features from which we can measure the star formation histories of individual galaxies. We measure a mass flux ratio that is higher than observed in the local universe, indicating the red sequence was growing faster when the universe was half its present age than today.

  17. Effect of local sequential VEGF and BMP2 delivery on ectopic and orthotopic bone regeneration

    Microsoft Academic Search

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

    2009-01-01

    Bone regeneration is a coordinated cascade of events regulated by several cytokines and growth factors. Angiogenic growth factors are predominantly expressed during the early phases for re-establishment of the vascularity, whereas osteogenic growth factors are continuously expressed during bone formation and remodeling. Since vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs) are key regulators of angiogenesis and osteogenesis

  18. Ectopic bone formation cannot occur by hydroxyapatite/?-tricalcium phosphate bioceramics in green fluorescent protein chimeric mice

    NASA Astrophysics Data System (ADS)

    Cheng, Lijia; Duan, Xin; Xiang, Zhou; Shi, Yujun; Lu, Xiaofeng; Ye, Feng; Bu, Hong

    2012-12-01

    Many studies have shown that calcium phosphate ceramics (CP) have osteoconductive and osteoinductive properties; however, the exact mechanism of bone induction has not yet been reported. This study was performed to investigate if destroying immunological function will influence osteogenesis, to explain the mechanism which is unclear. In this study, twenty C57BL/6 mice were divided into two groups (n = 10), in group 1, a hydroxyapatite/?-tricalcium phosphate (HA/?-TCP) ceramic was implanted into both the left and right leg muscles of each mouse; in group 2, ten mice experienced lethal irradiation, then were injected bone marrow (BM) cells from green fluorescent protein (GFP) transgenic mice by tail veil, after bone marrow transplantation (BMT), heart, liver, spleen, lung, kidney, and muscle were harvested for biological analysis, after the GFP chimera model was established successfully, the same HA/?-TCP ceramic was implanted into both leg muscles of each mouse immediately after irradiation. 45 and 90 days after implantation, the ceramics of the two groups were harvested to perform with hematoxylin and eosin (HE) and immunohistochemistry (IHC) staining; the results showed that there was no bone formation in group 2, while new bone tissues were detected in group 1. Our findings suggest that the BM cell from GFP transgenic mice is a good biomarker and it could set a good platform for chimera model; it also shows that BM cell is one of cell resources of bone induction, and destruction of immune function will impede osteoinduction by CP. Overall, our results may shed light on clear mechanism study of bone induction in the future.

  19. [Formation of the photosensing system function in early development].

    PubMed

    She?man, I M; Kreshchenko, N D; Netreba, M V

    2010-01-01

    The function of simple prototypic eyes in two planarian species, the two ocular Girardia tigrina and the multiocular Polycelis tenuis, has been studied. When exposed to light, planarians display the light avoidance reaction known as negative phototaxis. This reaction has been investigated in intact animals and in head and tail fragments after their section in the course of eye regeneration. Specific features of the phototaxis reaction have been described in all groups of animals. The differences in light response recovery were shown between two planarian species and two regenerating fragments. No correlation between phototaxic reactions and the restoration of the eye structure, the number of eyes, the maturation of ganglion, the growth of regenerative blastema, and motor system has been found. The phototaxic response occurred two days after the recovery of the morphology of eyes and their connection with the brain. The participation of conserved and novel genes in early development of the eye function is discussed. PMID:20968081

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

    PubMed Central

    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

    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

  1. Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit

    PubMed Central

    Sims, Natalie A; Martin, T ?John

    2014-01-01

    Coupling between bone formation and bone resorption refers to the process within basic multicellular units in which resorption by osteoclasts is met by the generation of osteoblasts from precursors, and their bone-forming activity, which needs to be sufficient to replace the bone lost. There are many sources of activities that contribute to coupling at remodeling sites, including growth factors released from the matrix, soluble and membrane products of osteoclasts and their precursors, signals from osteocytes and from immune cells and signaling taking place within the osteoblast lineage. Coupling is therefore a process that involves the interaction of a wide range of cell types and control mechanisms. As bone remodeling occurs at many sites asynchronously throughout the skeleton, locally generated activities comprise very important control mechanisms. In this review, we explore the potential roles of a number of these factors, including sphingosine-1-phosphate, semaphorins, ephrins, interleukin-6 (IL-6) family cytokines and marrow-derived factors. Their interactions achieve the essential tight control of coupling within individual remodeling units that is required for control of skeletal mass. PMID:24466412

  2. Impact of occupational health hazards on serum markers of bone formation in spray painters of Chennai region in Tamil Nadu

    PubMed Central

    Muthaiah, Vijaya Prakash Krishnan; Nathan, Abel Arul; Balakrishnan, Anandan; Rose, Rajiv; Gopalsamy, Jayaraman

    2012-01-01

    Context: The association between spray paint exposure and bone remodeling received little attention despite the high usage of spray paints in automobile industries, steel furniture workshops etc. Aim: The present study was aimed at investigating the level of serum markers of bone formation in spray painters. The spray painting subjects were selected from automobile body repair workshops in Chennai region of TamilNadu which constitutes 30% of India's automobile industry. Setting and Design: All the study subjects, exposed to spray paint were working in a workshop without standard spraying room and did not wore any aerosol removing respirator. The controls were selected from random population irrespective of occupation. Data relevant to the socioeconomic features and personal history was collected using a questionnaire. The current study included 50 spray painters and 25 control subjects of same age group. Materials and Methods: We examined the level of serum calcium, serum phosphorus, serum differentiation markers of bone such as alkaline phosphatase (bone specific) and serum osteocalcin in which these levels were found to be high in serum of spray painters. Conclusion: The current study concludes dysregulation in bone remodeling of spray painters exposed to chronic solvents and paint pigments. PMID:23580840

  3. Bone Mesenchymal Stem Cells Contributed to the Neointimal Formation after Arterial Injury

    PubMed Central

    Li, Mincai; Li, Suqin; Yu, Liangzhu; Wu, Jiliang; She, Tonghui; Gan, Yaping; Hu, Zhenwu; Liao, Wenli; Xia, Hongli

    2013-01-01

    Objectives Recent findings suggest that in response to repair-to-injury bone marrow mesenchymal stem cells (BMSCs) participate in the process of angiogenesis. It is unclear what role BMSCs play in the structure of the vessel wall. In present study, we aimed to determine whether BMSCs had the capacity of endothelial cells (ECs). Methods BMSCs were separated and cultured. FACS and RT-PCR analysis confirmed the gene expression phenotype. The capacity of migration and adhesion and the ultrastructure of BMSCs were examined. The effect of BMSCs transplantation on the vascular repair was investigated in a murine carotid artery-injured model. Results BMSCs could express some markers and form the tube-like structure. The migration and adhesion capacity of BMSCs increased significantly after stimulated. In addition, BMSCs had the intact cell junction. In vivo the local transfer of BMSCs differentiated into neo-endothelial cells in the injury model for carotid artery and contributed to the vascular remodeling. Conclusion These results showed that BMSCs could contribute to neointimal formation for vascular lesion and might be associated with the differentiation into ECs, which indicated the important therapeutic implications for vascular diseases. PMID:24349351

  4. NSAIDS inhibit in vitro MSC chondrogenesis but not osteogenesis: implications for mechanism of bone formation inhibition in man

    PubMed Central

    Pountos, Ippokratis; Giannoudis, Peter V; Jones, Elena; English, Anne; Churchman, Sarah; Field, Sarah; Ponchel, Frederique; Bird, Howard; Emery, Paul; McGonagle, Dennis

    2011-01-01

    Abstract The non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for analgesia but may inhibit bone formation. We investigated whether the reported NSAID effect on bone is related to inhibition of bone marrow mesenchymal stem cell (MSC) proliferation and osteogenic and chondrogenic differentiation and evaluated both cyclooxygenase (COX)-1 and COX-2 specific drugs. The effects of seven COX-1 and COX-2 inhibitors on MSC proliferation and osteogenic and chondrogenic differentiation were tested using Vybrant, sodium 3?-[1-(phenylaminocarbonyl)- 3,4-tetrazolium]-bis (4-methoxy-6-nitro) benzene sulfonic acid hydrate (XTT), functional and quantitative assays of MSC differentiation. The MSC expression of COX-1 and COX-2 and prostaglandin E2 (PGE-2) levels were evaluated serially during lineage differentiation by quantitative PCR and ELISA. None of the NSAIDs at broad range of concentration (range 10?3 to 100 ?g/ml) significantly affected MSC proliferation. Surprisingly, MSC osteogenic differentiation inhibition was not evident. However, NSAIDs affected chondrogenic potential with a reduction in sulphated glycosaminoglycans (sGAG) content by 45% and 55% with diclofenac and ketorolac, respectively (P < 0.05 compared to controls). Parecoxib and meloxicam, more COX-2 specific reagents inhibited sGAG to a lesser degree, 22% and 27% respectively (P < 0.05 compared to controls). Cartilage pellet immunohistochemistry confirmed the above results. Pellet chondrogenesis was associated with increased COX-1 expression levels but not COX-2, and COX-1 specific drugs suppressed MSC PGE-2 more than COX-2 specific inhibitors. These findings suggest that NSAIDs may inhibit bone formation via blockage of MSC chondrogenic differentiation which is an important intermediate phase in normal endochondral bone formation. PMID:20070439

  5. Dynamics of Alloplastic Bone Grafts on an Early Stage of Corticotomy-Facilitated Orthodontic Tooth Movement in Beagle Dogs

    PubMed Central

    Choi, Hyung-Joo; Kim, Tae-Woo

    2014-01-01

    Alveolar augmented corticotomy is effective in accelerating orthodontic tooth movement, but the effect only lasts for a relatively short time. Therefore, the purpose of this study was to investigate the underlying biology of the immediate periodontal response to orthodontic tooth movement after a corticotomy with alloplastic bone grafts. The results demonstrated that measurable tooth movement began as early as 3 days after the intervention in beagle dogs. Based on the results and histological findings, augmented corticotomy-facilitated orthodontic tooth movement might enhance the condition of the periodontal tissue and the stability of the outcomes of orthodontic treatment. PMID:25276787

  6. Orbital stability during the early stages of planetary formation

    NASA Astrophysics Data System (ADS)

    Donnison, J. R.; Williams, I. P.

    1985-09-01

    One theory of planetary formation suggests that the planets evolved from giant gaseous protoplanets which lost their volatile elements. Analytical calculations of the hierarchical stability of three-body systems suggest that the most likely configuration to be unstable is that of a large protoplanet moving in close proximity to a forming terrestrial planet which has already lost most of its excess hydrogen and helium, and not two large protoplanets as originally suggested by the present authors and others. The orbital stability of such configurations was examined numerically for various combinations of planets and protoplanets in the inner Solar System. It was found that all the systems considered were stable for at least a period of 103yr.

  7. Phenotypic characterization of early events of thymus repopulation in radiation bone marrow chimeras

    SciTech Connect

    Sharrow, S.O.; Singer, A.; Hammerling, U.; Mathieson, B.J.

    1983-04-01

    The phenotype of murine thymocytes repopulating the thymus of radiation bone marrow chimeras shortly after irradiation and bone marrow reconstitution was analyzed by immunofluorescence and flow microfluorometry. Thymuses in these chimeras, while essentially devoid of lymphoid cells at day 7, were repopulated by days 10 to 12 after irradiation. It was found that this initial repopulation arose from a radioresistant intrathymic precursor that expanded to an almost complete complement of host-type thymocytes. However, these host-derived thymocytes were unusual in that they were relatively deficient in Lyt 1+2- and peanut agglutinin ''dull'' cells as compared with normal thymocytes. Donor bone-marrow-derived cells first appeared in the irradiated chimeric thymuses between days 12 and 15 after irradiation and bone marrow transfer. By day 19, chimeric thymuses contained more than 98% donor cells. This course was identical for three chimeric combinations, each made across different genetic barriers. In contrast to the cells that populate the fetal thymus during normal ontogeny, the first donor bone-marrow-derived cells that can be detected within the irradiated chimeric thymuses already expressed phenotypically normal adult T cell subpopulations in that they contained significant numbers both of Lyt 1+2- and of Lyt 1+2+ thymocytes. Thus, the Lyt phenotype of donor cells that initially repopulate an adult thymus after irradiation is markedly different from the Lyt phenotype of cells that initially populate the fetal thymus. The differences between adult and fetal thymic development that are observed in radiation bone marrow chimeras may be important in our understanding of T cell differentiation in these animals.

  8. An experimental study on the application of radionuclide imaging in repair of the bone defect.

    PubMed

    Zhu, Weimin; Wang, Daping; Zhang, Xiaojun; Lu, Wei; Liu, Jianquan; Peng, Liangquan; Li, Hao; Han, Yun; Zeng, Yanjun

    2011-08-01

    The aim of our study was to validate the effect of radionuclide imaging in early monitoring of the bone's reconstruction, the animal model of bone defect was made on the rabbits repaired with HA artificial bone. The ability of bone defect repair was evaluated by using radionuclide bone imaging at 2, 4, 8 and 12 weeks postoperatively. The results indicate that the experimental group stimulated more bone formation than that of the control group. The differences of the bone reconstruction ability were statistically significant (p<0.05). The nano-HA artificial has good bone conduction, and it can be used for the treatment of bone defects. Radionuclide imaging may be an effective and first choice method for the early monitoring of the bone's reconstruction. PMID:21875418

  9. 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)

    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

    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.

  10. Changes in the Expression of Bone Morphogenetic Protein 7 and Tamm– Horsfall Protein in the Early Stages of Diabetic Nephropathy

    PubMed Central

    Qu, Yanchun; Du, E; Zhang, Yue; Li, Shengzhi; Han, Ruifa; Qiu, Mengsheng

    2012-01-01

    Background Bone morphogenetic protein 7 (BMP7) has been suggested to play a protective role against kidney injury in chronic kidney disease. Objectives To identify the critical molecular regulators in the early stage of diabetic nephropathy, we studied the expression of BMP7 and 2 important kidney-specific markers, podocin and Tamm–Horsfall protein (THP). Materials and Methods A diabetic nephropathy model was established by intraperitoneally injecting streptozotocin (STZ) in male Kunming mice. Kidney weight index was used as an indicator of early renal injury. Kidney tissue from the diabetic model mice was obtained at 4, 8, and 12 weeks, and total protein was extracted to assess the expression of BMP7, podocin, and THP by western blot analysis. Results Diabetic model mice were successfully established, and the kidney weight index of the model animals increased significantly. The expression of BMP7 was significantly downregulated, while the expression of THP was increased in the early stage of diabetic nephropathy. However, the expression of podocin did not change. Conclusions Our observations suggested that down-regulation of BMP7 expression and up-regulation of THP expression were early events that occur prior to podocyte injury with the structure protein, podocin spoiled, which further confirmed that BMP7 is a key molecular regulator in the early stage of diabetic nephropathy. PMID:23573468

  11. In vivo static creep loading of the rat forelimb reduces ulnar structural properties at time-zero and induces damage-dependent woven bone formation.

    PubMed

    Lynch, Jennifer A; Silva, Matthew J

    2008-05-01

    Periosteal woven bone forms in response to stress fractures and pathological overload. The mechanical factors that regulate woven bone formation are poorly understood. Fatigue loading of the rat ulna triggers a woven bone response in proportion to the level of applied fatigue displacement. However, because fatigue produces damage by application of cyclic loading it is unclear if the osteogenic response is due to bone damage (injury response) or dynamic strain (adaptive response). Creep loading, in contrast to fatigue, involves application of a static force. Our objectives were to use static creep loading of the rat forelimb to produce discrete levels of ulnar damage, and subsequently to determine the bone response over time. We hypothesized that 1) increases in applied displacement during loading correspond to ulnae with increased crack number, length and extent, as well as decreased mechanical properties; and 2) in vivo creep loading stimulates a damage-dependent dose-response in periosteal woven bone formation. Creep loading of the rat forelimb to progressive levels of sub-fracture displacement led to progressive bone damage (cracks) and loss of whole-bone mechanical properties (especially stiffness) at time-zero. For example, loading to 60% of fracture displacement caused a 60% loss of ulnar stiffness and a 25%