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Sample records for active bone remodeling

  1. Connecting Mechanics and Bone Cell Activities in the Bone Remodeling Process: An Integrated Finite Element Modeling

    PubMed Central

    Hambli, Ridha

    2014-01-01

    Bone adaptation occurs as a response to external loadings and involves bone resorption by osteoclasts followed by the formation of new bone by osteoblasts. It is directly triggered by the transduction phase by osteocytes embedded within the bone matrix. The bone remodeling process is governed by the interactions between osteoblasts and osteoclasts through the expression of several autocrine and paracrine factors that control bone cell populations and their relative rate of differentiation and proliferation. A review of the literature shows that despite the progress in bone remodeling simulation using the finite element (FE) method, there is still a lack of predictive models that explicitly consider the interaction between osteoblasts and osteoclasts combined with the mechanical response of bone. The current study attempts to develop an FE model to describe the bone remodeling process, taking into consideration the activities of osteoclasts and osteoblasts. The mechanical behavior of bone is described by taking into account the bone material fatigue damage accumulation and mineralization. A coupled strain–damage stimulus function is proposed, which controls the level of autocrine and paracrine factors. The cellular behavior is based on Komarova et al.’s (2003) dynamic law, which describes the autocrine and paracrine interactions between osteoblasts and osteoclasts and computes cell population dynamics and changes in bone mass at a discrete site of bone remodeling. Therefore, when an external mechanical stress is applied, bone formation and resorption is governed by cells dynamic rather than adaptive elasticity approaches. The proposed FE model has been implemented in the FE code Abaqus (UMAT routine). An example of human proximal femur is investigated using the model developed. The model was able to predict final human proximal femur adaptation similar to the patterns observed in a human proximal femur. The results obtained reveal complex spatio-temporal bone

  2. Immunoregulation of bone remodelling

    PubMed Central

    Singh, Ajai; Mehdi, Abbass A; Srivastava, Rajeshwer N; Verma, Nar Singh

    2012-01-01

    Remodeling, a continuous physiological process maintains the strength of the bones, which maintains a delicate balance between bone formation and resorption process. This review gives an insight to the complex interaction and correlation between the bone remodeling and the corresponding changes in host immunological environment and also summarises the most recent developments occuring in the understanding of this complex field. T cells, both directly and indirectly increase the expression of receptor activator of nuclear factor kB ligand (RANKL); a vital step in the activation of osteoclasts, thus positively regulates the osteoclastogenesis. Though various cytokines, chemikines, transcription factors and co-stimulatory molecules are shared by both skeletal and immune systems, but researches are being conducted to establish and analyse their role and / or control on this complex but vital process. The understanding of this part of research may open new horizons in the management of inflammatory and autoimmune diseases, resulting into bone loss and that of osteoporosis also. PMID:22837895

  3. Modulation of bone remodeling via mechanically activated ion channels

    NASA Technical Reports Server (NTRS)

    Duncan, Randall L. (Principal Investigator)

    1996-01-01

    A critical factor in the maintenance of bone mass is the physical forces imposed upon the skeleton. Removal of these forces, such as in a weightless environment, results in a rapid loss of bone, whereas application of exogenous mechanical strain has been shown to increase bone formation. Numerous flight and ground-based experiments indicate that the osteoblast is the key bone cell influenced by mechanical stimulation. Aside from early transient fluctuations in response to unloading, osteoclast number and activity seem unaffected by removal of strain. However, bone formation is drastically reduced in weightlessness and osteoblasts respond to mechanical strain with an increase in the activity of a number of second messenger pathways resulting in increased anabolic activity. Unfortunately, the mechanism by which the osteoblast converts physical stimuli into a biochemical message, a process we have termed biochemical coupling, remains elusive. Prior to the application of this grant, we had characterized a mechanosensitive, cation nonselective channel (SA-cat) in osteoblast-like osteosarcoma cells that we proposed is the initial signalling mechanism for mechanotransduction. During the execution of this grant, we have made considerable progress to further characterize this channel as well as to determine its role in the osteoblastic response to mechanical strain. To achieve these goals, we combined electrophysiologic techniques with cellular and molecular biology methods to examine the role of these channels in the normal function of the osteoblast in vitro.

  4. Activity and loading influence the predicted bone remodeling around cemented hip replacements.

    PubMed

    Dickinson, Alexander S

    2014-04-01

    Periprosthetic bone remodeling is frequently observed after total hip replacement. Reduced bone density increases the implant and bone fracture risk, and a gross loss of bone density challenges fixation in subsequent revision surgery. Computational approaches allow bone remodeling to be predicted in agreement with the general clinical observations of proximal resorption and distal hypertrophy. However, these models do not reproduce other clinically observed bone density trends, including faster stabilizing mid-stem density losses, and loss-recovery trends around the distal stem. These may resemble trends in postoperative joint loading and activity, during recovery and rehabilitation, but the established remodeling prediction approach is often used with identical pre- and postoperative load and activity assumptions. Therefore, this study aimed to evaluate the influence of pre- to postoperative changes in activity and loading upon the predicted progression of remodeling. A strain-adaptive finite element model of a femur implanted with a cemented Charnley stem was generated, to predict 60 months of periprosthetic remodeling. A control set of model input data assumed identical pre- and postoperative loading and activity, and was compared to the results obtained from another set of inputs with three varying activity and load profiles. These represented activity changes during rehabilitation for weak, intermediate and strong recoveries, and pre- to postoperative joint force changes due to hip center translation and the use of walking aids. Predicted temporal bone density change trends were analyzed, and absolute bone density changes and the time to homeostasis were inspected, alongside virtual X-rays. The predicted periprosthetic bone density changes obtained using modified loading inputs demonstrated closer agreement with clinical measurements than the control. The modified inputs also predicted the clinically observed temporal density change trends, but still under

  5. Activation of bone remodeling after fatigue: differential response to linear microcracks and diffuse damage.

    PubMed

    Herman, B C; Cardoso, L; Majeska, R J; Jepsen, K J; Schaffler, M B

    2010-10-01

    Recent experiments point to two predominant forms of fatigue microdamage in bone: linear microcracks (tens to a few hundred microns in length) and "diffuse damage" (patches of diffuse stain uptake in fatigued bone comprised of clusters of sublamellar-sized cracks). The physiological relevance of diffuse damage in activating bone remodeling is not known. In this study microdamage amount and type were varied to assess whether linear or diffuse microdamage has similar effects on the activation of intracortical resorption. Activation of resorption was correlated to the number of linear microcracks (Cr.Dn) in the bone (R(2)=0.60, p<0.01). In contrast, there was no activation of resorption in response to diffuse microdamage alone. Furthermore, there was no significant change in osteocyte viability in response to diffuse microdamage, suggesting that osteocyte apoptosis, which is known to activate remodeling at typical linear microcracks in bone, does not result from sublamellar damage. These findings indicate that inability of diffuse microdamage to activate resorption may be due to lack of a focal injury response. Finally, we found that duration of loading does not affect the remodeling response. In conclusion, our data indicate that osteocytes activate resorption in response to linear microcracks but not diffuse microdamage, perhaps due to lack of a focal injury-induced apoptotic response. PMID:20633708

  6. Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease

    PubMed Central

    Kearns, Ann E.; Khosla, Sundeep; Kostenuik, Paul J.

    2008-01-01

    Osteoclasts and osteoblasts dictate skeletal mass, structure, and strength via their respective roles in resorbing and forming bone. Bone remodeling is a spatially coordinated lifelong process whereby old bone is removed by osteoclasts and replaced by bone-forming osteoblasts. The refilling of resorption cavities is incomplete in many pathological states, which leads to a net loss of bone mass with each remodeling cycle. Postmenopausal osteoporosis and other conditions are associated with an increased rate of bone remodeling, which leads to accelerated bone loss and increased risk of fracture. Bone resorption is dependent on a cytokine known as RANKL (receptor activator of nuclear factor κB ligand), a TNF family member that is essential for osteoclast formation, activity, and survival in normal and pathological states of bone remodeling. The catabolic effects of RANKL are prevented by osteoprotegerin (OPG), a TNF receptor family member that binds RANKL and thereby prevents activation of its single cognate receptor called RANK. Osteoclast activity is likely to depend, at least in part, on the relative balance of RANKL and OPG. Studies in numerous animal models of bone disease show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density, and strength. RANKL inhibitors also prevent focal bone loss that occurs in animal models of rheumatoid arthritis and bone metastasis. Clinical trials are exploring the effects of denosumab, a fully human anti-RANKL antibody, on bone loss in patients with osteoporosis, bone metastasis, myeloma, and rheumatoid arthritis. PMID:18057140

  7. Osteocyte-Driven Bone Remodeling

    PubMed Central

    Bellido, Teresita

    2013-01-01

    Osteocytes, the most abundant cells in bone, have been long postulated to detect and respond to mechanical and hormonal stimuli and to coordinate the function of osteoblasts and osteoclasts. The discovery that the inhibitor of bone formation sclerostin is primarily expressed in osteocytes in bone and it is downregulated by anabolic stimuli provided a mechanism by which osteocytes influence the activity of osteoblasts. Advances of the last few years provided experimental evidence demonstrating that osteocytes also participate in the recruitment of osteoclasts and the initiation of bone remodeling. Apoptotic osteocytes trigger yet to be identified signals that attract osteoclast precursors to specific areas of bone, which in turn differentiate to mature, bone resorbing osteoclasts. Osteocytes are also the source of molecules that regulate generation and activity of osteoclasts, such as OPG and RANKL; and genetic manipulations of the mouse genome leading to loss or gain of function, or to altered expression of either molecule in osteocytes, markedly affect bone resorption. This review highlights these investigations and discusses how the novel concept of osteocyte-driven bone resorption and formation impacts our understanding of the mechanisms by which current therapies control bone remodeling. PMID:24002178

  8. Bone Remodeling Under Pathological Conditions.

    PubMed

    Xiao, Wenmei; Li, Shuai; Pacios, Sandra; Wang, Yu; Graves, Dana T

    2016-01-01

    Bone is masterfully programmed to repair itself through the coupling of bone formation following bone resorption, a process referred to as coupling. In inflammatory or other conditions, the balance between bone resorption and bone formation shifts so that a net bone loss results. This review focuses on four pathologic conditions in which remodeling leads to net loss of bone, postmenopausal osteoporosis, arthritis, periodontal disease, and disuse bone loss, which is similar to bone loss associated with microgravity. In most of these there is an acceleration of the resorptive process due to increased formation of bone metabolic units. This initially leads to a net bone loss since the time period of resorption is much faster than the time needed for bone formation that follows. In addition, each of these processes is characterized by an uncoupling that leads to net bone loss. Mechanisms responsible for increased rates of bone resorption, i.e. the formation of more bone metabolic units, involve enhanced expression of inflammatory cytokines and increased expression of RANKL. Moreover, the reasons for uncoupling are discussed which range from a decrease in expression of growth factors and bone morphogenetic proteins to increased expression of factors that inhibit Wnt signaling. PMID:26599114

  9. Bone Remodeling Monitor

    NASA Technical Reports Server (NTRS)

    Foucar, Charlie; Goldberg, Leslie; Hon, Bodin; Moore, Shannon; Williams, Evan

    2009-01-01

    The impact of bone loss due to different mechanical loadings in microgravity is a major concern for astronauts upon reintroduction to gravitational forces in exploration missions to the Moon and Mars. it has been shown that astronauts not only lose bone at differing rates, with levels up to 2% per month, but each astronaut will respond to bone loss treatments differently. Pre- and post-flight imaging techniques and frozen urine samples for post-flight laboratory immunoassays To develop a novel, non-invasive, highly . sensitive, portable, intuitive, and low-powered device to measure bone resorption levels in 'real time' to provide rapid and Individualized feedback to maximize the efficacy of bone loss countermeasures 1. Collect urine specimen and analyze the level of bone resorption marker, DPD (deoxypridinoline) excreted. 2. Antibodies specific to DPD conjugated with nanoshells and mixed with specimen, the change in absorbance from agglutination is measured by an optical device. 3. The concentration of DPD is displayed and recorded on a PDA

  10. Osteocytes: The master cells in bone remodelling.

    PubMed

    Prideaux, Matthew; Findlay, David M; Atkins, Gerald J

    2016-06-01

    Bone remodelling is an essential process for shaping and maintaining bone mass in the mature skeleton. During our lifetime bone is constantly being removed by osteoclasts and new bone is formed by osteoblasts. The activities of osteoclasts and osteoblasts must be regulated under a strict balance to ensure that bone homeostasis is maintained. Osteocytes, which form an extensive, multi-functional syncytium throughout the bone, are increasingly considered to be the cells that maintain this balance. Current research is elucidating key signalling pathways by which the osteocyte exerts control over the other cell types in bone and over its own activities, and potential ways in which these pathways may be exploited therapeutically. PMID:26927500

  11. Bone marrow mesenchymal stem cells and TGF-β signaling in bone remodeling

    PubMed Central

    Crane, Janet L.; Cao, Xu

    2014-01-01

    During bone resorption, abundant factors previously buried in the bone matrix are released into the bone marrow microenvironment, which results in recruitment and differentiation of bone marrow mesenchymal stem cells (MSCs) for subsequent bone formation, temporally and spatially coupling bone remodeling. Parathyroid hormone (PTH) orchestrates the signaling of many pathways that direct MSC fate. The spatiotemporal release and activation of matrix TGF-β during osteoclast bone resorption recruits MSCs to bone-resorptive sites. Dysregulation of TGF-β alters MSC fate, uncoupling bone remodeling and causing skeletal disorders. Modulation of TGF-β or PTH signaling may reestablish coupled bone remodeling and be a potential therapy. PMID:24487640

  12. Abnormal bone remodelling in inflammatory arthritis

    PubMed Central

    Bogoch, Earl R.; Moran, Erica

    1998-01-01

    Osteopenia is responsible for substantial comorbidity in patients suffering from rheumatoid arthritis and is an important factor in the surgical management of joint disease. In animal models of bone loss stimulated by inflammatory arthritis, increased bone remodelling and altered microstructure of bone have been documented. The subchondral bone plate near the joint surface is narrow and perforated by vascular inflammatory invasion, and in the shaft the thin cortices are weakened by giant resorption defects. Biomechanical tests and a mathematical model of bone strength suggest that cortical defects, much larger than those found in normal osteonal remodelling, are principally responsible for the experimentally observed loss of strength. Similarly, these defects may explain the increased femoral fracture risk in rheumatoid arthritis. The osteoclast, the cell resorbing bone, is demonstrated in increased number and activity in rheumatoid arthritis and in animal models. Bisphosphonates, drugs that inhibit osteoclast function, have been shown experimentally to reduce both focal and generalized osteopenia and to prevent loss of bone strength. Bisphosphonates also protect articular cartilage from damage characteristic of inflammatory arthritis. The mechanism of chondroprotection may be prevention of subchondral bone resorption by the osteoclast and also an altered distribution of bone marrow cells. Thus, bisphosphonates, currently in clinical use for other bone metabolic diseases, appear to have potential as prophylaxis and treatment for osteopenia and joint damage in inflammatory arthritis. PMID:9711159

  13. [Morphological analysis of bone dynamics and metabolic bone disease. Histomorphometric concepts of bone remodeling and modeling].

    PubMed

    Takahashi, Hideaki E

    2011-04-01

    In tissue level turnover of bone cells, bone remodeling shows a sequential events of activation, resorption, reversal and formation. This may be observed as secondary osteons in the cortical bone and trabecular packets in the cancellous bone. Microcracks are repaired by targeted remodeling, and calcium is released by non-targeted remodeling. In macromodeling, a macroscopic size of a bone increases with growth, without changing its basic figure. In micromodelimg, a shift of trabecula, a minishift, is biomechnically controlled. New lamellar bone is added parallel to compressive and tensile force, and bone resorption occurs at the opposite surface of formation. In minimodeling new lamellar bone is formed with a sequence of activation, then directly formation, without scalloping at the cement line between newly formed bone and its basic bone. PMID:21447918

  14. Bone remodeling and silicon deficiency in rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Alveolar bone undergoes continuous remodeling to meet physiologic and functional demands. The aim of the present work was to evaluate histologically and histomorphometrically the effect of silicon deficiency on bone modeling and remodeling in the periodontal cortical plate. Two groups of weaning mal...

  15. The Amiloride Derivative Phenamil Attenuates Pulmonary Vascular Remodeling by Activating NFAT and the Bone Morphogenetic Protein Signaling Pathway ▿

    PubMed Central

    Chan, Mun Chun; Weisman, Alexandra S.; Kang, Hara; Nguyen, Peter H.; Hickman, Tyler; Mecker, Samantha V.; Hill, Nicholas S.; Lagna, Giorgio; Hata, Akiko

    2011-01-01

    Pulmonary artery hypertension (PAH) is characterized by elevated pulmonary artery resistance and increased medial thickness due to deregulation of vascular remodeling. Inactivating mutations of the BMPRII gene, which encodes a receptor for bone morphogenetic proteins (BMPs), are identified in ∼60% of familial PAH (FPAH) and ∼30% of idiopathic PAH (IPAH) patients. It has been hypothesized that constitutive reduction in BMP signal by BMPRII mutations may cause abnormal vascular remodeling by promoting dedifferentiation of vascular smooth muscle cells (vSMCs). Here, we demonstrate that infusion of the amiloride analog phenamil during chronic-hypoxia treatment in rat attenuates development of PAH and vascular remodeling. Phenamil induces Tribbles homolog 3 (Trb3), a positive modulator of the BMP pathway that acts by stabilizing the Smad family signal transducers. Through induction of Trb3, phenamil promotes the differentiated, contractile vSMC phenotype characterized by elevated expression of contractile genes and reduced cell growth and migration. Phenamil activates the Trb3 gene transcription via activation of the calcium-calcineurin-nuclear factor of activated T cell (NFAT) pathway. These results indicate that constitutive elevation of Trb3 by phenamil is a potential therapy for IPAH and FPAH. PMID:21135135

  16. [Bone quality and strength relating with bone remodeling].

    PubMed

    Mori, Satoshi

    2016-01-01

    The bone has the functions of mineral reservoir and mechanical support as skeleton. Bone remodeling is the adult mode of bone metabolism, replacing old bone tissue to new one. Bone strength is determined by bone volume, structure and quality such as micro damage, degree of mineralization and collagen cross linkage, which are all controlled by bone remodeling. Bone strength decreases under high turn-over condition by decreasing bone volume and deterioration of bone structure, which also decreases under low turn-over condition by increased micro damage, increasing mineralization and AGE collagen cross linkage. PMID:26728527

  17. Control of bone remodelling by applied dynamic loads

    NASA Technical Reports Server (NTRS)

    Lanyon, L. E.; Rubin, C. T.

    1984-01-01

    The data showing the relationship between bone mass and peak strain magnitude prepared and submitted for publication. The data from experiments relating remodelling activity with static or dynamic loads were prepared and submitted for publication. Development of programs to relate the location of remodelling activity with he natural and artificial dynamic strain distributions continued. Experiments on the effect of different strain rates on the remodelling response continued.

  18. [Histamine in regulation of bone remodeling processes].

    PubMed

    Wiercigroch, Marek; Folwarczna, Joanna

    2013-01-01

    Bone remodeling is under autocrine, paracrine, endocrine and central nervous system control. One of the potential endogenous factors affecting bone remodeling is histamine, an endogenous amine which acts as a mediator of allergic reactions and neuromediator, and induces production of gastric acid. Histamine H₁ receptor antagonists are widely used in the treatment of allergic conditions, H₂ receptor antagonists in peptic ulcer disease, and betahistine (an H₃ receptor antagonist and H₁ receptor agonist) is used in the treatment of Ménière's disease. Excess histamine release in mastocytosis and allergic diseases may lead to development of osteoporosis. Clinical and population-based studies on the effects of histamine receptor antagonists on the skeletal system have not delivered unequivocal results. Expression of mRNA of histamine receptors has been discovered in bone cells (osteoblasts and osteoclasts). Histamine synthesis has been demonstrated in osteoclast precursors. Histamine increases bone resorption both by direct effects on osteoclast precursors and osteoclasts, and indirectly, by increasing the expression of RANKL in osteoblasts. In in vivo studies, H₁ and H₂ receptor antagonists exerted protective effects on the bone tissue, although not in all experimental models. In the present article, in vitro and in vivo studies conducted so far, concerning the effects of histamine and drugs modifying its activity on the skeletal system, have been reviewed. PMID:24018454

  19. Pulsatile Fluid Shear in Bone Remodeling

    NASA Technical Reports Server (NTRS)

    Frangos, John A.

    1997-01-01

    The objective of this investigation was to elucidate the sensitivity to transients in fluid shear stress in bone remodeling. Bone remodeling is clearly a function of the local mechanical environment which includes interstitial fluid flow. Traditionally, load-induced remodeling has been associated with low frequency (1-2 Hz) signals attributed to normal locomotion. McLeod and Rubin, however, demonstrated in vivo remodeling events associated with high frequency (15-30 Hz) loading. Likewise, other in vivo studies demonstrated that slowly applied strains did not trigger remodeling events. We therefore hypothesized that the mechanosensitive pathways which control bone maintenance and remodeling are differentially sensitive to varying rates of applied fluid shear stress.

  20. Assessment of bone vascularization and its role in bone remodeling

    PubMed Central

    Lafage-Proust, Marie-Hélène; Roche, Bernard; Langer, Max; Cleret, Damien; Vanden Bossche, Arnaud; Olivier, Thomas; Vico, Laurence

    2015-01-01

    Bone is a composite organ that fulfils several interconnected functions, which may conflict with each other in pathological conditions. Bone vascularization is at the interface between these functions. The roles of bone vascularization are better documented in bone development, growth and modeling than in bone remodeling. However, every bone remodeling unit is associated with a capillary in both cortical and trabecular envelopes. Here we summarize the most recent data on vessel involvement in bone remodeling, and we present the characteristics of bone vascularization. Finally, we describe the various techniques used for bone vessel imaging and quantitative assessment, including histology, immunohistochemistry, microtomography and intravital microscopy. Studying the role of vascularization in adult bone should provide benefits for the understanding and treatment of metabolic bone diseases. PMID:25861447

  1. [Determinants of bone quality and strength independent of bone remodeling].

    PubMed

    Saito, Mitsuru; Marumo, Keishi

    2016-01-01

    Bone mineral density(BMD)and bone microstructure are regulated mainly by bone remodeling. In contrast, bone collagen enzymatic immature and mature cross-links and advanced glycation end products such as pentosidine and carboxyl methyl lysine are affected by various factors. Aging bone tissue is repaired in the process of bone remodeling. However, deterioration of bone material properties markedly advances due to increases in oxidative stress, glycation stress, reactive oxygen species, carbonyl stress associated with aging and reduced sex hormone levels, and glucocorticoid use. To improve bone material properties in osteoporosis, we should use different drug (Saito M, Calcif Tissue Int, REVIEW, 97;242-261, 2015). In this review, we summarized determinants of bone quality and strength independent of bone remodeling. PMID:26728528

  2. Effect of material damping on bone remodelling.

    PubMed

    Misra, J C; Samanta, S

    1987-01-01

    This paper considers the effect of internal material damping on the stresses, strains, and surface and internal remodelling behaviour in a section of axisymmetrical bone with a force-fitted axially oriented medullary pin. The bone response to several loading situations is modelled using visco-elastic equations. An approximate method is developed to analyse the proposed mathematical model. By considering a numerical example, the effect of material damping on the remodelling stresses is quantified. PMID:3584150

  3. A Computational Model for Simulating Spaceflight Induced Bone Remodeling

    NASA Technical Reports Server (NTRS)

    Pennline, James A.; Mulugeta, Lealem

    2014-01-01

    An overview of an initial development of a model of bone loss due to skeletal unloading in weight bearing sites is presented. The skeletal site chosen for the initial application of the model is the femoral neck region because hip fractures can be debilitating to the overall performance health of astronauts. The paper begins with the motivation for developing such a model of the time course of change in bone in order to understand the mechanism of bone demineralization experienced by astronauts in microgravity, to quantify the health risk, and to establish countermeasures. Following this, a general description of a mathematical formulation of the process of bone remodeling is discussed. Equations governing the rate of change of mineralized bone volume fraction and active osteoclast and osteoblast are illustrated. Some of the physiology of bone remodeling, the theory of how imbalance in remodeling can cause bone loss, and how the model attempts to capture this is discussed. The results of a preliminary validation analysis that was carried out are presented. The analysis compares a set of simulation results against bone loss data from control subjects who participated in two different bed rest studies. Finally, the paper concludes with outlining the current limitations and caveats of the model, and planned future work to enhance the state of the model.

  4. Densitometric evaluation of periprosthetic bone remodeling

    PubMed Central

    Parchi, Paolo Domenico; Cervi, Valentina; Piolanti, Nicola; Ciapini, Gianluca; Andreani, Lorenzo; Castellini, Iacopo; Poggetti, Andrea; Lisanti, Michele

    2014-01-01

    Summary The application of Dual-energy X-ray absorptiometry (DEXA) in orthopaedic surgery gradually has been extended from the study of osteoporosis to different areas of interest like the study of the relation between bone and prosthetic implants. Aim of this review is to analyze changes that occur in periprosthetic bone after the implantation of a total hip arthroplasty (THA) or a total knee arthroplasty (TKA). In THA the pattern of adaptive bone remodeling with different cementless femoral stems varies and it appears to be strictly related to the design and more specifically to where the femoral stem is fixed on bone. Short stems with metaphyseal fixation allow the maintenance of a more physiologic load transfer to the proximal femur decreasing the entity of bone loss. Femoral bone loss after TKA seems to be related to the stress shielding induced by the implants while tibial bone remodeling seems to be related to postoperative changes in knee alignment (varus/valgus) and consequently in tibial load transfer. After both THA and TKA stress shielding seems to be an inevitable phenomenon that occurs mainly in the first year after surgery. PMID:25568658

  5. Suppressed bone remodeling in black bears conserves energy and bone mass during hibernation

    PubMed Central

    McGee-Lawrence, Meghan; Buckendahl, Patricia; Carpenter, Caren; Henriksen, Kim; Vaughan, Michael; Donahue, Seth

    2015-01-01

    ABSTRACT Decreased physical activity in mammals increases bone turnover and uncouples bone formation from bone resorption, leading to hypercalcemia, hypercalcuria, bone loss and increased fracture risk. Black bears, however, are physically inactive for up to 6 months annually during hibernation without losing cortical or trabecular bone mass. Bears have been shown to preserve trabecular bone volume and architectural parameters and cortical bone strength, porosity and geometrical properties during hibernation. The mechanisms that prevent disuse osteoporosis in bears are unclear as previous studies using histological and serum markers of bone remodeling show conflicting results. However, previous studies used serum markers of bone remodeling that are known to accumulate with decreased renal function, which bears have during hibernation. Therefore, we measured serum bone remodeling markers (BSALP and TRACP) that do not accumulate with decreased renal function, in addition to the concentrations of serum calcium and hormones involved in regulating bone remodeling in hibernating and active bears. Bone resorption and formation markers were decreased during hibernation compared with when bears were physically active, and these findings were supported by histomorphometric analyses of bone biopsies. The serum concentration of cocaine and amphetamine regulated transcript (CART), a hormone known to reduce bone resorption, was 15-fold higher during hibernation. Serum calcium concentration was unchanged between hibernation and non-hibernation seasons. Suppressed and balanced bone resorption and formation in hibernating bears contributes to energy conservation, eucalcemia and the preservation of bone mass and strength, allowing bears to survive prolonged periods of extreme environmental conditions, nutritional deprivation and anuria. PMID:26157160

  6. Bone Remodeling and Energy Metabolism: New Perspectives

    PubMed Central

    de Paula, Francisco J. A.; Rosen, Clifford J.

    2013-01-01

    Bone mineral, adipose tissue and energy metabolism are interconnected by a complex and multilevel series of networks. Calcium and phosphorus are utilized for insulin secretion and synthesis of high energy compounds. Adipose tissue store lipids and cholecalciferol, which, in turn, can influence calcium balance and energy expenditure. Hormones long-thought to solely modulate energy and mineral homeostasis may influence adipocytic function. Osteoblasts are a target of insulin action in bone. Moreover, endocrine mediators, such as osteocalcin, are synthesized in the skeleton but regulate carbohydrate disposal and insulin secretion. Finally, osteoblasts and adipocytes originate from the same mesenchymal progenitor. The mutual crosstalk between osteoblasts and adipocytes within the bone marrow microenvironment plays a crucial role in bone remodeling. In the present review we provide an overview of the reciprocal control between bone and energy metabolism and its clinical implications. PMID:26273493

  7. Expression of RANKL/OPG during bone remodeling in vivo

    SciTech Connect

    Tanaka, H.; Mine, T.; Ogasa, H.; Taguchi, T.; Liang, C.T.

    2011-08-12

    Highlights: {yields} This is the first study to determine the relationship between osteogenic differentiation and RANKL/OPG expression during bone remodeling in vivo. {yields} The OPG expression peak occurred during the bone formation phase, whereas the marked elevation of RANKL expression was observed during the bone resorption phase. {yields} Histological analysis showed that RANKL/OPG immunoreactivity was predominantly associated with bone marrow cells in the marrow cavity. {yields} The present study confirmed that RANKL/OPG are key factors linking bone formation to resorption during the bone remodeling process. -- Abstract: The interaction between receptor activator of nuclear factor {kappa}B ligand (RANKL) and osteoprotegerin (OPG) plays a dominant role in osteoclastogenesis. As both proteins are produced by osteoblast lineage cells, they are considered to represent a key link between bone formation and resorption. In this study, we investigated the expression of RANKL and OPG during bone remodeling in vivo to determine the relationship between osteoclastogenic stimulation and osteoblastic differentiation. Total RNA was prepared from rat femurs after marrow ablation on days 0, 3, 6, and 9. The temporal activation patterns of osteoblast-related genes (procollagen {alpha}1 (I), alkaline phosphatase, osteopontin, and osteocalcin) were examined by Northern blot analysis. An appreciable increase in the expression of these osteoblast markers was observed on day 3. The peak increase in gene expression was observed on day 6 followed by a slight reduction by day 9. Real-time PCR analysis showed that the OPG mRNA expression was markedly upregulated on day 6 and slightly decreased on day 9. In contrast, RANKL mRNA expression was increased by more than 20-fold on day 9. The RANKL/OPG ratio, an index of osteoclastogenic stimulation, peaked on day 9. Histological analysis showed that RANKL and OPG immunoreactivity were predominantly associated with bone marrow cells. The

  8. Development of Bone Remodeling Model for Spaceflight Bone Physiology Analysis

    NASA Technical Reports Server (NTRS)

    Pennline, James A.; Werner, Christopher R.; Lewandowski, Beth; Thompson, Bill; Sibonga, Jean; Mulugeta, Lealem

    2015-01-01

    Current spaceflight exercise countermeasures do not eliminate bone loss. Astronauts lose bone mass at a rate of 1-2% a month (Lang et al. 2004, Buckey 2006, LeBlanc et al. 2007). This may lead to early onset osteoporosis and place the astronauts at greater risk of fracture later in their lives. NASA seeks to improve understanding of the mechanisms of bone remodeling and demineralization in 1g in order to appropriately quantify long term risks to astronauts and improve countermeasures. NASA's Digital Astronaut Project (DAP) is working with NASA's bone discipline to develop a validated computational model to augment research efforts aimed at achieving this goal.

  9. ATF3 controls proliferation of osteoclast precursor and bone remodeling

    PubMed Central

    Fukasawa, Kazuya; Park, Gyujin; Iezaki, Takashi; Horie, Tetsuhiro; Kanayama, Takashi; Ozaki, Kakeru; Onishi, Yuki; Takahata, Yoshifumi; Yoneda, Yukio; Takarada, Takeshi; Kitajima, Shigetaka; Vacher, Jean; Hinoi, Eiichi

    2016-01-01

    Bone homeostasis is maintained by the sophisticated coupled actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Here we identify activating transcription factor 3 (ATF3) as a pivotal transcription factor for the regulation of bone resorption and bone remodeling under a pathological condition through modulating the proliferation of osteoclast precursors. The osteoclast precursor-specific deletion of ATF3 in mice led to the prevention of receptor activator of nuclear factor-κB (RANK) ligand (RANKL)-induced bone resorption and bone loss, although neither bone volume nor osteoclastic parameter were markedly altered in these knockout mice under the physiological condition. RANKL-dependent osteoclastogenesis was impaired in vitro in ATF3-deleted bone marrow macrophages (BMM). Mechanistically, the deficiency of ATF3 impaired the RANKL-induced transient increase in cell proliferation of osteoclast precursors in bone marrow in vivo as well as of BMM in vitro. Moreover, ATF3 regulated cyclin D1 mRNA expression though modulating activator protein-1-dependent transcription in the osteoclast precursor, and the introduction of cyclin D1 significantly rescued the impairment of osteoclastogenesis in ATF3-deleted BMM. Therefore, these findings suggest that ATF3 could have a pivotal role in osteoclastogenesis and bone homeostasis though modulating cell proliferation under pathological conditions, thereby providing a target for bone diseases. PMID:27480204

  10. Osteocalcin enhances bone remodeling around hydroxyapatite/collagen composites.

    PubMed

    Rammelt, Stefan; Neumann, Mirjam; Hanisch, Uwe; Reinstorf, Antje; Pompe, Wolfgang; Zwipp, Hans; Biewener, Achim

    2005-06-01

    The effect of osteocalcin (OC), an extracellular bone matrix protein, on bone healing around hydroxyapatite/collagen composites was investigated. Cylindrical nanocrystalline hydroxyapatite implants of 2.5-mm diameter containing 2.5% biomimetically mineralized collagen type I were inserted press-fit into the tibial head of adult Wistar rats. To one implant group, 10 mug/g OC was added. Six specimens per group were analyzed at 2, 7, 14, 28, and 56 days. After 14 days, newly formed woven bone had reached the implant surface of the OC implants whereas a broad fibrous interface could still be observed around controls. Woven bone was formed directly around both implant groups after 28 days and had been replaced partially by lamellar bone around the OC implants only. No significant differences in total bone contact were seen between both groups after 56 days. The higher number of phagocytosing cells and osteoclasts characterized immunohistochemically with ED1, cathepsin D, and tartate-resistant alkaline phosphatase around the OC implants at the early stages of bone healing suggests an earlier onset of bone remodeling. The earlier and increased expression of bone-specific matrix proteins and multifunctional adhesion proteins (osteopontin, bone sialoprotein, CD44) at the interface around the OC implants indicates that OC may accelerate bone formation and regeneration. This study supports the observations from in vitro studies that OC activates both osteoclasts and osteoblasts during early bone formation. PMID:15800855

  11. Altered thermogenesis and impaired bone remodeling in Misty mice.

    PubMed

    Motyl, Katherine J; Bishop, Kathleen A; DeMambro, Victoria E; Bornstein, Sheila A; Le, Phuong; Kawai, Masanobu; Lotinun, Sutada; Horowitz, Mark C; Baron, Roland; Bouxsein, Mary L; Rosen, Clifford J

    2013-09-01

    Fat mass may be modulated by the number of brown-like adipocytes in white adipose tissue (WAT) in humans and rodents. Bone remodeling is dependent on systemic energy metabolism and, with age, bone remodeling becomes uncoupled and brown adipose tissue (BAT) function declines. To test the interaction between BAT and bone, we employed Misty (m/m) mice, which were reported be deficient in BAT. We found that Misty mice have accelerated age-related trabecular bone loss and impaired brown fat function (including reduced temperature, lower expression of Pgc1a, and less sympathetic innervation compared to wild-type (+/ +)). Despite reduced BAT function, Misty mice had normal core body temperature, suggesting heat is produced from other sources. Indeed, upon acute cold exposure (4°C for 6 hours), inguinal WAT from Misty mice compensated for BAT dysfunction by increasing expression of Acadl, Pgc1a, Dio2, and other thermogenic genes. Interestingly, acute cold exposure also decreased Runx2 and increased Rankl expression in Misty bone, but only Runx2 was decreased in wild-type. Browning of WAT is under the control of the sympathetic nervous system (SNS) and, if present at room temperature, could impact bone metabolism. To test whether SNS activity could be responsible for accelerated trabecular bone loss, we treated wild-type and Misty mice with the β-blocker, propranolol. As predicted, propranolol slowed trabecular bone volume/total volume (BV/TV) loss in the distal femur of Misty mice without affecting wild-type. Finally, the Misty mutation (a truncation of DOCK7) also has a significant cell-autonomous role. We found DOCK7 expression in whole bone and osteoblasts. Primary osteoblast differentiation from Misty calvaria was impaired, demonstrating a novel role for DOCK7 in bone remodeling. Despite the multifaceted effects of the Misty mutation, we have shown that impaired brown fat function leads to altered SNS activity and bone loss, and for the first time that cold

  12. Phase field approaches of bone remodeling based on TIP

    NASA Astrophysics Data System (ADS)

    Ganghoffer, Jean-François; Rahouadj, Rachid; Boisse, Julien; Forest, Samuel

    2016-01-01

    The process of bone remodeling includes a cycle of repair, renewal, and optimization. This adaptation process, in response to variations in external loads and chemical driving factors, involves three main types of bone cells: osteoclasts, which remove the old pre-existing bone; osteoblasts, which form the new bone in a second phase; osteocytes, which are sensing cells embedded into the bone matrix, trigger the aforementioned sequence of events. The remodeling process involves mineralization of the bone in the diffuse interface separating the marrow, which contains all specialized cells, from the newly formed bone. The main objective advocated in this contribution is the setting up of a modeling and simulation framework relying on the phase field method to capture the evolution of the diffuse interface between the new bone and the marrow at the scale of individual trabeculae. The phase field describes the degree of mineralization of this diffuse interface; it varies continuously between the lower value (no mineral) and unity (fully mineralized phase, e.g. new bone), allowing the consideration of a diffuse moving interface. The modeling framework is the theory of continuous media, for which field equations for the mechanical, chemical, and interfacial phenomena are written, based on the thermodynamics of irreversible processes. Additional models for the cellular activity are formulated to describe the coupling of the cell activity responsible for bone production/resorption to the kinetics of the internal variables. Kinetic equations for the internal variables are obtained from a pseudo-potential of dissipation. The combination of the balance equations for the microforce associated to the phase field and the kinetic equations lead to the Ginzburg-Landau equation satisfied by the phase field with a source term accounting for the dissipative microforce. Simulations illustrating the proposed framework are performed in a one-dimensional situation showing the evolution of

  13. Parallel mechanisms suppress cochlear bone remodeling to protect hearing.

    PubMed

    Jáuregui, Emmanuel J; Akil, Omar; Acevedo, Claire; Hall-Glenn, Faith; Tsai, Betty S; Bale, Hrishikesh A; Liebenberg, Ellen; Humphrey, Mary Beth; Ritchie, Robert O; Lustig, Lawrence R; Alliston, Tamara

    2016-08-01

    Bone remodeling, a combination of bone resorption and formation, requires precise regulation of cellular and molecular signaling to maintain proper bone quality. Whereas osteoblasts deposit and osteoclasts resorb bone matrix, osteocytes both dynamically resorb and replace perilacunar bone matrix. Osteocytes secrete proteases like matrix metalloproteinase-13 (MMP13) to maintain the material quality of bone matrix through perilacunar remodeling (PLR). Deregulated bone remodeling impairs bone quality and can compromise hearing since the auditory transduction mechanism is within bone. Understanding the mechanisms regulating cochlear bone provides unique ways to assess bone quality independent of other aspects that contribute to bone mechanical behavior. Cochlear bone is singular in its regulation of remodeling by expressing high levels of osteoprotegerin. Since cochlear bone expresses a key PLR enzyme, MMP13, we examined whether cochlear bone relies on, or is protected from, osteocyte-mediated PLR to maintain hearing and bone quality using a mouse model lacking MMP13 (MMP13(-/-)). We investigated the canalicular network, collagen organization, lacunar volume via micro-computed tomography, and dynamic histomorphometry. Despite finding defects in these hallmarks of PLR in MMP13(-/-) long bones, cochlear bone revealed no differences in these markers, nor hearing loss as measured by auditory brainstem response (ABR) or distortion product oto-acoustic emissions (DPOAEs), between wild type and MMP13(-/-) mice. Dynamic histomorphometry revealed abundant PLR by tibial osteocytes, but near absence in cochlear bone. Cochlear suppression of PLR corresponds to repression of several key PLR genes in the cochlea relative to long bones. These data suggest that cochlear bone uniquely maintains bone quality and hearing independent of MMP13-mediated osteocytic PLR. Furthermore, the cochlea employs parallel mechanisms to inhibit remodeling by osteoclasts and osteoblasts, and by

  14. Remodeling in bone without osteocytes: Billfish challenge bone structure–function paradigms

    PubMed Central

    Atkins, Ayelet; Dean, Mason N.; Habegger, Maria Laura; Motta, Phillip J.; Ofer, Lior; Repp, Felix; Shipov, Anna; Weiner, Steve; Currey, John D.; Shahar, Ron

    2014-01-01

    A remarkable property of tetrapod bone is its ability to detect and remodel areas where damage has accumulated through prolonged use. This process, believed vital to the long-term health of bone, is considered to be initiated and orchestrated by osteocytes, cells within the bone matrix. It is therefore surprising that most extant fishes (neoteleosts) lack osteocytes, suggesting their bones are not constantly repaired, although many species exhibit long lives and high activity levels, factors that should induce considerable fatigue damage with time. Here, we show evidence for active and intense remodeling occurring in the anosteocytic, elongated rostral bones of billfishes (e.g., swordfish, marlins). Despite lacking osteocytes, this tissue exhibits a striking resemblance to the mature bone of large mammals, bearing structural features (overlapping secondary osteons) indicating intensive tissue repair, particularly in areas where high loads are expected. Billfish osteons are an order of magnitude smaller in diameter than mammalian osteons, however, implying that the nature of damage in this bone may be different. Whereas billfish bone material is as stiff as mammalian bone (unlike the bone of other fishes), it is able to withstand much greater strains (relative deformations) before failing. Our data show that fish bone can exhibit far more complex structure and physiology than previously known, and is apparently capable of localized repair even without the osteocytes believed essential for this process. These findings challenge the unique and primary role of osteocytes in bone remodeling, a basic tenet of bone biology, raising the possibility of an alternative mechanism driving this process. PMID:25331870

  15. Retinoid X receptors orchestrate osteoclast differentiation and postnatal bone remodeling

    PubMed Central

    Menéndez-Gutiérrez, María P.; Rőszer, Tamás; Fuentes, Lucía; Núñez, Vanessa; Escolano, Amelia; Redondo, Juan Miguel; De Clerck, Nora; Metzger, Daniel; Valledor, Annabel F.; Ricote, Mercedes

    2015-01-01

    Osteoclasts are bone-resorbing cells that are important for maintenance of bone remodeling and mineral homeostasis. Regulation of osteoclast differentiation and activity is important for the pathogenesis and treatment of diseases associated with bone loss. Here, we demonstrate that retinoid X receptors (RXRs) are key elements of the transcriptional program of differentiating osteoclasts. Loss of RXR function in hematopoietic cells resulted in formation of giant, nonresorbing osteoclasts and increased bone mass in male mice and protected female mice from bone loss following ovariectomy, which induces osteoporosis in WT females. The increase in bone mass associated with RXR deficiency was due to lack of expression of the RXR-dependent transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene family, protein B (MAFB) in osteoclast progenitors. Evaluation of osteoclast progenitor cells revealed that RXR homodimers directly target and bind to the Mafb promoter, and this interaction is required for proper osteoclast proliferation, differentiation, and activity. Pharmacological activation of RXRs inhibited osteoclast differentiation due to the formation of RXR/liver X receptor (LXR) heterodimers, which induced expression of sterol regulatory element binding protein-1c (SREBP-1c), resulting in indirect MAFB upregulation. Our study reveals that RXR signaling mediates bone homeostasis and suggests that RXRs have potential as targets for the treatment of bone pathologies such as osteoporosis. PMID:25574839

  16. Physiological bases of bone regeneration II. The remodeling process.

    PubMed

    Fernández-Tresguerres-Hernández-Gil, Isabel; Alobera-Gracia, Miguel Angel; del-Canto-Pingarrón, Mariano; Blanco-Jerez, Luis

    2006-03-01

    Bone remodeling is the restructuring process of existing bone, which is in constant resorption and formation. Under normal conditions, this balanced process allows the renewal of 5-10% of bone volume per year. At the microscopic level, bone remodeling is produced in basic multicellular units, where osteoclasts resorb a certain quantity of bone and osteoblasts form the osteoid matrix and mineralize it to fill the previously created cavity. These units contain osteoclasts, macrophages, preosteoblasts and osteoblasts, and are controlled by a series of factors, both general and local, allowing normal bone function and maintaining the bone mass. When this process becomes unbalanced then bone pathology appears, either in excess (osteopetrosis) or deficit (osteoporosis). The purpose of this study is to undertake a revision of current knowledge on the physiological and biological mechanisms of the bone remodeling process; highlighting the role played by the regulating factors, in particular that of the growth factors. PMID:16505794

  17. Adaptive scapula bone remodeling computational simulation: Relevance to regenerative medicine

    NASA Astrophysics Data System (ADS)

    Sharma, Gulshan B.; Robertson, Douglas D.

    2013-07-01

    Shoulder arthroplasty success has been attributed to many factors including, bone quality, soft tissue balancing, surgeon experience, and implant design. Improved long-term success is primarily limited by glenoid implant loosening. Prosthesis design examines materials and shape and determines whether the design should withstand a lifetime of use. Finite element (FE) analyses have been extensively used to study stresses and strains produced in implants and bone. However, these static analyses only measure a moment in time and not the adaptive response to the altered environment produced by the therapeutic intervention. Computational analyses that integrate remodeling rules predict how bone will respond over time. Recent work has shown that subject-specific two- and three dimensional adaptive bone remodeling models are feasible and valid. Feasibility and validation were achieved computationally, simulating bone remodeling using an intact human scapula, initially resetting the scapular bone material properties to be uniform, numerically simulating sequential loading, and comparing the bone remodeling simulation results to the actual scapula's material properties. Three-dimensional scapula FE bone model was created using volumetric computed tomography images. Muscle and joint load and boundary conditions were applied based on values reported in the literature. Internal bone remodeling was based on element strain-energy density. Initially, all bone elements were assigned a homogeneous density. All loads were applied for 10 iterations. After every iteration, each bone element's remodeling stimulus was compared to its corresponding reference stimulus and its material properties modified. The simulation achieved convergence. At the end of the simulation the predicted and actual specimen bone apparent density were plotted and compared. Location of high and low predicted bone density was comparable to the actual specimen. High predicted bone density was greater than actual

  18. Adaptive scapula bone remodeling computational simulation: Relevance to regenerative medicine

    SciTech Connect

    Sharma, Gulshan B.; Robertson, Douglas D.

    2013-07-01

    Shoulder arthroplasty success has been attributed to many factors including, bone quality, soft tissue balancing, surgeon experience, and implant design. Improved long-term success is primarily limited by glenoid implant loosening. Prosthesis design examines materials and shape and determines whether the design should withstand a lifetime of use. Finite element (FE) analyses have been extensively used to study stresses and strains produced in implants and bone. However, these static analyses only measure a moment in time and not the adaptive response to the altered environment produced by the therapeutic intervention. Computational analyses that integrate remodeling rules predict how bone will respond over time. Recent work has shown that subject-specific two- and three dimensional adaptive bone remodeling models are feasible and valid. Feasibility and validation were achieved computationally, simulating bone remodeling using an intact human scapula, initially resetting the scapular bone material properties to be uniform, numerically simulating sequential loading, and comparing the bone remodeling simulation results to the actual scapula’s material properties. Three-dimensional scapula FE bone model was created using volumetric computed tomography images. Muscle and joint load and boundary conditions were applied based on values reported in the literature. Internal bone remodeling was based on element strain-energy density. Initially, all bone elements were assigned a homogeneous density. All loads were applied for 10 iterations. After every iteration, each bone element’s remodeling stimulus was compared to its corresponding reference stimulus and its material properties modified. The simulation achieved convergence. At the end of the simulation the predicted and actual specimen bone apparent density were plotted and compared. Location of high and low predicted bone density was comparable to the actual specimen. High predicted bone density was greater than

  19. Remodeling of the bone material containing microcracks: A theoretical analysis

    NASA Astrophysics Data System (ADS)

    Ramtani, S.; Zidi, M.

    1999-12-01

    The question is, what happens when the bone loses its ability for load-driven adaptation, when damage is no longer repaired as it seems to be the case for bone loss associated with age, medication or disease? In this study, we tempt to show how damage can influence the remodeling process. A thermodynamic theoretical framework is therefore provided as a basis for a consistent formulation of bone remodeling involving a chemical reaction and mass transfer between two constituents in presence of microcracks.

  20. Alteration of proteoglycan sulfation affects bone growth and remodeling

    PubMed Central

    Gualeni, Benedetta; de Vernejoul, Marie-Christine; Marty-Morieux, Caroline; De Leonardis, Fabio; Franchi, Marco; Monti, Luca; Forlino, Antonella; Houillier, Pascal; Rossi, Antonio; Geoffroy, Valerie

    2013-01-01

    Diastrophic dysplasia (DTD) is a chondrodysplasia caused by mutations in the SLC26A2 gene, leading to reduced intracellular sulfate pool in chondrocytes, osteoblasts and fibroblasts. Hence, proteoglycans are undersulfated in the cartilage and bone of DTD patients. To characterize the bone phenotype of this skeletal dysplasia we used the Slc26a2 knock-in mouse (dtd mouse), that was previously validated as an animal model of DTD in humans. X-rays, bone densitometry, static and dynamic histomorphometry, and in vitro studies revealed a primary bone defect in the dtd mouse model. We showed in vivo that this primary bone defect in dtd mice is due to decreased bone accrual associated with a decreased trabecular and periosteal appositional rate at the cell level in one month-old mice. Although the osteoclast number evaluated by histomorphometry was not different in dtd compared to wild-type mice, urine analysis of deoxypyridinoline cross-links and serum levels of type I collagen C-terminal telopeptides showed a higher resorption rate in dtd mice compared to wild-type littermates. Electron microscopy studies showed that collagen fibrils in bone were thinner and less organized in dtd compared to wild-type mice. These data suggest that the low bone mass observed in mutant mice could possibly be linked to the different bone matrix compositions/organizations in dtd mice triggering changes in osteoblast and osteoclast activities. Overall, these results suggest that proteoglycan undersulfation not only affects the properties of hyaline cartilage, but can also lead to unbalanced bone modeling and remodeling activities, demonstrating the importance of proteoglycan sulfation in bone homeostasis. PMID:23369989

  1. Epigenetic Regulation of Bone Remodeling and Its Impacts in Osteoporosis.

    PubMed

    Ghayor, Chafik; Weber, Franz E

    2016-01-01

    Epigenetics describes mechanisms which control gene expression and cellular processes without changing the DNA sequence. The main mechanisms in epigenetics are DNA methylation in CpG-rich promoters, histone modifications and non-coding RNAs (ncRNAs). DNA methylation modifies the function of the DNA and correlates with gene silencing. Histone modifications including acetylation/deacetylation and phosphorylation act in diverse biological processes such as transcriptional activation/inactivation and DNA repair. Non-coding RNAs play a large part in epigenetic regulation of gene expression in addition to their roles at the transcriptional and post-transcriptional level. Osteoporosis is the most common skeletal disorder, characterized by compromised bone strength and bone micro-architectural deterioration that predisposes the bones to an increased risk of fracture. It is most often caused by an increase in bone resorption that is not sufficiently compensated by a corresponding increase in bone formation. Nowadays it is well accepted that osteoporosis is a multifactorial disorder and there are genetic risk factors for osteoporosis and bone fractures. Here we review emerging evidence that epigenetics contributes to the machinery that can alter DNA structure, gene expression, and cellular differentiation during physiological and pathological bone remodeling. PMID:27598138

  2. Bone ingrowth: an application of the boundary element method to bone remodeling at the implant interface.

    PubMed

    Sadegh, A M; Luo, G M; Cowin, S C

    1993-02-01

    Surface bone remodeling theory and the boundary element method are employed to investigate the microstructural remodeling of bone at the bone-implant interface. Three situations are considered: remodeling-induced penetration between the screw threads of an implanted screw, penetration of bone tissue into a slot or cavity in an implant, and the interaction of individual trabeculae in the remodeling processes near an implant. For each case the bone ingrowth is determined as a function of the geometry and the applied load. PMID:8429059

  3. Modalities for Visualization of Cortical Bone Remodeling: The Past, Present, and Future.

    PubMed

    Harrison, Kimberly D; Cooper, David M L

    2015-01-01

    Bone's ability to respond to load-related phenomena and repair microdamage is achieved through the remodeling process, which renews bone by activating groups of cells known as basic multicellular units (BMUs). The products of BMUs, secondary osteons, have been extensively studied via classic two-dimensional techniques, which have provided a wealth of information on how histomorphology relates to skeletal structure and function. Remodeling is critical in maintaining healthy bone tissue; however, in osteoporotic bone, imbalanced resorption results in increased bone fragility and fracture. With increasing life expectancy, such degenerative bone diseases are a growing concern. The three-dimensional (3D) morphology of BMUs and their correlation to function, however, are not well-characterized and little is known about the specific mechanisms that initiate and regulate their activity within cortical bone. We believe a key limitation has been the lack of 3D information about BMU morphology and activity. Thus, this paper reviews methodologies for 3D investigation of cortical bone remodeling and, specifically, structures associated with BMU activity (resorption spaces) and the structures they create (secondary osteons), spanning from histology to modern ex vivo imaging modalities, culminating with the growing potential of in vivo imaging. This collection of papers focuses on the theme of "putting the 'why' back into bone architecture." Remodeling is one of two mechanisms "how" bone structure is dynamically modified and thus an improved 3D understanding of this fundamental process is crucial to ultimately understanding the "why." PMID:26322017

  4. Subject-specific bone remodelling of the scapula.

    PubMed

    Quental, Carlos; Folgado, João; Fernandes, Paulo R; Monteiro, Jacinto

    2014-08-01

    Finite element analyses, with increasing levels of detail and complexity, are becoming effective tools to evaluate the performance of joint replacement prostheses and to predict the behaviour of bone. As a first step towards the study of the complications of shoulder arthroplasty, the aim of this work was the development and validation of a 3D finite element model of an intact scapula for the prediction of the bone remodelling process based on a previously published model that attempts to follow Wolff's law. The boundary conditions applied include full muscle and joint loads taken from a multibody system of the upper limb based on the same subject whose scapula was here analysed. To validate the bone remodelling simulations, qualitative and quantitative comparisons between the predicted and the specimen's bone density distribution were performed. The results showed that the bone remodelling model was able to successfully reproduce the actual bone density distribution of the analysed scapula. PMID:23210487

  5. Bone tissue remodeling and development: focus on matrix metalloproteinase functions.

    PubMed

    Paiva, Katiucia Batista Silva; Granjeiro, José Mauro

    2014-11-01

    Bone-forming cells originate from distinct embryological layers, mesoderm (axial and appendicular bones) and ectoderm (precursor of neural crest cells, which mainly form facial bones). These cells will develop bones by two principal mechanisms: intramembranous and endochondral ossification. In both cases, condensation of multipotent mesenchymal cells occurs, at the site of the future bone, which differentiate into bone and cartilage-forming cells. During long bone development, an initial cartilaginous template is formed and replaced by bone in a coordinated and refined program involving chondrocyte proliferation and maturation, vascular invasion, recruitment of adult stem cells and intense remodeling of cartilage and bone matrix. Matrix metalloproteinases (MMPs) are the most important enzymes for cleaving structural components of the extracellular matrix (ECM), as well as other non-ECM molecules in the ECM space, pericellular perimeter and intracellularly. Thus, the bioactive molecules generated act on several biological events, such as development, tissue remodeling and homeostasis. Since the discovery of collagenase in bone cells, more than half of the MMP members have been detected in bone tissues under both physiological and pathological conditions. Pivotal functions of MMPs during development and bone regeneration have been revealed by knockout mouse models, such as chondrocyte proliferation and differentiation, osteoclast recruitment and function, bone modeling, coupling of bone resorption and formation (bone remodeling), osteoblast recruitment and survival, angiogenesis, osteocyte viability and function (biomechanical properties); as such alterations in MMP function may alter bone quality. In this review, we look at the principal properties of MMPs and their inhibitors (TIMPs and RECK), provide an up-date on their known functions in bone development and remodeling and discuss their potential application to Bone Bioengineering. PMID:25157440

  6. 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-μm 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

  7. Chemistry of bone remodelling preserved in extant and fossil Sirenia.

    PubMed

    Anné, Jennifer; Wogelius, Roy A; Edwards, Nicholas P; van Veelen, Arjen; Ignatyev, Konstantin; Manning, Phillip L

    2016-05-01

    Bone remodelling is a crucial biological process needed to maintain elemental homeostasis. It is important to understand the trace elemental inventories that govern these processes as malfunctions in bone remodelling can have devastating effects on an organism. In this study, we use a combination of X-ray techniques to map, quantify, and characterise the coordination chemistry of trace elements within the highly remodelled bone tissues of extant and extinct Sirenia (manatees and dugongs). The dense bone structure and unique body chemistry of sirenians represent ideal tissues for studying both high remodelling rates as well as unique fossilisation pathways. Here, elemental maps revealed uncorrelated patterning of Ca and Zn within secondary osteons in both extant and fossil sirenians, as well as elevated Sr within the connecting canals of fossil sirenians. Concentrations of these elements are comparable between extant and fossil material indicating geochemical processing of the fossil bone has been minimal. Zn was found to be bound in the same coordination within the apatite structure in both extant and fossil bone. Accurate quantification of trace elements in extant material was only possible when the organic constituents of the bone were included. The comparable distributions, concentrations, and chemical coordination of these physiologically important trace elements indicate the chemistry of bone remodelling has been preserved for 19 million years. This study signifies the powerful potential of merging histological and chemical techniques in the understanding of physiological processes in both extant and extinct vertebrates. PMID:26923825

  8. Exploring the Bone Proteome to Help Explain Altered Bone Remodeling and Preservation of Bone Architecture and Strength in Hibernating Marmots.

    PubMed

    Doherty, Alison H; Roteliuk, Danielle M; Gookin, Sara E; McGrew, Ashley K; Broccardo, Carolyn J; Condon, Keith W; Prenni, Jessica E; Wojda, Samantha J; Florant, Gregory L; Donahue, Seth W

    2016-01-01

    Periods of physical inactivity increase bone resorption and cause bone loss and increased fracture risk. However, hibernating bears, marmots, and woodchucks maintain bone structure and strength, despite being physically inactive for prolonged periods annually. We tested the hypothesis that bone turnover rates would decrease and bone structural and mechanical properties would be preserved in hibernating marmots (Marmota flaviventris). Femurs and tibias were collected from marmots during hibernation and in the summer following hibernation. Bone remodeling was significantly altered in cortical and trabecular bone during hibernation with suppressed formation and no change in resorption, unlike the increased bone resorption that occurs during disuse in humans and other animals. Trabecular bone architecture and cortical bone geometrical and mechanical properties were not different between hibernating and active marmots, but bone marrow adiposity was significantly greater in hibernators. Of the 506 proteins identified in marmot bone, 40 were significantly different in abundance between active and hibernating marmots. Monoaglycerol lipase, which plays an important role in fatty acid metabolism and the endocannabinoid system, was 98-fold higher in hibernating marmots compared with summer marmots and may play a role in regulating the changes in bone and fat metabolism that occur during hibernation. PMID:27617358

  9. Bone remodeling rates and skeletal maturation in three archaeological skeletal populations.

    PubMed

    Stout, S D; Lueck, R

    1995-10-01

    Cortical bone remodeling rates for rib samples from three archaeological populations and a modern autopsy sample were determined using an algorithm developed by Frost (Frost [1987a] Calcif. Tissue Res. 3:211-237). When plotted against the relative antiquities for population samples, histomorphometric variables; i.e., activation frequency (mu rc), net bone formation (netVf,r,t), and mean annual bone formation rate (Vf,r,t), exhibit a concordant trend of increased cortical bone remodeling activity levels over time. Two intensive foraging populations, Windover and Gibson, are similar for all bone remodeling parameters and have the lowest remodeling activity levels among the samples. The more recent Ledders sample, which is reported to practice agricultural subsistence, is consistently intermediate between these and a modern autopsy sample. Although there appear to be differences in bone formation rates among the populations it is concluded that these differences cannot be attributed to differences in bone remodeling rates among the populations, but rather are reflecting different effective ages of adult compacta for their ribs. These findings suggest that the earlier populations, particularly Windsor and Gibson, appear to have reached skeletal maturity at an older age than observed for modern. PMID:8644877

  10. Static versus dynamic loads as an influence on bone remodelling

    NASA Technical Reports Server (NTRS)

    Lanyon, L. E.; Rubin, C. T.

    1983-01-01

    Bone remodelling activity in the avian ulna was assessed under conditions of disuse alone, disuse with a superimposed continuous compressive load, and disuse interrupted by a short daily period of intermittent loading. The ulna preparation is made by two submetaphyseal osteotomies, the cut ends of the bone being covered with stainless steel caps which, together with the bone they enclosed, are pierced by pins emerging transcutaneously on the dorsal and ventral surfaces of the wing. The 110 mm long undisturbed section of the bone shaft can be protected from functional loading, loaded continuously in compression by joining the pins with springs, or loaded intermittently in compression by engaging the pins in an Instron machine. Similar loads (525 n) were used in both static and dynamic cases engendering similar peak strains at the bone's midshaft (-2000 x 10-6). The intermitent load was applied at a frequency of 1 Hz during a single 100 second period per day as a ramped square wave, with a rate of change of strain during the ramp of 0.01 per second.

  11. Trabecular bone remodelling simulated by a stochastic exchange of discrete bone packets from the surface.

    PubMed

    Hartmann, M A; Dunlop, J W C; Bréchet, Y J M; Fratzl, P; Weinkamer, R

    2011-08-01

    Human bone is constantly renewed through life via the process of bone remodelling, in which individual packets of bone are removed by osteoclasts and replaced by osteoblasts. Remodelling is mechanically controlled, where osteocytes embedded within the bone matrix are thought to act as mechanical sensors. In this computational work, a stochastic model for bone remodelling is used in which the renewal of bone material occurs by exchange of discrete bone packets. We tested different hypotheses of how the mechanical stimulus for bone remodelling is integrated by osteocytes and sent to actor cells on the bone's surface. A collective (summed) signal from multiple osteocytes as opposed to an individual (maximal) signal from a single osteocyte was found to lead to lower inner porosity and surface roughness of the simulated bone structure. This observation can be interpreted in that collective osteocyte signalling provides an effective surface tension to the remodelling process. Furthermore, the material heterogeneity due to remodelling was studied on a network of trabeculae. As the model is discrete, the age of individual bone packets can be monitored with time. The simulation results were compared with experimental data coming from quantitative back scattered electron imaging by transforming the information about the age of the bone packet into a mineral content. Discrepancies with experiments indicate that osteoclasts preferentially resorb low mineralized, i.e. young, bone at the bone's surface. PMID:21616469

  12. Hierarchical Structure and Repair of Bone: Deformation, Remodelling, Healing

    NASA Astrophysics Data System (ADS)

    Fratzl, Peter; Weinkamer, Richard

    The design of natural materials follows a radically different paradigm as compared to engineering materials: organs are growing rather than being fabricated. As a main consequence, adaptation to changing conditions remains possible during the whole lifetime of a biological material. As a typical example of such a biological material, bone is constantly laid down by bone forming cells, osteoblasts, and removed by bone resorbing cells, osteoclasts. With this remodelling cycle of bone resorption and formation, the skeleton is able to adapt to changing needs at all levels of structural hierarchy. The hierarchical structure of bone is summarized in the second part of this chapter.

  13. The role of microRNAs in bone remodeling

    PubMed Central

    Jing, Dian; Hao, Jin; Shen, Yu; Tang, Ge; Li, Mei-Le; Huang, Shi-Hu; Zhao, Zhi-He

    2015-01-01

    Bone remodeling is balanced by bone formation and bone resorption as well as by alterations in the quantities and functions of seed cells, leading to either the maintenance or deterioration of bone status. The existing evidence indicates that microRNAs (miRNAs), known as a family of short non-coding RNAs, are the key post-transcriptional repressors of gene expression, and growing numbers of novel miRNAs have been verified to play vital roles in the regulation of osteogenesis, osteoclastogenesis, and adipogenesis, revealing how they interact with signaling molecules to control these processes. This review summarizes the current knowledge of the roles of miRNAs in regulating bone remodeling as well as novel applications for miRNAs in biomaterials for therapeutic purposes. PMID:26208037

  14. Nutritional modulators of bone remodeling during aging.

    PubMed

    Mundy, Gregory R

    2006-02-01

    Bone mass declines progressively with age in both men and women from the age of approximately 30 y. Increased longevity will inevitability be associated with an increase in the incidence of osteoporosis, its associated complications, and incurred health care costs. Current pharmacologic approaches focus on inhibiting bone resorption in those with osteoporosis but do little to improve bone mass. Increased understanding of the cellular events responsible for normal bone formation has led to multiple pathways that can be targeted to positively influence bone mass. Bone morphogenetic proteins (BMPs) have been shown to stimulate bone formation, and the BMP2 gene was recently linked to osteoporosis. BMP-2 therefore represents one potential molecular target to identify new agents to simulate bone formation. Research is accumulating on the positive effects of dietary sources that stimulate the BMP2 promoter and their effects on bone formation. Flavonoids and statins occur naturally in food products and have been shown to promote bone formation. It may be possible to influence peak bone mass by dietary means and to decrease the risk of osteoporosis in later life. To ease the future burden of osteoporosis, focusing on prevention will be key, and this could include dietary interventions to stimulate bone formation. PMID:16470007

  15. A mathematical model of cortical bone remodeling at cellular level under mechanical stimulus

    NASA Astrophysics Data System (ADS)

    Qin, Qing-Hua; Wang, Ya-Nan

    2012-12-01

    A bone cell population dynamics model for cortical bone remodeling under mechanical stimulus is developed in this paper. The external experiments extracted from the literature which have not been used in the creation of the model are used to test the validity of the model. Not only can the model compare reasonably well with these experimental results such as the increase percentage of final values of bone mineral content (BMC) and bone fracture energy (BFE) among different loading schemes (which proves the validity of the model), but also predict the realtime development pattern of BMC and BFE, as well as the dynamics of osteoblasts (OBA), osteoclasts (OCA), nitric oxide (NO) and prostaglandin E2 (PGE2) for each loading scheme, which can hardly be monitored through experiment. In conclusion, the model is the first of its kind that is able to provide an insight into the quantitative mechanism of bone remodeling at cellular level by which bone cells are activated by mechanical stimulus in order to start resorption/formation of bone mass. More importantly, this model has laid a solid foundation based on which future work such as systemic control theory analysis of bone remodeling under mechanical stimulus can be investigated. The to-be identified control mechanism will help to develop effective drugs and combined nonpharmacological therapies to combat bone loss pathologies. Also this deeper understanding of how mechanical forces quantitatively interact with skeletal tissue is essential for the generation of bone tissue for tissue replacement purposes in tissue engineering.

  16. Effect of strontium-containing hydroxyapatite bone cement on bone remodeling following hip replacement.

    PubMed

    Ni, Guo X; Lin, Jian H; Chiu, Peter K Y; Li, Zhao Y; Lu, William W

    2010-01-01

    It is uncertain whether the use of bioactive bone cement has any beneficial effect on local bone adaptation following hip replacement. In this study, twelve goats underwent cemented hip hemiarthroplasty unilaterally, with either PMMA bone cement or strontium-containing hydroxyapatite (Sr-HA) bioactive bone cement. Nine months later, the femoral cortical bones at different levels were analyzed by microhardness testing and micro-CT scanning. Extensive bone remodeling was found at proximal and mid-levels in both PMMA and Sr-HA groups. However, with regard to the differences of bone mineral density, cortical bone area and bone hardness between implanted and non-implanted femur, less decreases were found in Sr-HA group than PMMA group at proximal and mid-levels, and significant differences were shown for bone area and hardness at proximal level. The results suggested that the use of Sr-HA cement might alleviate femoral bone remodeling after hip replacement. PMID:19728042

  17. Intracortical remodeling parameters are associated with measures of bone robustness

    PubMed Central

    Goldman, Haviva M.; Hampson, Naomi A.; Guth, J. Jared; Lin, David; Jepsen, Karl J.

    2014-01-01

    Prior work identified a novel association between bone robustness and porosity, which may be part of a broader interaction whereby the skeletal system compensates for the natural variation in robustness (bone width relative to length) by modulating tissue-level mechanical properties to increase stiffness of slender bones and to reduce mass of robust bones. To further understand this association, we tested the hypothesis that the relationship between robustness and porosity is mediated through intracortical, BMU-based (basic multicellular unit) remodeling. We quantified cortical porosity, mineralization, and histomorphometry at two sites (38 and 66% of the length) in human cadaveric tibiae. We found significant correlations between robustness and several histomorphometric variables (e.g., % secondary tissue [R2 = 0.68, p < 0.004], total osteon area [R2=0.42, p<0.04]) at the 66% site. Although these associations were weaker at the 38% site, significant correlations between histological variables were identified between the two sites indicating that both respond to the same global effects and demonstrate a similar character at the whole bone level. Thus, robust bones tended to have larger and more numerous osteons with less infilling, resulting in bigger pores and more secondary bone area. These results suggest that local regulation of BMU-based remodeling may be further modulated by a global signal associated with robustness, such that remodeling is suppressed in slender bones but not in robust bones. Elucidating this mechanism further is crucial for better understanding the complex adaptive nature of the skeleton, and how inter-individual variation in remodeling differentially impacts skeletal aging and an individuals’ potential response to prophylactic treatments. PMID:24962664

  18. The Digital Astronaut Project Bone Remodeling Model

    NASA Technical Reports Server (NTRS)

    Pennline, J. A.; Mulugeta, L.; Lewandowski, B. E.; Thompson, W. K.; Sibonga, J. D.

    2013-01-01

    One of the main objectives is to provide a tool to help HHC address Bone Gap Osteo 4: We don't know the contribution of each risk factor on bone loss and recovery of bone strength and which factors are the best targets for countermeasure application; and Osteo7: We need to identify options for mitigation of early onset osteoporosis before, during, and after spaceflight.

  19. Remodeling of tissue-engineered bone structures in vivo.

    PubMed

    Hofmann, Sandra; Hilbe, Monika; Fajardo, Robert J; Hagenmüller, Henri; Nuss, Katja; Arras, Margarete; Müller, Ralph; von Rechenberg, Brigitte; Kaplan, David L; Merkle, Hans P; Meinel, Lorenz

    2013-09-01

    Implant design for bone regeneration is expected to be optimized when implant structures resemble the anatomical situation of the defect site. We tested the validity of this hypothesis by exploring the feasibility of generating different in vitro engineered bone-like structures originating from porous silk fibroin scaffolds decorated with RGD sequences (SF-RGD), seeded with human mesenchymal stem cells (hMSC). Scaffolds with small (106-212 μm), medium (212-300 μm), and large pore diameter ranges (300-425 μm) were seeded with hMSC and subsequently differentiated in vitro into bone-like tissue resembling initial scaffold geometries and featuring bone-like structures. Eight weeks after implantation into calvarial defects in mice, the in vitro engineered bone-like tissues had remodeled into bone featuring different proportions of woven/lamellar bone bridging the defects. Regardless of pore diameter, all implants integrated well, vascularization was advanced, and bone marrow ingrowth had started. Ultimately, in this defect model, the geometry of the in vitro generated tissue-engineered bone structure, trabecular- or plate-like, had no significant impact on the healing of the defect, owing to an efficient remodeling of its structure after implantation. PMID:23958323

  20. Remodeling of tissue-engineered bone structures in vivo

    PubMed Central

    Hofmann, Sandra; Hilbe, Monika; Fajardo, Robert J.; Hagenmüller, Henri; Nuss, Katja; Arras, Margarete; Müller, Ralph; von Rechenberg, Brigitte; Kaplan, David L.; Merkle, Hans P.; Meinel, Lorenz

    2013-01-01

    Implant design for bone regeneration is expected to be optimized when implant structures resemble the anatomical situation of the defect site. We tested the validity of this hypothesis by exploring the feasibility of generating different in vitro engineered bone-like structures originating from porous silk fibroin scaffolds decorated with RGD sequences (SF-RGD), seeded with human mesenchymal stem cells (hMSC). Scaffolds with small (106 – 212 μm), medium (212 – 300 μm) and large pore diameter ranges (300 – 425 μm) were seeded with hMSC and subsequently differentiated in vitro into bone-like tissue resembling initial scaffold geometries and featuring bone-like structures. Eight weeks after implantation into calvarial defects in mice, the in vitro engineered bone-like tissues had remodeled into bone featuring different proportions of woven/lamellar bone bridging the defects. Regardless of pore diameter all implants integrated well, vascularization was advanced and, bone marrow ingrowth had started. Ultimately, in this defect model, the geometry of the in vitro generated tissue-engineered bone structure, trabecular- or plate-like, had no significant impact on the healing of the defect, owing to an efficient remodeling of its structure after implantation. PMID:23958323

  1. The Digital Astronaut Project Bone Remodeling Model

    NASA Technical Reports Server (NTRS)

    Pennline, James A.; Mulugeta, Lealem; Lewandowski, Beth E.; Thompson, William K.; Sibonga, Jean D.

    2014-01-01

    Under the conditions of microgravity, astronauts lose bone mass at a rate of 1% to 2% a month, particularly in the lower extremities such as the proximal femur: (1) The most commonly used countermeasure against bone loss has been prescribed exercise, (2) However, current exercise countermeasures do not completely eliminate bone loss in long duration, 4 to 6 months, spaceflight, (3,4) leaving the astronaut susceptible to early onset osteoporosis and a greater risk of fracture later in their lives. The introduction of the Advanced Resistive Exercise Device, coupled with improved nutrition, has further minimized the 4 to 6 month bone loss. But further work is needed to implement optimal exercise prescriptions, and (5) In this light, NASA's Digital Astronaut Project (DAP) is working with NASA physiologists to implement well-validated computational models that can help understand the mechanisms of bone demineralization in microgravity, and enhance exercise countermeasure development.

  2. Retinoid Receptors in Bone and Their Role in Bone Remodeling

    PubMed Central

    Henning, Petra; Conaway, H. Herschel; Lerner, Ulf H.

    2015-01-01

    Vitamin A (retinol) is a necessary and important constituent of the body which is provided by food intake of retinyl esters and carotenoids. Vitamin A is known best for being important for vision, but in addition to the eye, vitamin A is necessary in numerous other organs in the body, including the skeleton. Vitamin A is converted to an active compound, all-trans-retinoic acid (ATRA), which is responsible for most of its biological actions. ATRA binds to intracellular nuclear receptors called retinoic acid receptors (RARα, RARβ, RARγ). RARs and closely related retinoid X receptors (RXRα, RXRβ, RXRγ) form heterodimers which bind to DNA and function as ligand-activated transcription factors. It has been known for many years that hypervitaminosis A promotes skeleton fragility by increasing osteoclast formation and decreasing cortical bone mass. Some epidemiological studies have suggested that increased intake of vitamin A and increased serum levels of retinoids may decrease bone mineral density and increase fracture rate, but the literature on this is not conclusive. The current review summarizes how vitamin A is taken up by the intestine, metabolized, stored in the liver, and processed to ATRA. ATRA’s effects on formation and activity of osteoclasts and osteoblasts are outlined, and a summary of clinical data pertaining to vitamin A and bone is presented. PMID:25814978

  3. Miniplates and mini-implants: bone remodeling as their biological foundation1

    PubMed Central

    Consolaro, Alberto

    2015-01-01

    Abstract The tridimensional network formed by osteocytes controls bone design by coordinating cell activity on trabecular and cortical bone surfaces, especially osteoblasts and clasts. Miniplates and mini-implants provide anchorage, allowing all other orthodontic and orthopedic components, albeit afar, to deform and stimulate the network of osteocytes to command bone design remodeling upon "functional demand" established by force and its vectors. By means of transmission of forces, whether near or distant, based on anchorage provided by miniplates, it is possible to change the position, shape and size as well as the relationship established between the bones of the jaws. Understanding bone biology and the continuous remodeling of the skeleton allows the clinician to perform safe and accurate rehabilitation treatment of patients, thus increasing the possibilities and types of intervention procedures to be applied in order to restore patient's esthetics and function. PMID:26691966

  4. Uranium inhibits bone formation in physiologic alveolar bone modeling and remodeling

    SciTech Connect

    Ubios, A.M.; Guglielmotti, M.B.; Steimetz, T.; Cabrini, R.L. )

    1991-02-01

    The toxic effect of uranium (U) on bone modeling and remodeling was studied by performing histomorphometric measurements in the periodontal cortical bone of rats. Two different single intraperitoneal doses of uranyl nitrate (238U) were administered to two sets of rats respectively (2 and 0.8 mg/kg body wt). Rats treated with the first dose were killed 14 days postinjection (PI) and those treated with the second were killed 14, 30, and 60 days PI. The results revealed a decrease in bone formation in rats treated with uranium. On the remodeling side the decrease in bone formation was coupled to an increase in bone resorption on the 14th day PI. On the modeling side no bone resorption was observed and the decrease in bone formation was linked to an increase in resting bone zones. Bone formation depression as a key event in U intoxication is stressed.

  5. Modalities for Visualization of Cortical Bone Remodeling: The Past, Present, and Future

    PubMed Central

    Harrison, Kimberly D.; Cooper, David M. L.

    2015-01-01

    Bone’s ability to respond to load-related phenomena and repair microdamage is achieved through the remodeling process, which renews bone by activating groups of cells known as basic multicellular units (BMUs). The products of BMUs, secondary osteons, have been extensively studied via classic two-dimensional techniques, which have provided a wealth of information on how histomorphology relates to skeletal structure and function. Remodeling is critical in maintaining healthy bone tissue; however, in osteoporotic bone, imbalanced resorption results in increased bone fragility and fracture. With increasing life expectancy, such degenerative bone diseases are a growing concern. The three-dimensional (3D) morphology of BMUs and their correlation to function, however, are not well-characterized and little is known about the specific mechanisms that initiate and regulate their activity within cortical bone. We believe a key limitation has been the lack of 3D information about BMU morphology and activity. Thus, this paper reviews methodologies for 3D investigation of cortical bone remodeling and, specifically, structures associated with BMU activity (resorption spaces) and the structures they create (secondary osteons), spanning from histology to modern ex vivo imaging modalities, culminating with the growing potential of in vivo imaging. This collection of papers focuses on the theme of “putting the ‘why’ back into bone architecture.” Remodeling is one of two mechanisms “how” bone structure is dynamically modified and thus an improved 3D understanding of this fundamental process is crucial to ultimately understanding the “why.” PMID:26322017

  6. Prediction of denosumab effects on bone remodeling: A combined pharmacokinetics and finite element modeling.

    PubMed

    Hambli, Ridha; Boughattas, Mohamed Hafedh; Daniel, Jean-Luc; Kourta, Azeddine

    2016-07-01

    Denosumab is a fully human monoclonal antibody that inhibits receptor activator of nuclearfactor-kappa B ligand (RANKL). This key mediator of osteoclast activities has been shown to inhibit osteoclast differentiation and hence, to increase bone mineral density (BMD) in treated patients. In the current study, we develop a computer model to simulate the effects of denosumab treatments (dose and duration) on the proximal femur bone remodeling process quantified by the variation in proximal femur BMD. The simulation model is based on a coupled pharmacokinetics model of denosumab with a pharmacodynamics model consisting of a mechanobiological finite element remodeling model which describes the activities of osteoclasts and osteoblasts. The mechanical behavior of bone is described by taking into account the bone material fatigue damage accumulation and mineralization. A coupled strain-damage stimulus function is proposed which controls the level of bone cell autocrine and paracrine factors. The cellular behavior is based on Komarova et al.׳s (2003) dynamic law which describes the autocrine and paracrine interactions between osteoblasts and osteoclasts and computes cell population dynamics and changes in bone mass at a discrete site of bone remodeling. Therefore, when an external mechanical stress is applied, bone formation and resorption is governed by cell dynamics rather than by adaptive elasticity approaches. The proposed finite element model was implemented in the finite element code Abaqus (UMAT routine). In order to perform a preliminary validation, in vivo human proximal femurs were selected and scanned at two different time intervals (at baseline and at a 36-month interval). Then, a 3D FE model was generated and the denosumab-remodeling algorithm was applied to the scans at t0 simulating daily walking activities for a duration of 36 months. The predicted results (density variation) were compared to existing published ones performed on a human cohort (FREEDOM

  7. Osteoprotegerin in breast cancer: beyond bone remodeling.

    PubMed

    Weichhaus, Michael; Chung, Stephanie Tsang Mui; Connelly, Linda

    2015-01-01

    Osteoprotegerin (OPG) is a secreted protein and member of the Tumor Necrosis Factor (TNF) Receptor superfamily. OPG has been well characterized as a regulator of bone metabolism which acts by blocking osteoclast maturation and preventing bone breakdown. Given this role, early studies on OPG in breast cancer focused on the administration of OPG in order to prevent the osteolysis observed with bone metastases. However OPG is also produced by the breast tumor cells themselves. Research focusing on OPG produced by breast tumor cells has revealed actions of OPG which promote tumor progression. In vitro studies into the role of OPG produced by breast tumor cells have demonstrated that OPG can block TNF-related apoptosis inducing ligand (TRAIL)-mediated apoptosis. Furthermore, in vivo studies show that OPG expression by breast tumors can promote tumor growth and metastasis. In addition it has been shown that OPG stimulates endothelial cell survival and tube formation thus it may indirectly promote breast tumor progression through impacting angiogenesis. This article will present a summary of the data concerning the tumor-promoting effects of OPG in breast cancer. PMID:26054853

  8. Integration of a Finite Element Model with the DAP Bone Remodeling Model to Characterize Bone Response to Skeletal Loading

    NASA Technical Reports Server (NTRS)

    Werner, Christopher R.; Mulugeta, Lealem; Myers, J. G.; Pennline, J. A.

    2015-01-01

    NASA's Digital Astronaut Project (DAP) has developed a bone remodeling model that has been validated for predicting volumetric bone mineral density (vBMD) changes of trabecular and cortical bone in the absence of mechanical loading. The model was recently updated to include skeletal loading from exercise and free living activities to maintain healthy bone using a new daily load stimulus (DLS). This new formula was developed based on an extensive review of existing DLS formulas, as discussed in the abstract by Pennline et al. The DLS formula incorporated into the bone remodeling model utilizes strains and stress calculated from finite element model (FEM) of the bone region of interest. The proximal femur was selected for the initial application of the DLS formula, with a specific focus on the femoral neck. METHODS: The FEM was generated from CAD geometry of a femur using de-identified CT data. The femur was meshed using linear tetrahedral elements Figure (1) with higher mesh densities in the femoral neck region, which is the primary region of interest for the initial application of the DLS formula in concert with the DAP bone remodeling model. Nodal loads were applied to the femoral head and the greater trochanter and the base of the femur was held fixed. An L2 norm study was conducted to reduce the length of the femoral shaft without significantly impacting the stresses in the femoral neck. The material properties of the FEM of the proximal femur were separated between cortical and trabecular regions to work with the bone remodeling model. Determining the elements with cortical material properties in the FEM was based off of publicly available CT hip scans [4] that were segmented, cleaned, and overlaid onto the FEM.

  9. Probabilistic Study of Bone Remodeling Using Finite Element Analysis

    NASA Astrophysics Data System (ADS)

    Werner, C.; Gorla, R. S. R.

    2013-08-01

    The dynamic bone remodeling process is a computationally challenging research area that struggles to understand the actual mechanisms. It has been observed that a mechanical stimulus in the bone greatly affects the remodeling process. A 3D finite element model of a femur is created and a probabilistic analysis is performed on the model. The probabilistic analysis measures the sensitivities of various parameters related to the material properties, geometric properties, and the three load cases defined as Single Leg Stance, Abduction, and Adduction. The sensitivity of each parameter is based on the calculated maximum mechanical stimulus and analyzed at various values of probabilities ranging from 0.001 to 0.999. The analysis showed that the parameters associated with the Single Leg Stance load case had the highest sensitivity with a probability of 0.99 and the angle of the force applied to the joint of the proximal femur had the overall highest sensitivity

  10. Twelve Months of Voluntary Heavy Alcohol Consumption in Male Rhesus Macaques Suppresses Intracortical Bone Remodeling

    PubMed Central

    Gaddini, Gino W.; Grant, Kathleen A.; Woodall, Andrew; Stull, Cara; Maddalozzo, Gianni F.; Zhang, Bo; Turner, Russell T.; Iwaniec, Urszula T.

    2015-01-01

    Chronic heavy alcohol consumption is a risk factor for cortical bone fractures in males. The increase in fracture risk may be due, in part, to reduced bone quality. Intracortical (osteonal) bone remodeling is the principle mechanism for maintaining cortical bone quality. However, it is not clear how alcohol abuse impacts intracortical bone remodeling. This study investigated the effects of long-duration heavy alcohol consumption on intracortical bone remodeling in a non-human primate model. Following a 4-month induction period, male rhesus macaques (Macaca mulatta, n = 21) were allowed to voluntarily self-administer water or alcohol (4% ethanol w/v) for 22 h/d, 7 d/wk for 12 months. Control monkeys (n = 13) received water and an isocaloric maltose-dextrin solution. Tetracycline hydrochloride was administered orally 17 and 3 days prior to sacrifice for determination of active mineralization sites. Animals in the alcohol group consumed 2.7 ± 0.2 g alcohol/kg/d (mean ± SE) during the 12 months of self-administration, resulting in a mean daily blood alcohol concentration of 77 ± 9 mg/dl from samples taken at 7 h after the start of a daily session. However, blood alcohol concentration varied widely from day to day, with peak levels exceeding 250 mg/dl, modeling a binge-drinking pattern of alcohol consumption. The skeletal response to alcohol was determined by densitometry, microcomputed tomography and histomorphometry. Significant differences in tibial bone mineral content, bone mineral density, and cortical bone architecture (cross-sectional volume, cortical volume, marrow volume, cortical thickness, and polar moment of inertia) in the tibial diaphysis were not detected with treatment. However, cortical porosity was lower (1.8 ± 0.5 % versus 0.6 ± 0.1 %, p = 0.021) and labeled osteon density was lower (0.41 ± 0.2/mm2 versus 0.04 ± 0.01/mm2, p < 0.003) in alcohol-consuming monkeys compared to controls, indicating a reduced rate of intracortical bone remodeling

  11. Effect of subchronic exposure to tetradifon on bone remodelling and metabolism in female rat.

    PubMed

    Badraoui, Riadh; Abdelmoula, Nouha Bouayed; Sahnoun, Zouhaier; Fakhfakh, Zouhaier; Rebai, Tarek

    2007-12-01

    This study investigates the effect of subchronic exposure to tetradifon, an organochlorine pesticide with an oestrogen-like structure, in female rat. A single cumulative dose of 2430 mg/kg BW was administrated orally for 12 female rats of 190 g BW. Twelve non-treated additional rats have served as controls. Animals were sacrificed after 6 and 12 weeks of treatment. We studied bone remodelling through histomorphometry and scanning electron microscopy (SEM) analyses. The serum and the right femora were used to determine phosphatase alkaline (AlkP) and/or calcium and phosphorus content. No sign of toxicity was observed until the end of the experiment. The SEM results revealed no structural alteration of the treated animal bone tissue. However, in both treated groups, we have noted an increase in the trabecular distance and a heterogeneous aspect of the endosteum that could be explained by bone-remodelling disturbance, with relative delay of ossification. Following histomorphomotric analysis, these results were coupled with significant increases in Tb.Th and OS/BS. Elsewhere, tetradifon intoxication increased significant serum AlkP level in the group treated for 12 weeks, which could be explained by an osteoblastic hyperactivity. Tetradifon intoxication decreased significantly bone calcium end phosphorus contents. Tetradifon seems not to exert major effects on bone remodelling. However, the osteoblastic hyperactivity could be explained by the oestrogen-like activity of tetradifon and its fatty metabolism. In fact, oestrogen inhibits bone remodelling, and enhances bone formation, which could result in an increase of the osteoid surface and explain the relative delay of ossification. PMID:18068648

  12. Simulating Bone Loss in Microgravity Using Mathematical Formulations of Bone Remodeling

    NASA Technical Reports Server (NTRS)

    Pennline, James A.

    2009-01-01

    Most mathematical models of bone remodeling are used to simulate a specific bone disease, by disrupting the steady state or balance in the normal remodeling process, and to simulate a therapeutic strategy. In this work, the ability of a mathematical model of bone remodeling to simulate bone loss as a function of time under the conditions of microgravity is investigated. The model is formed by combining a previously developed set of biochemical, cellular dynamics, and mechanical stimulus equations in the literature with two newly proposed equations; one governing the rate of change of the area of cortical bone tissue in a cross section of a cylindrical section of bone and one governing the rate of change of calcium in the bone fluid. The mechanical stimulus comes from a simple model of stress due to a compressive force on a cylindrical section of bone which can be reduced to zero to mimic the effects of skeletal unloading in microgravity. The complete set of equations formed is a system of first order ordinary differential equations. The results of selected simulations are displayed and discussed. Limitations and deficiencies of the model are also discussed as well as suggestions for further research.

  13. Urokinase plasminogen activator gene deficiency inhibits fracture cartilage remodeling.

    PubMed

    Popa, Nicoleta L; Wergedal, Jon E; Lau, K-H William; Mohan, Subburaman; Rundle, Charles H

    2014-03-01

    Urokinase plasminogen activator (uPA) regulates a proteolytic cascade of extracellular matrix degradation that functions in tissue development and tissue repair. The development and remodeling of the skeletal extracellular matrix during wound healing suggests that uPA might regulate bone development and repair. To determine whether uPA functions regulate bone development and repair, we examined the basal skeletal phenotype and endochondral bone fracture repair in uPA-deficient mice. The skeletal phenotype of uPA knockout mice was compared with that of control mice under basal conditions by dual-energy X-ray absorptiometry and micro-CT analysis, and during femur fracture repair by micro-CT and histological examination of the fracture callus. No effects of uPA gene deficiency were observed in the basal skeletal phenotype of the whole body or the femur. However, uPA gene deficiency resulted in increased fracture callus cartilage abundance during femur fracture repair at 14 days healing. The increase in cartilage corresponded to reduced tartrate-resistant acid phosphatase (TRAP) staining for osteoclasts in the uPA knockout fracture callus at this time, consistent with impaired osteoclast-mediated remodeling of the fracture cartilage. CD31 staining was reduced in the knockout fracture tissues at this time, suggesting that angiogenesis was also reduced. Osteoclasts also colocalized with CD31 expression in the endothelial cells of the fracture tissues during callus remodeling. These results indicate that uPA promotes remodeling of the fracture cartilage by osteoclasts that are associated with angiogenesis and suggest that uPA promotes angiogenesis and remodeling of the fracture cartilage at this time of bone fracture repair. PMID:23700285

  14. A supra-cellular model for coupling of bone resorption to formation during remodeling: lessons from two bone resorption inhibitors affecting bone formation differently.

    PubMed

    Jensen, Pia Rosgaard; Andersen, Thomas Levin; Pennypacker, Brenda L; Duong, Le T; Engelholm, Lars H; Delaissé, Jean-Marie

    2014-01-10

    The bone matrix is maintained functional through the combined action of bone resorbing osteoclasts and bone forming osteoblasts, in so-called bone remodeling units. The coupling of these two activities is critical for securing bone replenishment and involves osteogenic factors released by the osteoclasts. However, the osteoclasts are separated from the mature bone forming osteoblasts in time and space. Therefore the target cell of these osteoclastic factors has remained unknown. Recent explorations of the physical microenvironment of osteoclasts revealed a cell layer lining the bone marrow and forming a canopy over the whole remodeling surface, spanning from the osteoclasts to the bone forming osteoblasts. Several observations show that these canopy cells are a source of osteoblast progenitors, and we hypothesized therefore that they are the likely cells targeted by the osteogenic factors of the osteoclasts. Here we provide evidence supporting this hypothesis, by comparing the osteoclast-canopy interface in response to two types of bone resorption inhibitors in rabbit lumbar vertebrae. The bisphosphonate alendronate, an inhibitor leading to low bone formation levels, reduces the extent of canopy coverage above osteoclasts. This effect is in accordance with its toxic action on periosteoclastic cells. In contrast, odanacatib, an inhibitor preserving bone formation, increases the extent of the osteoclast-canopy interface. Interestingly, these distinct effects correlate with how fast bone formation follows resorption during these respective treatments. Furthermore, canopy cells exhibit uPARAP/Endo180, a receptor able to bind the collagen made available by osteoclasts, and reported to mediate osteoblast recruitment. Overall these observations support a mechanism where the recruitment of bone forming osteoblasts from the canopy is induced by osteoclastic factors, thereby favoring initiation of bone formation. They lead to a model where the osteoclast-canopy interface is

  15. Biomechanical competence of microstructural bone in the progress of adaptive bone remodeling

    NASA Astrophysics Data System (ADS)

    Mueller, Ralph; Hayes, Wilson C.

    1997-10-01

    The mechanical behavior of trabecular bone depends on the internal bone structure as well as the load applied. Mechanical stresses and strains influence the modeling process and subsequently the structure and strength of the bone. Although the basic concepts of adaptive bone remodeling are generally accepted, the mathematical laws relating bone remodeling to the stress/strain relations are still under investigation. The aim of this project was to develop an algorithm which allows simulation of the response of the trabecular bone is age-related bone loss and to determine the biomechanical consequences of such a response based on realistic 3D models of the trabecular microstructure. Today, such models can be generated directly using micro-computed tomography ((mu) CT). For the purpose of the study, a compact fan-beam type tomograph was used, also referred to as desktop (mu) CT, providing a nominal isotropic resolution of 14 micrometers . Two groups of seven trabecular bone specimens were measured including specimens from pre- menopausal and post-menopausal women respectively. In order to control bone loss over age, a novel algorithm to simulate bone resorption and adaptive process was developed. The algorithm, also referred to as simulated bone atrophy, generates a set of microstructural models, iteratively derived from the original 3D structure. Simulated bone atrophy was used to 'age-match' the first and the second group incorporating an underlying realistic time-frame for the simulation. Using quantitative bone morphometry and 3D animation tools, the changes in bone density and bone architecture could be monitored in the progress of age- related bone loss over a total observation time of 28 years. The structures at the end-point of the simulations were then compared qualitatively and quantitatively to the structures of the post-menopausal group directly assessed by (mu) CT. The results suggest the possibility of transforming 'normal' to osteopenic' bone on a

  16. A mechanostatistical approach to cortical bone remodelling: an equine model.

    PubMed

    Wang, X; Thomas, C D L; Clement, J G; Das, R; Davies, H; Fernandez, J W

    2016-02-01

    In this study, the development of a mechanostatistical model of three-dimensional cortical bone remodelling informed with in vivo equine data is presented. The equine model was chosen as it is highly translational to the human condition due to similar Haversian systems, availability of in vivo bone strain and biomarker data, and furthermore, equine models are recommended by the US Federal Drugs Administration for comparative joint research. The model was derived from micro-computed tomography imaged specimens taken from the equine third metacarpal bone, and the Frost-based 'mechanostat' was informed from both in vivo strain gauges and biomarkers to estimate bone growth rates. The model also described the well-known 'cutting cone' phenomena where Haversian canals tunnel and replace bone. In order to make this model useful in practice, a partial least squares regression (PLSR) surrogate model was derived based on training data from finite element simulations with different loads. The PLSR model was able to predict microstructure and homogenised Young's modulus with errors less than 2.2% and 0.6%, respectively. PMID:25862068

  17. Would increased interstitial fluid flow through in situ mechanical stimulation enhance bone remodeling?

    PubMed

    Letechipia, J E; Alessi, A; Rodriguez, G; Asbun, J

    2010-08-01

    Bone accommodates to changes in its functional environment ensuring that sufficient skeletal mass is appropriately positioned to withstand the mechanical loads that result from functional activities. Increasing physical activity will result in increased bone mass, while the removal of functional loading would result in bone loss. Bone is a composite material made up of a collagen-hydroxyapatite matrix and a complex network of lacunae-canaliculi channels occupied by osteocyte and osteoblast processes, immersed in interstitial fluid. There are strong indications that changes in interstitial fluid flow velocity or pressure are the means by which an external load signal is communicated to the cell. In vitro studies indicate that shear stress, induced by interstitial fluid flow, is a potent bone cell behavior regulator. One of the forms of altering interstitial fluid flow is through the mechanical deformation of skeletal tissue in response to applied loads. Other methods include increased intramedullary pressure, negative-pressure tissue regeneration, or external mechanical stimulation. Analysis of these methods poses the question of process effectiveness. The efficacy of each method theoretically will depend on the mechanical efficiency of transmitting an external load and converting it into changes in interstitial fluid flow. In this paper, we combine recent knowledge on the effect of the bone's interstitial fluid flow, different fluid patterns, the role of gap junctions, and the concept of mechanical effectiveness of different methods that influence interstitial fluid flow within bone, and we hypothesize that the efficiency of bone remodeling can be improved if a small mechanical percussion device could be placed directly in contact with the bone, thus inducing local interstitial fluid flow variations. Enhancement of bone repair and remodeling through controlled interstitial fluid flow possesses many clinical applications. Further investigations and in vivo

  18. The effect of bisphosphonate treatment on the biochemical and cellular events during bone remodelling in response to microinjury stimulation.

    PubMed

    Mulcahy, L E; Curtin, C M; McCoy, R J; O'Brien, F J; Taylor, D; Lee, T C; Duffy, G P

    2015-01-01

    Osteoporosis is one of the most prevalent bone diseases worldwide and is characterised by high levels of bone turnover, a marked loss in bone mass and accumulation of microdamage, which leads to an increased fracture incidence that places a huge burden on global health care systems. Bisphosphonates have been used to treat osteoporosis and have shown great success in conserving bone mass and reducing fracture incidence. In spite of the existing knowledge of the in vivo responses of bone to bisphosphonates, the cellular responses to these drugs have yet to be fully elucidated. In vitro model systems that allow the decoupling of complex highly integrated events, such as bone remodelling, provide a tool whereby these biological processes may be studied in a more simplified context. This study firstly utilised an in vitro model system of bone remodelling and comprising all three major cell types of the bone (osteocytes, osteoclasts and osteoblasts), which was representative of the bone's capacity to sense microdamage and subsequently initiate a basic multicellular unit response. Secondly, this system was used to study the effect of two commonly utilised aminobisphosphonate treatments for osteoporosis, alendronate and zoledronate. We demonstrated that microinjury to osteocyte networks being treated with bisphosphonates modulates receptor activator of nuclear factor kappa-B ligand and osteoprotegerin activity, and subsequently osteoclastogenesis. Furthermore, bisphosphonates increased the osteogenic potential following microinjury. Thus, we have shown for the first time that bisphosphonates act at all three stages of bone remodelling, from microinjury to osteoclastogenesis and ultimately osteogenesis. PMID:26614482

  19. The effects of proteasome inhibitors on bone remodeling in multiple myeloma.

    PubMed

    Zangari, Maurizio; Suva, Larry J

    2016-05-01

    Bone disease is a characteristic feature of multiple myeloma, a malignant plasma cell dyscrasia. In patients with multiple myeloma, the normal process of bone remodeling is dysregulated by aberrant bone marrow plasma cells, resulting in increased bone resorption, prevention of new bone formation, and consequent bone destruction. The ubiquitin-proteasome system, which is hyperactive in patients with multiple myeloma, controls the catabolism of several proteins that regulate bone remodeling. Clinical studies have reported that treatment with the first-in-class proteasome inhibitor bortezomib reduces bone resorption and increases bone formation and bone mineral density in patients with multiple myeloma. Since the introduction of bortezomib in 2003, several next-generation proteasome inhibitors have also been used clinically, including carfilzomib, oprozomib, ixazomib, and delanzomib. This review summarizes the available preclinical and clinical evidence regarding the effect of proteasome inhibitors on bone remodeling in multiple myeloma. PMID:26947893

  20. Inner Ear Vestibular Signals Regulate Bone Remodeling via the Sympathetic Nervous System.

    PubMed

    Vignaux, Guillaume; Ndong, Jean Dlc; Perrien, Daniel S; Elefteriou, Florent

    2015-06-01

    The inner ear vestibular system has numerous projections on central brain centers that regulate sympathetic outflow, and skeletal sympathetic projections affect bone remodeling by inhibiting bone formation by osteoblasts and promoting bone resorption by osteoclasts. In this study, we show that bilateral vestibular lesions in mice cause a low bone mass phenotype associated with decreased bone formation and increased bone resorption. This reduction in bone mass is most pronounced in lower limbs, is not associated with reduced locomotor activity or chronic inflammation, and could be prevented by the administration of the β-blocker propranolol and by genetic deletion of the β2-adrenergic receptor, globally or specifically in osteoblasts. These results provide novel experimental evidence supporting a functional autonomic link between central proprioceptive vestibular structures and the skeleton. Because vestibular dysfunction often affects the elderly, these results also suggest that age-related bone loss might have a vestibular component and that patients with inner ear pathologies might be at risk for fracture. Lastly, these data might have relevance to the bone loss observed in microgravity, as vestibular function is altered in this condition as well. © 2015 American Society for Bone and Mineral Research. PMID:25491117

  1. Variants of Osteoprotegerin Lacking TRAIL Binding for Therapeutic Bone Remodeling in Osteolytic Malignancies

    PubMed Central

    Higgs, Jerome T.; Jarboe, John S.; Lee, Joo Hyoung; Chanda, Diptiman; Lee, Carnellia M.; Deivanayagam, Champion; Ponnazhagan, Selvarangan

    2015-01-01

    Osteolytic bone damage is a major cause of morbidity in several metastatic pathologies. Current therapies using bisphosphonates provide modest improvement, but cytotoxic side effects still occur prompting the need to develop more effective therapies to target aggressive osteoclastogenesis. Increased levels of Receptor Activator of Nuclear Factor Kappa B Ligand (TNFSF11/RANKL), leading to RANKL-RANK signaling, remains the key axis for osteoclast activation and bone resorption. Osteoprotegerin (TNFRSF11B/OPG), a decoy receptor for RANKL is significantly decreased in patients who present with bone lesions. Despite its potential in inhibiting osteoclast activation, OPG also binds to tumor necrosis factor related apoptosis-inducing ligand (TNFSF10/TRAIL), making tumor cells resistant to apoptosis. Towards uncoupling the events of TRAIL binding of OPG and to improve its utility for bone remodeling without inducing tumor resistance to apoptosis, OPG mutants were developed by structural homology modeling based on interactive domain identification and by superimposing models of OPG, TRAIL and its receptor DR5 (TNFRSF10B) to identify regions of OPG for rational design. The OPG mutants were purified and extensively characterized for their ability to decrease osteoclast damage without affecting tumor apoptosis pathway both in vitro and in vivo, confirming their potential in bone remodeling following cancer-induced osteolytic damage. PMID:25636966

  2. The Effect of Inital-Phase Bone Remodeling on Implant Wound Healing.

    PubMed

    Hsu, Yung-Ting; Oh, Tae-Ju; Rudek, Ivan; Wang, Hom-Lay

    2016-01-01

    This case series aimed to investigate the initial-phase bone remodeling during implant wound healing and to discuss the possible contributing factors. A total of 11 implants with polished collars were placed in premaxillary regions via flapless approach with the aid of computer technology. After 15 months of follow-up, the results suggested that the presence of polished collars triggered bone resorption via a bone remodeling mechanism. The overall vertical crestal resorption was 0.78 ± 0.46 mm on average. This initial-phase bone remodeling primarily occurred within the first 3 months postoperatively. The slightly exposed polished collar may not worsen crestal bone level. PMID:27560679

  3. Bone remodelling in Neanderthal mandibles from the El Sidrón site (Asturias, Spain)

    PubMed Central

    Martinez-Maza, Cayetana; Rosas, Antonio; García-Vargas, Samuel; Estalrrich, Almudena; de la Rasilla, Marco

    2011-01-01

    Skull morphology results from the bone remodelling mechanism that underlies the specific bone growth dynamics. Histological study of the bone surface from Neanderthal mandible specimens of El Sidrón (Spain) provides information about the distribution of the remodelling fields (bone remodelling patterns or BRP) indicative of the bone growth directions. In comparison with other primate species, BRP shows that Neanderthal mandibles from the El Sidrón (Spain) sample present a specific BRP. The interpretation of this map allows inferences concerning the growth directions that explain specific morphological traits of the Neanderthal mandible, such as its quadrangular shape and the posterior location of the mental foramen. PMID:21307043

  4. sFRP4-dependent Wnt signal modulation is critical for bone remodeling during postnatal development and age-related bone loss

    PubMed Central

    Haraguchi, Ryuma; Kitazawa, Riko; Mori, Kiyoshi; Tachibana, Ryosuke; Kiyonari, Hiroshi; Imai, Yuuki; Abe, Takaya; Kitazawa, Sohei

    2016-01-01

    sFRP4 is an extracellular Wnt antagonist that fine-tunes its signal activity by direct binding to Wnts. Bone fragility under oxidative stress by diabetes and aging is partly related to the suppression of the Wnt signal through upregulated sFRP4. Here, to explore the functions of sFRP4 as a balancer molecule in bone development and remodeling, we analyzed the sFRP4 knock-in mouse strain. X-gal and immunohistochemically stained signals in sFRP4-LacZ heterozygous mice were detectable in restricted areas, mostly in osteoblasts and osteoclasts, of the femoral diaphysis after neonatal and postnatal stages. Histological and μCT analyses showed increased trabecular bone mass with alteration of the Wnt signal and osteogenic activity in sFRP4 mutants; this augmented the effect of the buildup of trabecular bone during the ageing period. Our results indicate that sFRP4 plays a critical role in bone development and remodeling by regulating osteoblasts and osteoclasts, and that its functional loss prevents age-related bone loss in the trabecular bone area. These findings imply that sFRP4 functions as a key potential endogenous balancer of the Wnt signaling pathway by efficiently having direct influence on both bone formation and bone absorption during skeletal bone development and maintenance through remodeling. PMID:27117872

  5. sFRP4-dependent Wnt signal modulation is critical for bone remodeling during postnatal development and age-related bone loss.

    PubMed

    Haraguchi, Ryuma; Kitazawa, Riko; Mori, Kiyoshi; Tachibana, Ryosuke; Kiyonari, Hiroshi; Imai, Yuuki; Abe, Takaya; Kitazawa, Sohei

    2016-01-01

    sFRP4 is an extracellular Wnt antagonist that fine-tunes its signal activity by direct binding to Wnts. Bone fragility under oxidative stress by diabetes and aging is partly related to the suppression of the Wnt signal through upregulated sFRP4. Here, to explore the functions of sFRP4 as a balancer molecule in bone development and remodeling, we analyzed the sFRP4 knock-in mouse strain. X-gal and immunohistochemically stained signals in sFRP4-LacZ heterozygous mice were detectable in restricted areas, mostly in osteoblasts and osteoclasts, of the femoral diaphysis after neonatal and postnatal stages. Histological and μCT analyses showed increased trabecular bone mass with alteration of the Wnt signal and osteogenic activity in sFRP4 mutants; this augmented the effect of the buildup of trabecular bone during the ageing period. Our results indicate that sFRP4 plays a critical role in bone development and remodeling by regulating osteoblasts and osteoclasts, and that its functional loss prevents age-related bone loss in the trabecular bone area. These findings imply that sFRP4 functions as a key potential endogenous balancer of the Wnt signaling pathway by efficiently having direct influence on both bone formation and bone absorption during skeletal bone development and maintenance through remodeling. PMID:27117872

  6. Concise review: Insights from normal bone remodeling and stem cell-based therapies for bone repair.

    PubMed

    Khosla, Sundeep; Westendorf, Jennifer J; Mödder, Ulrike I

    2010-12-01

    There is growing interest in the use of mesenchymal stem cells for bone repair. As a major reason for normal bone remodeling is the removal of fatigue microcracks, advances in our understanding of this process may inform approaches to enhance fracture healing. Increasing evidence now indicates that physiological bone remodeling occurs in close proximity to blood vessels and that these vessels carry perivascular stem cells that differentiate into osteoblasts. Similarly, fracture healing is critically dependent on the ingrowth of blood vessels not only for a nutrient supply but also for the influx of osteoblasts. A number of animal and human studies have now shown the potential benefit of bone marrow-derived mesenchymal stem cells in enhancing bone repair. However, as in other tissues, the question of whether these cells improve fracture healing directly by differentiating into osteoblasts or indirectly by secreting paracrine factors that recruit blood vessels and the accompanying perivascular stem cells remains a major unresolved issue. Moreover, CD34+ cells, which are enriched for endothelial/hematopoietic cells, have also shown efficacy in various bone repair models, at least in part due to the induction of angiogenesis and recruitment of host progenitor cells. Thus, mesenchymal and nonmesenchymal stem/progenitor cells are attractive options for bone repair. It is possible that they contribute directly to bone repair, but it is also likely that they express paracrine factors in the appropriate amounts and combinations that promote and sustain the healing process. PMID:20960512

  7. Peptide YY Regulates Bone Remodeling in Mice: A Link between Gut and Skeletal Biology

    PubMed Central

    Wong, Iris P. L.; Driessler, Frank; Khor, Ee Cheng; Shi, Yan-Chuan; Hörmer, Birgit; Nguyen, Amy D.; Enriquez, Ronaldo F.; Eisman, John A.; Sainsbury, Amanda; Herzog, Herbert; Baldock, Paul A.

    2012-01-01

    Background & Aims Gastrointestinal peptides are increasingly being linked to processes controlling the maintenance of bone mass. Peptide YY (PYY), a gut-derived satiety peptide of the neuropeptide Y family, is upregulated in some states that also display low bone mass. Importantly, PYY has high affinity for Y-receptors, particularly Y1R and Y2R, which are known to regulate bone mass. Anorexic conditions and bariatric surgery for obesity influence circulating levels of PYY and have a negative impact on bone mass, but the precise mechanism behind this is unclear. We thus examined whether alterations in PYY expression affect bone mass. Methods Bone microstructure and cellular activity were analyzed in germline PYY knockout and conditional adult-onset PYY over-expressing mice at lumbar and femoral sites using histomorphometry and micro-computed tomography. Results PYY displayed a negative relationship with osteoblast activity. Male and female PYY knockout mice showed enhanced osteoblast activity, with greater cancellous bone mass. Conversely, PYY over-expression lowered osteoblast activity in vivo, via a direct Y1 receptor mediated mechanism involving MAPK stimulation evident in vitro. In contrast to PYY knockout mice, PYY over expression also altered bone resorption, as indicated by greater osteoclast surface, despite the lack of Y-receptor expression in osteoclastic cells. While evident in both sexes, cellular changes were generally more pronounced in females. Conclusions These data demonstrate that the gut peptide PYY is critical for the control of bone remodeling. This regulatory axis from the intestine to bone has the potential to contribute to the marked bone loss observed in situations of extreme weight loss and higher circulating PYY levels, such as anorexia and bariatric obesity surgery, and may be important in the maintenance of bone mass in the general population. PMID:22792209

  8. Assessment of failure of cemented polyethylene acetabular component due to bone remodeling: A finite element study.

    PubMed

    Ghosh, Rajesh

    2016-09-01

    The aim of the study is to determine failure of the cemented polyethylene acetabular component, which might occur due to excessive bone resorption, cement-bone interface debonding and fatigue failure of the cement mantle. Three-dimensional finite element models of intact and implanted pelvic bone were developed and bone remodeling algorithm was implemented for present analysis. Soderberg fatigue failure diagram was used for fatigue assessment of the cement mantle. Hoffman failure criterion was considered for prediction of cement-bone interface debonding. Results indicate fatigue failure of the cement mantle and implant-bone interface debonding might not occur due to bone remodeling. PMID:27408485

  9. Inner Ear Vestibular Signals Regulate Bone Remodeling via the Sympathetic Nervous System

    PubMed Central

    Vignaux, Guillaume; Ndong, Jean DLC; Perrien, Daniel S; Elefteriou, Florent

    2016-01-01

    The inner ear vestibular system has numerous projections on central brain centers that regulate sympathetic outflow, and skeletal sympathetic projections affect bone remodeling by inhibiting bone formation by osteoblasts and promoting bone resorption by osteoclasts. In this study, we show that bilateral vestibular lesions in mice cause a low bone mass phenotype associated with decreased bone formation and increased bone resorption. This reduction in bone mass is most pronounced in lower limbs, is not associated with reduced locomotor activity or chronic inflammation, and could be prevented by the administration of the β-blocker propranolol and by genetic deletion of the β2-adrenergic receptor, globally or specifically in osteoblasts. These results provide novel experimental evidence supporting a functional autonomic link between central proprioceptive vestibular structures and the skeleton. Because vestibular dysfunction often affects the elderly, these results also suggest that age-related bone loss might have a vestibular component and that patients with inner ear pathologies might be at risk for fracture. Lastly, these data might have relevance to the bone loss observed in microgravity, as vestibular function is altered in this condition as well. PMID:25491117

  10. Influence of different mechanical stimuli in a multi-scale mechanobiological isotropic model for bone remodelling.

    PubMed

    Mercuri, E G F; Daniel, A L; Hecke, M B; Carvalho, L

    2016-09-01

    This work represents a study of a mathematical model that describes the biological response to different mechanical stimuli in a cellular dynamics model for bone remodelling. The biological system discussed herein consists of three specialised cellular types, responsive osteoblasts, active osteoblasts and osteoclasts, three types of signalling molecules, transforming growth factor beta (TGF-β), receptor activator of nuclear factor kappa-b ligand (RANKL) and osteoprotegerin (OPG) and the parathyroid hormone (PTH). Three proposals for mechanical stimuli were tested: strain energy density (SED), hydrostatic and deviatoric parts of SED. The model was tested in a two-dimensional geometry of a standard human femur. The spatial discretization was performed by the finite element method while the temporal evolution of the variables was calculated by the 4th order Runge-Kutta method. The obtained results represent the temporal evolution of the apparent density distribution and the mean apparent density and thickness for the cortical bone after 600 days of remodelling simulation. The main contributions of this paper are the coupling of mechanical and biological models and the exploration of how the different mechanical stimuli affect the cellular activity in different types of physical activities. The results revealed that hydrostatic SED stimulus was able to form more cortical bone than deviatoric SED and total SED stimuli. The computational model confirms how different mechanical stimuli can impact in the balance of bone homeostasis. PMID:27215171

  11. A thermodynamic model of bone remodelling: the influence of dynamic loading together with biochemical control.

    PubMed

    Klika, V; Marsik, F

    2010-09-01

    Understanding of the bone remodelling process has considerably increased during the last 20 years. Since the ability to simulate (and predict) the effects of bone remodelling offers substantial insights, several models have been proposed to describe this phenomenon. The strength of the presented model is that it includes biochemical control factors (e.g., the necessity of cell-to-cell contact, which is mediated by the RANKL-RANK-OPG chain during osteoclastogenesis) and mechanical stimulation, the governing equations are derived from interaction kinetics (e.g., mass is preserved in running reactions), and the parameters are measurable. Behaviour of the model is in accordance with experimental and clinical observations, such as the role of dynamic loading, the inhibitory effect of dynamic loading on osteoclastogenesis, the observation that polykaryon osteoclasts are activated and formed by a direct cell-to-cell contact, and the correct concentrations of osteoblasts, osteoclasts, and osteocytes. The model does not yet describe the bone remodelling process in complete detail, but the implemented simplifications describe the key features and further details of control mechanisms may be added. PMID:20811146

  12. Control of Bone Remodeling by the Peripheral Sympathetic Nervous System

    PubMed Central

    Campbell, Preston; Ma, Yun

    2013-01-01

    The skeleton is no longer seen as a static, isolated, and mostly structural organ. Over the last two decades, a more complete picture of the multiple functions of the skeleton has emerged, and its interactions with a growing number of apparently unrelated organs have become evident. The skeleton not only reacts to mechanical loading and inflammatory, hormonal, and mineral challenges, but also acts of its own accord by secreting factors controlling the function of other tissues, including the kidney and possibly the pancreas and gonads. It is thus becoming widely recognized that it is by nature an endocrine organ, in addition to a structural organ and site of mineral storage and hematopoiesis. Consequently and by definition, bone homeostasis must be tightly regulated and integrated with the biology of other organs to maintain whole body homeostasis, and data uncovering the involvement of the central nervous system (CNS) in the control of bone remodeling support this concept. The sympathetic nervous system (SNS) represents one of the main links between the CNS and the skeleton, based on a number of anatomic, pharmacologic, and genetic studies focused on β-adrenergic receptor (βAR) signaling in bone cells. The goal of this report was to review the data supporting the role of the SNS and βAR signaling in the regulation of skeletal homeostasis. PMID:23765388

  13. Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma.

    PubMed

    Breitkreutz, I; Raab, M S; Vallet, S; Hideshima, T; Raje, N; Mitsiades, C; Chauhan, D; Okawa, Y; Munshi, N C; Richardson, P G; Anderson, K C

    2008-10-01

    Osteolytic bone disease in multiple myeloma (MM) is caused by enhanced osteoclast (OCL) activation and inhibition of osteoblast function. Lenalidomide and bortezomib have shown promising response rates in relapsed and newly diagnosed MM, and bortezomib has recently been reported to inhibit OCLs. We here investigated the effect of lenalidomide on OCL formation and osteoclastogenesis in comparison with bortezomib. Both drugs decreased alpha V beta 3-integrin, tartrate-resistant acid phosphatase-positive cells and bone resorption on dentin disks. In addition, both agents decreased receptor activator of nuclear factor-kappaB ligand (RANKL) secretion of bone marrow stromal cells (BMSCs) derived from MM patients. We identified PU.1 and pERK as major targets of lenalidomide, and nuclear factor of activated T cells of bortezomib, resulting in inhibition of osteoclastogenesis. Furthermore, downregulation of cathepsin K, essential for resorption of the bone collagen matrix, was observed. We demonstrated a significant decrease of growth and survival factors including macrophage inflammatory protein-alpha, B-cell activating factor and a proliferation-inducing ligand. Importantly, in serum from MM patients treated with lenalidomide, the essential bone-remodeling factor RANKL, as well as the RANKL/OPG ratio, were significantly reduced, whereas osteoprotegerin (OPG) was increased. We conclude that both agents specifically target key factors in osteoclastogenesis, and could directly affect the MM-OCL-BMSCs activation loop in osteolytic bone disease. PMID:18596740

  14. The Regulatory Roles of MicroRNAs in Bone Remodeling and Perspectives as Biomarkers in Osteoporosis

    PubMed Central

    Sun, Mengge; Zhou, Xiaoya; Chen, Lili; Huang, Shishu; Leung, Victor; Wu, Nan; Pan, Haobo; Zhen, Wanxin; Lu, William; Peng, Songlin

    2016-01-01

    MicroRNAs are involved in many cellular and molecular activities and played important roles in many biological and pathological processes, such as tissue formation, cancer development, diabetes, neurodegenerative diseases, and cardiovascular diseases. Recently, it has been reported that microRNAs can modulate the differentiation and activities of osteoblasts and osteoclasts, the key cells that are involved in bone remodeling process. Meanwhile, the results from our and other research groups showed that the expression profiles of microRNAs in the serum and bone tissues are significantly different in postmenopausal women with or without fractures compared to the control. Therefore, it can be postulated that microRNAs might play important roles in bone remodeling and that they are very likely to be involved in the pathological process of postmenopausal osteoporosis. In this review, we will present the updated research on the regulatory roles of microRNAs in osteoblasts and osteoclasts and the expression profiles of microRNAs in osteoporosis and osteoporotic fracture patients. The perspective of serum microRNAs as novel biomarkers in bone loss disorders such as osteoporosis has also been discussed. PMID:27073801

  15. Radiation dose to trabecular bone marrow stem cells from 3H, 14C and selected α-emitters incorporated in a bone remodeling compartment

    NASA Astrophysics Data System (ADS)

    Nie, Huiling; Richardson, Richard B.

    2009-02-01

    A Monte Carlo simulation of repeated cubic units representing trabecular bone cavities in adult bone was employed to determine absorbed dose fractions evaluated for 3H, 14C and a set of α-emitters incorporated within a bone remodeling compartment (BRC). The BRC consists of a well-oxygenated vascular microenvironment located within a canopy of bone-lining cells. The International Commission on Radiological Protection (ICRP) considers that an important target for radiation-induced bone cancer is the endosteum marrow layer adjacent to bone surface where quiescent bone stem cells reside. It is proposed that the active stem cells and progenitor cells located above the BRC canopy, the 'BRC stem cell niche', is a more important radiation-induced cancer target volume. Simulation results from a static model, where no remodeling occurs, indicate that the mean dose from bone and bone surface to the 50 µm quiescent bone stem cell niche, the current ICRP target, was substantially lower (two to three times lower) than that to the narrower and hypoxic 10 µm endosteum for 3H, 14C and α-particles with energy range 0.5-10 MeV. The results from a dynamic model indicate that the temporal α-radiation dose to active stem/progenitor cells located in the BRC stem cell niche from the material incorporated in and buried by forming bone was 9- to 111-fold greater than the dose to the quiescent bone stem cell niche. This work indicates that the remodeling portion of the bone surface, rather than the quiescent (endosteal) surface, has the greatest risk of radiation-induced bone cancer, particularly from short-range radiation, due to the elevated dose and the radiosensitizing oxygen effect.

  16. Numerical investigations on the strain-adaptive bone remodelling in the periprosthetic femur: Influence of the boundary conditions

    PubMed Central

    Behrens, Bernd-Arno; Nolte, Ingo; Wefstaedt, Patrick; Stukenborg-Colsman, Christina; Bouguecha, Anas

    2009-01-01

    Background There are several numerical investigations on bone remodelling after total hip arthroplasty (THA) on the basis of the finite element analysis (FEA). For such computations certain boundary conditions have to be defined. The authors chose a maximum of three static load situations, usually taken from the gait cycle because this is the most frequent dynamic activity of a patient after THA. Materials and methods The numerical study presented here investigates whether it is useful to consider only one static load situation of the gait cycle in the FE calculation of the bone remodelling. For this purpose, 5 different loading cases were examined in order to determine their influence on the change in the physiological load distribution within the femur and on the resulting strain-adaptive bone remodelling. First, four different static loading cases at 25%, 45%, 65% and 85% of the gait cycle, respectively, and then the whole gait cycle in a loading regime were examined in order to regard all the different loadings of the cycle in the simulation. Results The computed evolution of the apparent bone density (ABD) and the calculated mass losses in the periprosthetic femur show that the simulation results are highly dependent on the chosen boundary conditions. Conclusion These numerical investigations prove that a static load situation is insufficient for representing the whole gait cycle. This causes severe deviations in the FE calculation of the bone remodelling. However, accompanying clinical examinations are necessary to calibrate the bone adaptation law and thus to validate the FE calculations. PMID:19371424

  17. Changes in the population of perivascular cells in the bone tissue remodeling zones under microgravity

    NASA Astrophysics Data System (ADS)

    Katkova, Olena; Rodionova, Natalia; Shevel, Ivan

    2016-07-01

    Microgravity and long-term hypokinesia induce reduction both in bone mass and mineral saturation, which can lead to the development of osteoporosis and osteopenia. (Oganov, 2003). Reorganizations and adaptive remodeling processes in the skeleton bones occur in the topographical interconnection with blood capillaries and perivascular cells. Radioautographic studies with 3H- thymidine (Kimmel, Fee, 1980; Rodionova, 1989, 2006) have shown that in osteogenesis zones there is sequential differentiation process of the perivascular cells into osteogenic. Hence the study of populations of perivascular stromal cells in areas of destructive changes is actual. Perivascular cells from metaphysis of the rat femoral bones under conditions of modeling microgravity were studied using electron microscopy and cytochemistry (hindlimb unloading, 28 days duration) and biosatellite «Bion-M1» (duration of flight from April 19 till May 19, 2013 on C57, black mice). It was revealed that both control and test groups populations of the perivascular cells are not homogeneous in remodeling adaptive zones. These populations comprise of adjacent to endothelium poorly differentiated forms and isolated cells with signs of differentiation (specific increased volume of rough endoplasmic reticulum in cytoplasm). Majority of the perivascular cells in the control group (modeling microgravity) reveals reaction to alkaline phosphatase (marker of the osteogenic differentiation). In poorly differentiated cells this reaction is registered in nucleolus, nucleous and cytoplasm. In differentiating cells activity of the alkaline phosphatase is also detected on the outer surface of the cellular membrane. Unlike the control group in the bones of experimental animals reaction to the alkaline phosphatase is registered not in all cells of perivascular population. Part of the differentiating perivascular cells does not contain a product of the reaction. Under microgravity some poorly differentiated perivascular

  18. Notch regulation of bone development and remodeling and related skeletal disorders.

    PubMed

    Zanotti, Stefano; Canalis, Ernesto

    2012-02-01

    Notch signaling mediates cell-to-cell interactions that are critical for embryonic development and tissue renewal. In the canonical signaling pathway, the Notch receptor is cleaved following ligand binding, resulting in the release and nuclear translocation of the Notch intracellular domain (NICD). NICD induces gene expression by forming a ternary complex with the DNA binding protein CBF1/Rbp-Jk, Suppressor of Hairless, Lag1, and Mastermind-Like (Maml). Hairy Enhancer of Split (Hes) and Hes related with YRPW motif (Hey) are classic Notch targets. Notch canonical signaling plays a central role in skeletal development and bone remodeling by suppressing the differentiation of skeletal cells. The skeletal phenotype of mice misexpressing Hes1 phenocopies partially the effects of Notch misexpression, suggesting that Hey proteins mediate most of the skeletal effects of Notch. Dysregulation of Notch signaling is associated with diseases affecting human skeletal development, such as Alagille syndrome, brachydactyly and spondylocostal dysostosis. Somatic mutations in Notch receptors and ligands are found in tumors of the skeletal system. Overexpression of NOTCH1 is associated with osteosarcoma, and overexpression of NOTCH3 or JAGGED1 in breast cancer cells favors the formation of osteolytic bone metastasis. Activating mutations in NOTCH2 cause Hajdu-Cheney syndrome, which is characterized by skeletal defects and fractures, and JAG1 polymorphisms, are associated with variations in bone mineral density. In conclusion, Notch is a regulator of skeletal development and bone remodeling, and abnormal Notch signaling is associated with developmental and postnatal skeletal disorders. PMID:22002679

  19. Subchondral bone microstructural damage by increased remodelling aggravates experimental osteoarthritis preceded by osteoporosis

    PubMed Central

    2010-01-01

    Introduction Osteoporosis (OP) increases cartilage damage in a combined rabbit model of OP and osteoarthritis (OA). Accordingly, we assessed whether microstructure impairment at subchondral bone aggravates cartilage damage in this experimental model. Methods OP was induced in 20 female rabbits, by ovariectomy and intramuscular injections of methylprednisolone hemisuccinate for four weeks. Ten healthy animals were used as controls. At week 7, OA was surgically induced in left knees of all rabbits. At 22 weeks, after sacrifice, microstructure parameters were assessed by micro-computed tomography, and osteoprotegerin (OPG), receptor activator of nuclear factor-κB ligand (RANKL), alkaline phosphatase (ALP) and metalloproteinase 9 (MMP9) protein expressions were evaluated by Western Blot at subchondral bone. In addition, cartilage damage was estimated using the histopathological Mankin score. Mann-Whitney and Spearman statistical tests were performed as appropriate, using SPSS software v 11.0. Significant difference was established at P < 0.05. Results Subchondral bone area/tissue area, trabecular thickness and polar moment of inertia were diminished in OPOA knees compared with control or OA knees (P < 0.05). A decrease of plate thickness, ALP expression and OPG/RANKL ratio as well as an increased fractal dimension and MMP9 expression occurred at subchondral bone of OA, OP and OPOA knees vs. controls (P < 0.05). In addition, the severity of cartilage damage was increased in OPOA knees vs. controls (P < 0.05). Remarkably, good correlations were observed between structural and remodelling parameters at subchondral bone, and furthermore, between subchondral structural parameters and cartilage Mankin score. Conclusions Microstructure impairment at subchondral bone associated with an increased remodelling aggravated cartilage damage in OA rabbits with previous OP. Our results suggest that an increased subchondral bone resorption may account for the exacerbation of cartilage

  20. Periosteal PTHrP Regulates Cortical Bone Remodeling During Fracture Healing.

    PubMed

    Wang, Meina; Nasiri, Ali R; Broadus, Arthur E; Tommasini, Steven M

    2015-12-01

    Parathyroid hormone-related protein (PTHrP) is widely expressed in the fibrous outer layer of the periosteum (PO), and the PTH/PTHrP type I receptor (PTHR1) is expressed in the inner PO cambial layer. The cambial layer gives rise to the PO osteoblasts (OBs) and osteoclasts (OCs) that model/remodel the cortical bone surface during development as well as during fracture healing. PTHrP has been implicated in the regulation of PO modeling during development, but nothing is known as regards a role of PTHrP in this location during fracture healing. We propose that PTHrP in the fibrous layer of the PO may be a key regulatory factor in remodeling bone formation during fracture repair. We first assessed whether PTHrP expression in the fibrous PO is associated with PO osteoblast induction in the subjacent cambial PO using a tibial fracture model in PTHrP-lacZ mice. Our results revealed that both PTHrP expression and osteoblast induction in PO were induced 3 days post-fracture. We then investigated a potential functional role of PO PTHrP during fracture repair by performing tibial fracture surgery in 10-week-old CD1 control and PTHrP conditional knockout (PTHrP cKO) mice that lack PO PTHrP. We found that callus size and formation as well as woven bone mineralization in PTHrP cKO mice were impaired compared to that in CD1 mice. Concordant with these findings, functional enzyme staining revealed impaired OB formation and OC activity in the cKO mice. We conclude that deleting PO PTHrP impairs cartilaginous callus formation, maturation and ossification as well as remodeling during fracture healing. These data are the initial genetic evidence suggesting that PO PTHrP may induce osteoblastic activity and regulate fracture healing on the cortical bone surface. PMID:26164475

  1. Does Simulated Spaceflight Modify Epigenetic Status During Bone Remodeling?

    NASA Technical Reports Server (NTRS)

    Thomas, Nicholas J.; Stevick, Rebecca J.; Tran, Luan H.; Nalavadi, Mohit O.; Almeida, Eduardo A.C.; Globus, Ruth K.; Alwood, Joshua S.

    2015-01-01

    Little is known about the effects of spaceflight conditions on epigenetics. The term epigenetics describes changes to the genome that can affect expression of a gene without changes to the sequence of DNA. Epigenetic processes are thought to underlie cellular differentiation, where transcription of specific genes occurs in response to key stimuli, and may be heritable - passing from one cell to its daughter cell. We hypothesize that the mechanical environment during spaceflight, namely microgravity-induced weightlessness or exercise regulate gene expression in the osteoblast-lineage cells both to control bone formation by osteoblasts and bone resorption by osteoclasts, which continually shapes bone structure throughout life. Similarly we intend to evaluate how radiation regulates these same bone cell activity and differentiation related genes. We further hypothesize that the regulation in bone cell gene expression is at least partially controlled through epigenetic mechanisms of methylation or small non-coding RNA (microRNAs). We have acquired preliminary data suggesting that global genome methylation is modified in response to axial compression of the tibia - a model of exercise. We intend to pursue these hypotheses wherein we will evaluate changes in gene expression and, congruently, changes in epigenetic state in bones from mice subjected to the aforementioned conditions: hindlimb unloading to simulate weightlessness, axial compression of the tibia, or radiation exposure in order to gain insight into the role of epigenetics in spaceflight-induced bone loss.

  2. Remodeling of the thoracic aorta after bone marrow cell transplantation

    PubMed Central

    Felix, Alyne; Monteiro, Nemesis; Rocha, Vinícius Novaes; Oliveira, Genilza; Moraes, Alan Cesar; Andrade, Cherley; Nascimento, Ana Lucia; de Carvalho, Laís; Thole, Alessandra; Carvalho, Jorge

    2014-01-01

    Stem cells are characterized by their ability to differentiate into multiple cell lineages and display the paracrine effect. The aim of this work was to evaluate the effect of therapy with bone marrow cells (BMCs) on blood glucose, lipid metabolism and aortic wall remodeling in mice through the administration of a high fat diet and subsequent BMCs transplantation. C57BL/6 mice were fed a control diet (CO group) or an atherogenic diet (AT group). After 16 weeks, the AT group was divided into four groups: an AT 14 days group and AT 21 days group, that were given an injection of vehicle and sacrificed at 14 and 21 days after, respectively; AT-BMC 14 days group and AT-BMC 21 days group that was given an injection of BMCs and sacrificed at 14 and 21 days after. The CO group was sacrificed along with other groups. The BMCs transplant had reduced blood glucose, triglycerides and total cholesterol. The Qa (1/mm2) was quantitatively reduced in AT 14 days group, AT 21 days group and was high in AT-BMC 21 days group. The AT 21 days group exhibited increased tunica media and elastic system fibers. The immunolabeling for α-SMA and VEGF showed less immunolabeling in transplanted groups with BMCs. The immunostaining for PCNA seems to be more expressive in the group AT-BMC 21 days group. To conclude, our results support the concept that in mice, the injection of BMCs improve glucose levels, lipid metabolism and remodeling of the aortic wall in animals using atherogenic diet. PMID:25337194

  3. Bone microdamage, remodeling and bone fragility: how much damage is too much damage?

    PubMed

    Seref-Ferlengez, Zeynep; Kennedy, Oran D; Schaffler, Mitchell B

    2015-01-01

    Microdamage resulting from fatigue or 'wear and tear' loading contributes to bone fragility; however, the full extent of its influence is not completely understood. Linear microcracks (∼50-100 μm) and diffuse damage (clusters of sublamellar-sized cracks) are the two major bone microdamage types, each with different mechanical and biological consequences. Healthy bone, due to its numerous microstructural interfaces and its ability to affect matrix level repair, deals effectively with microdamage. From a material standpoint, healthy bone behaves much like engineering composites like carbon-fiber reinforced plastics. Both materials allow matrix damage to form during fatigue loading and use microstructural interfaces to dissipate energy and limit microcrack propagation to slow fracture. The terms fracture toughness and 'toughening mechanism', respectively, describe mechanical behavior and microstructural features that prevent crack growth and make it harder to fracture a material. Critically, toughness is independent of strength. In bone, primary toughening features include mineral and collagen interfaces, lamellae and tissue heterogeneity among osteons. The damage tolerance of bone and other composites can be overcome with sustained loading and/or matrix changes such that the microstructure no longer limits microcrack propagation. With reduced remodeling due to aging, disease or remodeling suppression, microdamage accumulation can occur along with loss of tissue heterogeneity. Both contribute additively to reduced fracture toughness. Thus, the answer to the key question for bone fragility of how much microdamage is too much is extremely complex. It ultimately depends on the interplay between matrix damage content, internal repair and effectiveness of matrix-toughening mechanisms. PMID:25848533

  4. Bone microdamage, remodeling and bone fragility: how much damage is too much damage?

    PubMed Central

    Seref-Ferlengez, Zeynep; Kennedy, Oran D; Schaffler, Mitchell B

    2015-01-01

    Microdamage resulting from fatigue or ‘wear and tear' loading contributes to bone fragility; however, the full extent of its influence is not completely understood. Linear microcracks (∼50–100 μm) and diffuse damage (clusters of sublamellar-sized cracks) are the two major bone microdamage types, each with different mechanical and biological consequences. Healthy bone, due to its numerous microstructural interfaces and its ability to affect matrix level repair, deals effectively with microdamage. From a material standpoint, healthy bone behaves much like engineering composites like carbon-fiber reinforced plastics. Both materials allow matrix damage to form during fatigue loading and use microstructural interfaces to dissipate energy and limit microcrack propagation to slow fracture. The terms fracture toughness and 'toughening mechanism', respectively, describe mechanical behavior and microstructural features that prevent crack growth and make it harder to fracture a material. Critically, toughness is independent of strength. In bone, primary toughening features include mineral and collagen interfaces, lamellae and tissue heterogeneity among osteons. The damage tolerance of bone and other composites can be overcome with sustained loading and/or matrix changes such that the microstructure no longer limits microcrack propagation. With reduced remodeling due to aging, disease or remodeling suppression, microdamage accumulation can occur along with loss of tissue heterogeneity. Both contribute additively to reduced fracture toughness. Thus, the answer to the key question for bone fragility of how much microdamage is too much is extremely complex. It ultimately depends on the interplay between matrix damage content, internal repair and effectiveness of matrix-toughening mechanisms. PMID:25848533

  5. The Digital Astronaut Project Computational Bone Remodeling Model (Beta Version) Bone Summit Summary Report

    NASA Technical Reports Server (NTRS)

    Pennline, James; Mulugeta, Lealem

    2013-01-01

    changes in bone cell populations that remove and replace bone in packets within the bone region. The DAP bone model is unique in several respects. In particular in takes former models of volume fraction changes one step higher in fidelity and separates BVF into separate equations for mineralized and osteoid volume fractions governed by a mineralization rate. This more closely follows the physiology of the remodeling unit cycles where bone is first resorbed and then followed by the action of osteoblasts to lay down collagen matrix which eventually becomes mineralized. In another respect, the modules allow the functional description of the time rate of change of other parameters and variables in the model during a computational simulation. More detailed description of the model, preliminary validation results, current limitation and caveats, and planned advancements are provided in sections 2 through 5. The DAP bone model is being developed primarily as a research tool, and not as a clinical tool like QCT. Even if it transitions to a clinical tool, it is not intended to replace QCT or any other clinical tool. Moreover, the DAP bone model does not predict bone fracture. Its purpose is to provide valuable additional data via "forward prediction" simulations for during and after spaceflight missions to gain insight on, (1) mechanisms of bone demineralization in microgravity, and (2) the volumetric changes at the various bone sites in response to in-flight and post-flight exercise countermeasures. This data can then be used as input to the Keyak [8] (or equivalent) FE analysis method to gain insight on how bone strength may change during and after flight. This information can also be useful to help optimize exercise countermeasure protocols to minimize changes in bone strength during flight, and improve regain of bone strength post-flight. To achieve this goal, the bone model will be integrated with DAP's exercise countermeasure models to simulate the effect of exercise

  6. Differentiation potentials of perivascular cells in the bone tissue remodeling zones under microgravity

    NASA Astrophysics Data System (ADS)

    Rodionova, Natalia; Katkova, Olena

    Adaptive remodeling processes in the skeleton bones occur in the close topographical interconnection with blood capillaries followed by perivascular cells. Radioautographic studies with 3Н- thymidine (Kimmel D.B., Fee W.S., 1980; Rodionova N.V., 1989, 2006) has shown that in osteogenesis zones there is sequential differentiation process of the perivascular cells into osteogenic ones. Using electron microscopy and cytochemistry we studied perivsacular cells in metaphysis of the rats femoral bones under conditions of modeling microgravity (28 days duration) and in femoral bonеs metaphyses of rats flown on board of the space laboratory (Spacelab - 2) It was revealed that population of the perivascular cells is not homogeneous in adaptive zones of the remodeling in both control and test groups (lowering support loading). This population comprises adjacent to endothelium little differentiated forms and isolated cells with differentiation features (specific volume of rough endoplasmic reticulum in cytoplasm is increased). Majority of the perivascular cells in the control group reveals reaction to alkaline phosphatase (marker of the osteogenic differentiation). In little differentiated cells this reaction is registered in nucleolus, nucleous and cytoplasm. In differentiating cells activity of the alkaline phosphatase is also detected on the outer surface of the cellular membrane. Unlike the control group in the bones of animals under microgravitaty reaction to the alkaline phosphatase is registered not for all cells of perivascular population. Part of the differentiating perivascular cells does not contain a product of the reaction. There is also visible trend of individual alkaline phosphatase containing perivascular cells amounts decrease (i.e. osteogenic cells-precursors). Under microgravity some little differentiated perivascular cells reveal destruction signs. Found decrease trend of the alkaline phosphatase containing cells (i.e. osteogenic cells) number in

  7. Osteoclast function and bone-resorbing activity: An overview.

    PubMed

    Soysa, Niroshani Surangika; Alles, Neil

    2016-07-29

    Bone resorption is an important cellular function in skeletal development and remodeling of the adult skeleton. Most of the pathological bone disease conditions like osteoporosis reflect increased osteoclast activity; hence, increased bone resorption. Researchers have unraveled most of the intracellular mechanisms responsible for osteoclast bone-resorbing activity in last few decades. Therefore, understanding the fundamentals of osteoclast-induced bone resorption and the cytokines and other substances that modulate the osteoclast activity unequivocally provide insights into the development of drugs to ameliorate pathological bone diseases with enhanced bone resorption. The aim of this review is to examine the literature on osteoclast function and bone-resorbing activity. PMID:27157135

  8. Soy Isoflavones and Osteoporotic Bone Loss: A Review with an Emphasis on Modulation of Bone Remodeling.

    PubMed

    Zheng, Xi; Lee, Sun-Kyeong; Chun, Ock K

    2016-01-01

    Osteoporosis is an age-related disorder that affects both women and men, although estrogen deficiency induced by menopause accelerates bone loss in older women. As the demographic shifts to a more aged population, a growing number of men and women will be afflicted with osteoporosis. Since the current drug therapies available have multiple side effects, including increased risk of developing certain types of cancer or complications, a search for potential nonpharmacologic alternative therapies for osteoporosis is of prime interest. Soy isoflavones (SI) have demonstrated potential bone-specific effects in a number of studies. This article provides a systematic review of studies on osteoporotic bone loss in relation to SI intake from diet or supplements to comprehensively explain how SI affect the modulation of bone remodeling. Evidence from epidemiologic studies supports that dietary SI attenuate menopause-induced osteoporotic bone loss by decreasing bone resorption and stimulating bone formation. Other studies have also illustrated that bone site-specific trophic and synergistic effects combined with exercise intervention might contribute to improve the bioavailability of SI or strengthen the bone-specific effects. To date, however, the effects of dietary SI on osteoporotic bone loss remain inconclusive, and study results vary from study to study. The current review will discuss the potential factors that result in the conflicting outcomes of these studies, including dosages, intervention materials, study duration, race, and genetic differences. Further well-designed studies are needed to fully understand the underlying mechanism and evaluate the effects of SI on osteoporosis in humans. PMID:26670451

  9. A secreted bacterial protease tailors the Staphylococcus aureus virulence repertoire to modulate bone remodeling during osteomyelitis

    PubMed Central

    Cassat, James E.; Hammer, Neal D.; Campbell, J. Preston; Benson, Meredith A.; Perrien, Daniel S.; Mrak, Lara N.; Smeltzer, Mark S.; Torres, Victor J.; Skaar, Eric P.

    2013-01-01

    Summary Osteomyelitis is a common manifestation of invasive Staphylococcus aureus infection. Pathogen-induced bone destruction limits antimicrobial penetration to the infectious focus and compromises treatment of osteomyelitis. To investigate mechanisms of S. aureus-induced bone destruction, we developed a murine model of osteomyelitis. Micro-computed tomography of infected femurs revealed that S. aureus triggers profound alterations in bone turnover. The bacterial regulatory locus sae was found to be critical for osteomyelitis pathogenesis, as Sae-regulated factors promote pathologic bone remodeling and intraosseous bacterial survival. Exoproteome analyses revealed the Sae-regulated protease aureolysin as a major determinant of the S. aureus secretome and identified the phenol soluble modulins as aureolysin-degraded, osteolytic peptides that trigger osteoblast cell death and bone destruction. These studies establish a murine model for pathogen-induced bone remodeling, define Sae as critical for osteomyelitis pathogenesis, and identify protease-dependent exoproteome remodeling as a major determinant of the staphylococcal virulence repertoire. PMID:23768499

  10. Impact of targeted PPAR gamma disruption on bone remodeling

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Peroxisome proliferator-activated receptor gamma (PPAR gamma), known as the master regulator of adipogenesis, has been regarded as a promising target for new anti-osteoporosis therapy due to its role in regulating bone marrow mesenchymal stem/progenitor cell (BMSC) lineage commitment. However, the p...

  11. Remodeling of the Mandibular Bone Induced by Overdentures Supported by Different Numbers of Implants.

    PubMed

    Li, Kai; Xin, Haitao; Zhao, Yanfang; Zhang, Zhiyuan; Wu, Yulu

    2016-05-01

    The objective of this study was to investigate the process of mandibular bone remodeling induced by implant-supported overdentures. computed tomography (CT) images were collected from edentulous patients to reconstruct the geometry of the mandibular bone and overdentures supported by implants. Based on the theory of strain energy density (SED), bone remodeling models were established using the user material subroutine (UMAT) in abaqus. The stress distribution in the mandible and bone density change was investigated to determine the effect of implant number on the remodeling of the mandibular bone. The results indicated that the areas where high Mises stress values were observed were mainly situated around the implants. The stress was concentrated in the distal neck region of the distal-most implants. With an increased number of implants, the biting force applied on the dentures was almost all taken up by implants. The stress and bone density in peri-implant bone increased. When the stress reached the threshold of remodeling, the bone density began to decrease. In the posterior mandible area, the stress was well distributed but increased with decreased implant numbers. Changes in bone density were not observed in this area. The computational results were consistent with the clinical data. The results demonstrate that the risk of bone resorption around the distal-most implants increases with increased numbers of implants and that the occlusal force applied to overdentures should be adjusted to be distributed more in the distal areas of the mandible. PMID:26963740

  12. E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-β in the bone microenvironment

    PubMed Central

    Yang, Tao; Grafe, Ingo; Bae, Yangjin; Chen, Shan; Chen, Yuqing; Bertin, Terry K.; Jiang, Ming-Ming; Ambrose, Catherine G.; Lee, Brendan

    2013-01-01

    TGF-β is abundantly produced in the skeletal system and plays a crucial role in skeletal homeostasis. E-selectin ligand-1 (ESL-1), a Golgi apparatus-localized protein, acts as a negative regulator of TGF-β bioavailability by attenuating maturation of pro–TGF-β during cartilage homeostasis. However, whether regulation of intracellular TGF-β maturation by ESL-1 is also crucial during bone homeostasis has not been well defined. Here, we show that Esl-1−/− mice exhibit a severe osteopenia with elevated bone resorption and decreased bone mineralization. In primary culture, Esl-1−/− osteoclast progenitors show no difference in osteoclastogenesis. However, Esl-1−/− osteoblasts show delayed differentiation and mineralization and stimulate osteoclastogenesis more potently in the osteoblast–osteoclast coculture, suggesting that ESL-1 primarily acts in osteoblasts to regulate bone homeostasis. In addition, Esl-1−/− calvaria exhibit an elevated mature TGF-β/pro–TGF-β ratio, with increased expression of TGF-β downstream targets (plasminogen activator inhibitor-1, parathyroid hormone-related peptide, connective tissue growth factor, and matrix metallopeptidase 13, etc.) and a key regulator of osteoclastogenesis (receptor activator of nuclear factor κB ligand). Moreover, in vivo treatment with 1D11, a pan–TGF-β antibody, significantly improved the low bone mass of Esl-1−/− mice, suggesting that elevated TGF-β signaling is the major cause of osteopenia in Esl-1−/− mice. In summary, our study identifies ESL-1 as an important regulator of bone remodeling and demonstrates that the modulation of TGF-β maturation is pivotal in the maintenance of a homeostatic bone microenvironment and for proper osteoblast–osteoclast coupling. PMID:23589896

  13. Bone-Remodeling Transcript Levels Are Independent of Perching in End-of-Lay White Leghorn Chickens

    PubMed Central

    Dale, Maurice D.; Mortimer, Erin M.; Kolli, Santharam; Achramowicz, Erik; Borchert, Glenn; Juliano, Steven A.; Halkyard, Scott; Sietz, Nick; Gatto, Craig; Hester, Patricia Y.; Rubin, David A.

    2015-01-01

    Osteoporosis is a bone disease that commonly results in a 30% incidence of fracture in hens used to produce eggs for human consumption. One of the causes of osteoporosis is the lack of mechanical strain placed on weight-bearing bones. In conventionally-caged hens, there is inadequate space for chickens to exercise and induce mechanical strain on their bones. One approach is to encourage mechanical stress on bones by the addition of perches to conventional cages. Our study focuses on the molecular mechanism of bone remodeling in end-of-lay hens (71 weeks) with access to perches. We examined bone-specific transcripts that are actively involved during development and remodeling. Using real-time quantitative PCR, we examined seven transcripts (COL2A1 (collagen, type II, alpha 1), RANKL (receptor activator of nuclear factor kappa-B ligand), OPG (osteoprotegerin), PTHLH (PTH-like hormone), PTH1R (PTH/PTHLH type-1 receptor), PTH3R (PTH/PTHLH type-3 receptor), and SOX9 (Sry-related high mobility group box)) in phalange, tibia and femur. Our results indicate that the only significant effect was a difference among bones for COL2A1 (femur > phalange). Therefore, we conclude that access to a perch did not alter transcript expression. Furthermore, because hens have been used as a model for human bone metabolism and osteoporosis, the results indicate that bone remodeling due to mechanical loading in chickens may be a product of different pathways than those involved in the mammalian model. PMID:25625518

  14. Bone-remodeling transcript levels are independent of perching in end-of-lay white leghorn chickens.

    PubMed

    Dale, Maurice D; Mortimer, Erin M; Kolli, Santharam; Achramowicz, Erik; Borchert, Glenn; Juliano, Steven A; Halkyard, Scott; Sietz, Nick; Gatto, Craig; Hester, Patricia Y; Rubin, David A

    2015-01-01

    Osteoporosis is a bone disease that commonly results in a 30% incidence of fracture in hens used to produce eggs for human consumption. One of the causes of osteoporosis is the lack of mechanical strain placed on weight-bearing bones. In conventionally-caged hens, there is inadequate space for chickens to exercise and induce mechanical strain on their bones. One approach is to encourage mechanical stress on bones by the addition of perches to conventional cages. Our study focuses on the molecular mechanism of bone remodeling in end-of-lay hens (71 weeks) with access to perches. We examined bone-specific transcripts that are actively involved during development and remodeling. Using real-time quantitative PCR, we examined seven transcripts (COL2A1 (collagen, type II, alpha 1), RANKL (receptor activator of nuclear factor kappa-B ligand), OPG (osteoprotegerin), PTHLH (PTH-like hormone), PTH1R (PTH/PTHLH type-1 receptor), PTH3R (PTH/PTHLH type-3 receptor), and SOX9 (Sry-related high mobility group box)) in phalange, tibia and femur. Our results indicate that the only significant effect was a difference among bones for COL2A1 (femur > phalange). Therefore, we conclude that access to a perch did not alter transcript expression. Furthermore, because hens have been used as a model for human bone metabolism and osteoporosis, the results indicate that bone remodeling due to mechanical loading in chickens may be a product of different pathways than those involved in the mammalian model. PMID:25625518

  15. Analysis of vitamin D metabolism gene expression in human bone: evidence for autocrine control of bone remodelling.

    PubMed

    Ormsby, Renee T; Findlay, David M; Kogawa, Masakazu; Anderson, Paul H; Morris, Howard A; Atkins, Gerald J

    2014-10-01

    The metabolism of 25-hydroxyvitamin D (25D) to active 1α,25-dihydroxyvitamin D (1,25D) by endogenous expression of 25D 1-α hydroxylase (CYP27B1) in bone cells appears to have functional effects in both osteoclasts and osteoblasts. To examine relationships between CYP27B1 expression in bone and its potential function in vivo, we examined the expression of vitamin D metabolism genes (CYP27B1, CYP24A1, VDR) in human trabecular bone samples and compared them by linear regression analysis with the expression of osteoclast (TRAP, CA2, CATK, NFATC1), osteoblast (TNAP, COL1A1, OCN, MEPE, BRIL), osteocyte (DMP1, SOST, PHEX, MEPE, FGF23)-related gene markers, genes associated with osteoblast/osteocyte control of osteoclastogenesis (RANKL, M-CSF, OPG, IL-8, TWEAK) and transcription factors (NFATC1, RUNX2, OSX, MSX2, HIF1A). This revealed multiple significant gene expression relationships between CYP27B1 and the transcription factors RUNX2, NFATC1, consistent with the coordinated expression of this gene by both osteoblast and osteoclast-lineage cells, and with MSX2 and the hypoxia-inducible transcription factor, HIF1A. CYP27B1 expression associated mainly with gene markers of bone resorption. VDR mRNA expression was also associated with resorption-related genes. Against expectations, CYP27B1 expression did not associate with bone expressed genes known to be 1,25D responsive, such as OCN, RANKL and DMP1. The major implication of these relationships in gene expression is that endogenous 1,25D synthesis and the response to 1,25D in human trabecular bone is linked with coordinated functions in both the osteoclastic and osteoblastic compartments towards the control of bone remodelling. This article is part of a Special Issue entitled '16th Vitamin D Workshop'. PMID:24120913

  16. Computational biomechanics of bone's responses to dental prostheses - osseointegration, remodeling and resorption

    NASA Astrophysics Data System (ADS)

    Li, Wei; Rungsiyakull, Chaiy; Field, Clarice; Lin, Daniel; Zhang, Leo; Li, Qing; Swain, Michael

    2010-06-01

    Clinical and experimental studies showed that human bone has the ability to remodel itself to better adapt to its biomechanical environment by changing both its material properties and geometry. As a consequence of the rapid development and extensive applications of major dental restorations such as implantation and fixed partial denture (FPD), the effect of bone remodeling on the success of a dental restorative surgery is becoming critical for prosthetic design and pre-surgical assessment. This paper aims to provide a computational biomechanics framework to address dental bone's responses as a result of dental restoration. It explored three important issues of resorption, apposition and osseointegration in terms of remodeling simulation. The published remodeling data in long bones were regulated to drive the computational remodeling prediction for the dental bones by correlating the results to clinical data. It is anticipated that the study will provide a more predictive model of dental bone response and help develop a new design methodology for patient-specific dental prosthetic restoration.

  17. A bone remodelling model including the effect of damage on the steering of BMUs.

    PubMed

    Martínez-Reina, J; Reina, I; Domínguez, J; García-Aznar, J M

    2014-04-01

    Bone remodelling in cortical bone is performed by the so-called basic multicellular units (BMUs), which produce osteons after completing the remodelling sequence. Burger et al. (2003) hypothesized that BMUs follow the direction of the prevalent local stress in the bone. More recently, Martin (2007) has shown that BMUs must be somehow guided by microstructural damage as well. The interaction of both variables, strain and damage, in the guidance of BMUs has been incorporated into a bone remodelling model for cortical bone. This model accounts for variations in porosity, anisotropy and damage level. The bone remodelling model has been applied to a finite element model of the diaphysis of a human femur. The trajectories of the BMUs have been analysed throughout the diaphysis and compared with the orientation of osteons measured experimentally. Some interesting observations, like the typical fan arrangement of osteons near the periosteum, can be explained with the proposed remodelling model. Moreover, the efficiency of BMUs in damage repairing has been shown to be greater if BMUs are guided by damage. PMID:24445006

  18. Early reversal cells in adult human bone remodeling: osteoblastic nature, catabolic functions and interactions with osteoclasts.

    PubMed

    Abdelgawad, Mohamed Essameldin; Delaisse, Jean-Marie; Hinge, Maja; Jensen, Pia Rosgaard; Alnaimi, Ragad Walid; Rolighed, Lars; Engelholm, Lars H; Marcussen, Niels; Andersen, Thomas Levin

    2016-06-01

    The mechanism coupling bone resorption and formation is a burning question that remains incompletely answered through the current investigations on osteoclasts and osteoblasts. An attractive hypothesis is that the reversal cells are likely mediators of this coupling. Their nature is a big matter of debate. The present study performed on human cancellous bone is the first one combining in situ hybridization and immunohistochemistry to demonstrate their osteoblastic nature. It shows that the Runx2 and CD56 immunoreactive reversal cells appear to take up TRAcP released by neighboring osteoclasts. Earlier preclinical studies indicate that reversal cells degrade the organic matrix left behind by the osteoclasts and that this degradation is crucial for the initiation of the subsequent bone formation. To our knowledge, this study is the first addressing these catabolic activities in adult human bone through electron microscopy and analysis of molecular markers. Periosteoclastic reversal cells show direct contacts with the osteoclasts and with the demineralized resorption debris. These early reversal cells show (1) ¾-collagen fragments typically generated by extracellular collagenases of the MMP family, (2) MMP-13 (collagenase-3) and (3) the endocytic collagen receptor uPARAP/Endo180. The prevalence of these markers was lower in the later reversal cells, which are located near the osteoid surfaces and morphologically resemble mature bone-forming osteoblasts. In conclusion, this study demonstrates that reversal cells colonizing bone surfaces right after resorption are osteoblast-lineage cells, and extends to adult human bone remodeling their role in rendering eroded surfaces osteogenic. PMID:26860863

  19. On the Use of Bone Remodelling Models to Estimate the Density Distribution of Bones. Uniqueness of the Solution

    PubMed Central

    Martínez-Reina, Javier; Ojeda, Joaquín; Mayo, Juana

    2016-01-01

    Bone remodelling models are widely used in a phenomenological manner to estimate numerically the distribution of apparent density in bones from the loads they are daily subjected to. These simulations start from an arbitrary initial distribution, usually homogeneous, and the density changes locally until a bone remodelling equilibrium is achieved. The bone response to mechanical stimulus is traditionally formulated with a mathematical relation that considers the existence of a range of stimulus, called dead or lazy zone, for which no net bone mass change occurs. Implementing a relation like that leads to different solutions depending on the starting density. The non-uniqueness of the solution has been shown in this paper using two different bone remodelling models: one isotropic and another anisotropic. It has also been shown that the problem of non-uniqueness is only mitigated by removing the dead zone, but it is not completely solved unless the bone formation and bone resorption rates are limited to certain maximum values. PMID:26859888

  20. Systemic zoledronate treatment both prevents resorption of allograft bone and increases the retention of new formed bone during revascularization and remodelling. A bone chamber study in rats

    PubMed Central

    Åstrand, Jörgen; Harding, Anna Kajsa; Aspenberg, Per; Tägil, Magnus

    2006-01-01

    Background In osteonecrosis the vascular supply of the bone is interrupted and the living cells die. The inorganic mineral network remains intact until ingrowing blood vessels invade the graft. Accompanying osteoclasts start to resorb the bone trabeculae and gradually replace the bone. If the osteonecrosis occurs in mechanically loaded parts, like in the subchondral bone of a loaded joint, the remodelling might lead to a weakening of the bone and, in consequence to a joint collapse. Systemic bisphosphonate treatment can reduce the resorption of necrotic bone. In the present study we investigate if zoledronate, the most potent of the commercially available bisphosphonates, can be used to reduce the amount or speed of bone graft remodeling. Methods Bone grafts were harvested and placed in a bone chamber inserted into the tibia of a rat. Host tissue could grow into the graft through openings in the chamber. Weekly injections with 1.05 μg zoledronate or saline were given subcutaneously until the rats were harvested after 6 weeks. The specimens were fixed, cut and stained with haematoxylin/eosin and used for histologic and histomorphometric analyses. Results By histology, the control specimens were almost totally resorbed in the remodeled area and the graft replaced by bone marrow. In the zoledronate treated specimens, both the old graft and new-formed bone remained and the graft trabeculas were lined with new bone. By histomorphometry, the total amount of bone (graft+ new bone) within the remodelled area was 35 % (SD 13) in the zoledronate treated grafts and 19 % (SD 12) in the controls (p = 0.001). Also the amount of new bone was increased in the treated specimens (22 %, SD 7) compared to the controls (14 %, SD 9, p = 0.032). Conclusion We show that zoledronate can be used to decrease the resorption of both old graft and new-formed bone during bone graft remodelling. This might be useful in bone grafting procedure but also in other orthopedic conditions, both where

  1. Mechanism of Action of Bortezomib and the New Proteasome Inhibitors on Myeloma Cells and the Bone Microenvironment: Impact on Myeloma-Induced Alterations of Bone Remodeling

    PubMed Central

    Accardi, Fabrizio; Toscani, Denise; Bolzoni, Marina; Dalla Palma, Benedetta; Aversa, Franco; Giuliani, Nicola

    2015-01-01

    Multiple myeloma (MM) is characterized by a high capacity to induce alterations in the bone remodeling process. The increase in osteoclastogenesis and the suppression of osteoblast formation are both involved in the pathophysiology of the bone lesions in MM. The proteasome inhibitor (PI) bortezomib is the first drug designed and approved for the treatment of MM patients by targeting the proteasome. However, recently novel PIs have been developed to overcome bortezomib resistance. Interestingly, several preclinical data indicate that the proteasome complex is involved in both osteoclast and osteoblast formation. It is also evident that bortezomib either inhibits osteoclast differentiation induced by the receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL) or stimulates the osteoblast differentiation. Similarly, the new PIs including carfilzomib and ixazomib can inhibit bone resorption and stimulate the osteoblast differentiation. In a clinical setting, PIs restore the abnormal bone remodeling by normalizing the levels of bone turnover markers. In addition, a bone anabolic effect was described in responding MM patients treated with PIs, as demonstrated by the increase in the osteoblast number. This review summarizes the preclinical and clinical evidence on the effects of bortezomib and other new PIs on myeloma bone disease. PMID:26579531

  2. Mechanism of Action of Bortezomib and the New Proteasome Inhibitors on Myeloma Cells and the Bone Microenvironment: Impact on Myeloma-Induced Alterations of Bone Remodeling.

    PubMed

    Accardi, Fabrizio; Toscani, Denise; Bolzoni, Marina; Dalla Palma, Benedetta; Aversa, Franco; Giuliani, Nicola

    2015-01-01

    Multiple myeloma (MM) is characterized by a high capacity to induce alterations in the bone remodeling process. The increase in osteoclastogenesis and the suppression of osteoblast formation are both involved in the pathophysiology of the bone lesions in MM. The proteasome inhibitor (PI) bortezomib is the first drug designed and approved for the treatment of MM patients by targeting the proteasome. However, recently novel PIs have been developed to overcome bortezomib resistance. Interestingly, several preclinical data indicate that the proteasome complex is involved in both osteoclast and osteoblast formation. It is also evident that bortezomib either inhibits osteoclast differentiation induced by the receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL) or stimulates the osteoblast differentiation. Similarly, the new PIs including carfilzomib and ixazomib can inhibit bone resorption and stimulate the osteoblast differentiation. In a clinical setting, PIs restore the abnormal bone remodeling by normalizing the levels of bone turnover markers. In addition, a bone anabolic effect was described in responding MM patients treated with PIs, as demonstrated by the increase in the osteoblast number. This review summarizes the preclinical and clinical evidence on the effects of bortezomib and other new PIs on myeloma bone disease. PMID:26579531

  3. A reconciliation of local and global models for bone remodeling through optimization theory.

    PubMed

    Subbarayan, G; Bartel, D L

    2000-02-01

    Remodeling rules with either a global or a local mathematical form have been proposed for load-bearing bones in the literature. In the local models, the bone architecture (shape, density) is related to the strains/energies sensed at any point in the bone, while in the global models, a criterion believed to be applicable to the whole bone is used. In the present paper, a local remodeling rule with a strain "error" form is derived as the necessary condition for the optimum of a global remodeling criterion, suggesting that many of the local error-driven remodeling rules may have corresponding global optimization-based criteria. The global criterion proposed in the present study is a trade-off between the cost of metabolic growth and use, mathematically represented by the mass, and the cost of failure, mathematically represented by the total strain energy. The proposed global criterion is shown to be related to the optimality criteria methods of structural optimization by the equivalence of the model solution and the fully stressed solution for statically determinate structures. In related work, the global criterion is applied to simulate the strength recovery in bones with screw holes left behind after removal of fracture fixation plates. The results predicted by the model are shown to be in good agreement with experimental results, leading to the conclusion that load-bearing bones are structures with optimal shape and property for their function. PMID:10790832

  4. Functional adaptation in long bones: establishing in vivo values for surface remodeling rate coefficients.

    PubMed

    Cowin, S C; Hart, R T; Balser, J R; Kohn, D H

    1985-01-01

    In this paper we describe a computational means, based on beam theory, for application of the theory of adaptive elasticity to examples of real bone geometries. The results of the animal experiments were taken from the literature, and each documented the temporal evolution of a change in bone shape after a significant change in the mechanical loading environment of the bone. For each of these studies, we establish preliminary estimates of the in vivo values of the surface remodeling rate coefficients--the key parameters in the theory of surface remodeling. Our preliminary parameter estimates are established by comparison of published animal experimental results with surface remodeling theory predictions generated by the computational method. PMID:4077864

  5. A qualitative evaluation of scaphoid remodeling in bone-grafted scaphoid nonunions.

    PubMed

    Grewal, Ruby; Boyd, Kirsty U; Macdermid, Joy; McMurtry, Robert Y

    2010-12-01

    The purpose of this case series is to identify and illustrate the phenomenon of scaphoid remodeling in skeletally mature subjects following bone grafting for scaphoid nonunion. Nine patients with scaphoid nonunions were treated with interpositional bone grafting (with iliac crest bone graft) and K-wire fixation. The mean length of follow-up was 28.6 ± 9 months. Radiographs and CT scans were reviewed and assessed for degree of union and a qualitative assessment of scaphoid architecture. Following surgery, there was marked distortion of the scaphoid. Once healed, the contour of the scaphoid was still significantly distorted in all nine patients. Remodeling then became evident along the articular surfaces between 8 and 12 months. By 3 years, the scaphoid was completely recontoured and the normal architecture was completely restored in all nine patients. We conclude that the articular surface of the scaphoid remodels over time in skeletally mature subjects. PMID:22131928

  6. Simulated bone remodeling around tilted dental implants in the anterior maxilla.

    PubMed

    Wang, Chao; Zhang, Weiping; Ajmera, Deepal Haresh; Zhang, Yun; Fan, Yubo; Ji, Ping

    2016-06-01

    Dental implants have to be placed with the long axis in different angulations due to the change in bone morphology. The objective of this study was to investigate the different bone remodeling response induced by the tilted dental implants and to assess whether it could lead to bone loss and implant failure. In this study, bone remodeling due to palato-labially inclined dental implants placed in the anterior maxillary incisor region was simulated. CT-based finite element models of a maxillary bone with dental implants were created herein. Five dental implants were placed at [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text], respectively. The remodeling progression was recorded and compared. Model [Formula: see text] (palatal side) shows the highest bone density values, but the inclined implant at [Formula: see text] (labial side) leads to significant bone loss. From a biomechanical perspective, it is speculated that a palatally inclined implant is more likely to enhance the bone density in the maxillary anterior region, but labial inclination of implant could jeopardize its stability. PMID:26285769

  7. Cytokine Combination Therapy Prediction for Bone Remodeling in Tissue Engineering Based on the Intracellular Signaling Pathway

    PubMed Central

    Sun, Xiaoqiang; Su, Jing; Bao, Jiguang; Peng, Tao; Zhang, Le; Zhang, Yuanyuan; Yang, Yunzhi; Zhou, Xiaobo

    2012-01-01

    The long-term performance of tissue-engineered bone grafts is determined by a dynamic balance between bone regeneration and resorption. We proposed using embedded cytokine slow-releasing hydrogels to tune this balance toward a desirable final bone density. In this study we established a systems biology model, and quantitatively explored the combinatorial effects of delivered cytokines from hydrogels on final bone density. We hypothesized that: 1) bone regeneration was driven by transcription factors Runx2 and Osterix, which responded to released cytokines, such as Wnt, BMP2, and TGFβ, drove the development of osteoblast lineage, and contributed to bone mass generation; and 2) the osteoclast lineage, on the other hand, governed the bone resorption, and communications between these two lineages determined the dynamics of bone remodeling. In our model, Intracellular signaling pathways were represented by ordinary differential equations, while the intercellular communications and cellular population dynamics were modeled by stochastic differential equations. Effects of synergistic cytokine combinations were evaluated by Loewe index and Bliss index. Simulation results revealed that the Wnt/BMP2 combinations released from hydrogels showed best control of bone regeneration and synergistic effects, and suggested optimal dose ratios of given cytokine combinations released from hydrogels to most efficiently control the long-term bone remodeling. We revealed the characteristics of cytokine combinations of Wnt/BMP2 which could be used to guide the design of in vivo bone scaffolds and the clinical treatment of some diseases such as osteoporosis. PMID:22910219

  8. Numerical simulation of strain-adaptive bone remodelling in the ankle joint

    PubMed Central

    2011-01-01

    Background The use of artificial endoprostheses has become a routine procedure for knee and hip joints while ankle arthritis has traditionally been treated by means of arthrodesis. Due to its advantages, the implantation of endoprostheses is constantly increasing. While finite element analyses (FEA) of strain-adaptive bone remodelling have been carried out for the hip joint in previous studies, to our knowledge there are no investigations that have considered remodelling processes of the ankle joint. In order to evaluate and optimise new generation implants of the ankle joint, as well as to gain additional knowledge regarding the biomechanics, strain-adaptive bone remodelling has been calculated separately for the tibia and the talus after providing them with an implant. Methods FE models of the bone-implant assembly for both the tibia and the talus have been developed. Bone characteristics such as the density distribution have been applied corresponding to CT scans. A force of 5,200 N, which corresponds to the compression force during normal walking of a person with a weight of 100 kg according to Stauffer et al., has been used in the simulation. The bone adaptation law, previously developed by our research team, has been used for the calculation of the remodelling processes. Results A total bone mass loss of 2% in the tibia and 13% in the talus was calculated. The greater decline of density in the talus is due to its smaller size compared to the relatively large implant dimensions causing remodelling processes in the whole bone tissue. In the tibia, bone remodelling processes are only calculated in areas adjacent to the implant. Thus, a smaller bone mass loss than in the talus can be expected. There is a high agreement between the simulation results in the distal tibia and the literature regarding. Conclusions In this study, strain-adaptive bone remodelling processes are simulated using the FE method. The results contribute to a better understanding of the

  9. Blood flow for bone remodelling correlates with locomotion in living and extinct birds.

    PubMed

    Allan, Georgina H; Cassey, Phillip; Snelling, Edward P; Maloney, Shane K; Seymour, Roger S

    2014-08-15

    Nutrient arteries enter limb bones through discrete foramina on the shafts. They are required for bone remodelling in response to mechanical loading and dynamic forces imposed by locomotion. The cross-sectional area of the nutrient foramen of the femur represents an index of blood flow rate to the shaft and thus provides insight into the animal's level of activity. Morphometric data on femoral length, mass and foramen size from 100 extant bird species and eight extinct moa species were analysed allometrically and phylogenetically. The nutrient foramen blood flow index (Qi) and femur mass (Mf) increase with body mass (Mb). At 1 kg body mass, cursorial species have approximately 2.1 times higher Qi and 1.9 times heavier Mf than volant species. The scaling of Qi on Mf is independent of the primary mode of locomotion, but the ratio Qi/Mf decreases significantly in larger birds, although absolute Qi increases. The overall avian equation for Qi on Mb is not significantly different from previous data from mammals, but when differences in blood pressure are accounted for, estimated blood flow to the femur is approximately 1.9 times higher in cursorial birds than in mammals, possibly in relation to bipedalism and quadrupedalism, respectively. Femoral bone blood flow in both endothermic groups is estimated to be 50-100 times higher than in ectothermic reptiles. PMID:24902751

  10. Bone remodeling adjacent to total hip replacements: A naturally occurring material design problem

    NASA Astrophysics Data System (ADS)

    Harrigan, Timothy P.; Hamilton, James J.

    1993-10-01

    The reaction of bone to orthopedic implants is an example of a self-adjusting material which changes from a ‘normal state’ to an altered state, based on the mechanical features of the implant and the loads applied to it. The changes in bone around cemented and uncemented femoral total hip components are well documented, and many numerical characterizations of the material reaction to stress have attempted to mimic the natural remodeling process. In this study we review the development of a simple material remodeling rule which yields a stable structure which is optimal and which allows a unique solution. We then use this algorithm to assess the effect of prosthesis stiffness and the presence of a compliant layer on bone remodeling around these implants. An axisymmetric model for axial loading is used to model changes in bone density through the thickness of the cancellous bone around the implants. With cortical remodeling left out of the simulation, the simulations showed density distributions that agreed in general with the results in the literature, and showed a marked difference in response if a compliant layer was added to the prosthesis.

  11. Histone deacetylase 3 supports endochondral bone formation by controlling cytokine signaling and matrix remodeling.

    PubMed

    Carpio, Lomeli R; Bradley, Elizabeth W; McGee-Lawrence, Meghan E; Weivoda, Megan M; Poston, Daniel D; Dudakovic, Amel; Xu, Ming; Tchkonia, Tamar; Kirkland, James L; van Wijnen, Andre J; Oursler, Merry Jo; Westendorf, Jennifer J

    2016-01-01

    Histone deacetylase (HDAC) inhibitors are efficacious epigenetic-based therapies for some cancers and neurological disorders; however, each of these drugs inhibits multiple HDACs and has detrimental effects on the skeleton. To better understand how HDAC inhibitors affect endochondral bone formation, we conditionally deleted one of their targets, Hdac3, pre- and postnatally in type II collagen α1 (Col2α1)-expressing chondrocytes. Embryonic deletion was lethal, but postnatal deletion of Hdac3 delayed secondary ossification center formation, altered maturation of growth plate chondrocytes, and increased osteoclast activity in the primary spongiosa. HDAC3-deficient chondrocytes exhibited increased expression of cytokine and matrix-degrading genes (Il-6, Mmp3, Mmp13, and Saa3) and a reduced abundance of genes related to extracellular matrix production, bone development, and ossification (Acan, Col2a1, Ihh, and Col10a1). Histone acetylation increased at and near genes that had increased expression. The acetylation and activation of nuclear factor κB (NF-κB) were also increased in HDAC3-deficient chondrocytes. Increased cytokine signaling promoted autocrine activation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and NF-κB pathways to suppress chondrocyte maturation, as well as paracrine activation of osteoclasts and bone resorption. Blockade of interleukin-6 (IL-6)-JAK-STAT signaling, NF-κB signaling, and bromodomain extraterminal proteins, which recognize acetylated lysines and promote transcriptional elongation, significantly reduced Il-6 and Mmp13 expression in HDAC3-deficient chondrocytes and secondary activation in osteoclasts. The JAK inhibitor ruxolitinib also reduced osteoclast activity in Hdac3 conditional knockout mice. Thus, HDAC3 controls the temporal and spatial expression of tissue-remodeling genes and inflammatory responses in chondrocytes to ensure proper endochondral ossification during development. PMID:27507649

  12. Genetic determination of the cellular basis of the ghrelin-dependent bone remodeling

    PubMed Central

    Ma, Chengshan; Fukuda, Toru; Ochi, Hiroki; Sunamura, Satoko; Xu, Cheng; Xu, Ren; Okawa, Atsushi; Takeda, Shu

    2015-01-01

    Objective Bone mass is maintained through a balance of bone formation and resorption. This homeostatic balance is regulated by various systems involving humoral and local factors. The discovery that the anorexigenic hormone leptin regulates bone mass via neuronal pathways revealed that neurons and neuropeptides are intimately involved in bone homeostasis. Ghrelin is a stomach-derived orexigenic hormone that counteracts leptin's action. However, the physiological role of ghrelin in bone homeostasis remains unknown. In this study, through the global knockout of ghrelin receptor (Ghsr) followed by tissue-specific re-expression, we addressed the molecular basis of the action of ghrelin in bone remodeling in vivo. Methods We performed molecular, genetic and cell biological analyses of Ghsr-null mice and Ghsr-null mice with tissue specific Ghsr restoration. Furthermore, we evaluated the molecular mechanism of ghrelin by molecular and cell-based assays. Results Ghsr-null mice showed a low bone mass phenotype with poor bone formation. Restoring the expression of Ghsr specifically in osteoblasts, and not in osteoclasts or the central nervous system, ameliorated bone abnormalities in Ghsr-null mice. Cell-based assays revealed ghrelin induced the phosphorylation of CREB and the expression of Runx2, which in turn accelerated osteoblast differentiation. Conclusions Our data show that ghrelin regulates bone remodeling through Ghsr in osteoblasts by modulating the CREB and Runx2 pathways. PMID:25737953

  13. Chromatin remodeling effects on enhancer activity.

    PubMed

    García-González, Estela; Escamilla-Del-Arenal, Martín; Arzate-Mejía, Rodrigo; Recillas-Targa, Félix

    2016-08-01

    During organism development, a diversity of cell types emerges with disparate, yet stable profiles of gene expression with distinctive cellular functions. In addition to gene promoters, the genome contains enhancer regulatory sequences, which are implicated in cellular specialization by facilitating cell-type and tissue-specific gene expression. Enhancers are DNA binding elements characterized by highly sophisticated and various mechanisms of action allowing for the specific interaction of general and tissue-specific transcription factors (TFs). However, eukaryotic organisms package their genetic material into chromatin, generating a physical barrier for TFs to interact with their cognate sequences. The ability of TFs to bind DNA regulatory elements is also modulated by changes in the chromatin structure, including histone modifications, histone variants, ATP-dependent chromatin remodeling, and the methylation status of DNA. Furthermore, it has recently been revealed that enhancer sequences are also transcribed into a set of enhancer RNAs with regulatory potential. These interdependent processes act in the context of a complex network of chromatin interactions, which together contributes to a renewed vision of how gene activation is coordinated in a cell-type-dependent manner. In this review, we describe the interplay between genetic and epigenetic aspects associated with enhancers and discuss their possible roles on enhancer function. PMID:27026300

  14. Frontal bone remodeling for gender reassignment of the male forehead: a gender-reassignment surgery.

    PubMed

    Hoenig, Johannes Franz

    2011-12-01

    Gender-reassignment therapy, especially for reshaping of the forehead, can be an effective treatment to improve self-esteem. Contouring of the cranial vault, especially of the forehead, still is a rarely performed surgical procedure for gender reassignment. In addition to surgical bone remodeling, several materials have been used for remodeling and refinement of the frontal bone. But due to shortcomings of autogenous bone material and the disadvantages of polyethylene or methylmethacrylate, hydroxyapatite cement (HAC) composed of tetracalcium phosphate and dicalcium phosphate seems to be an alternative. This study aimed to analyze the clinical outcome after frontal bone remodeling with HAC for gender male-to-female reassignment. The 21 patients in the study were treated for gender reassignment of the male frontal bone using HAC. The average age of these patients was 33.4 years (range, 21-42 years). The average volume of HAC used per patient was 3.83 g. The authors' clinical series demonstrated a satisfactory result. The surgery was easy to perform, and HAC was easy to apply and shape to suit individual needs. Overall satisfaction was very high. Therefore, HAC is a welcome alternative to the traditional use of autogenous bone graft for correction of cranial vault irregularities. PMID:21573830

  15. Bone Remodeling in Choroidal Osteoma Monitored by Fundus Photography and Spectral-Domain Optical Coherence Tomography

    PubMed Central

    Kamalden, Tengku Ain; Lingam, Gopal; Sundar, Gangadhara

    2014-01-01

    Choroidal osteoma is a benign ossifying tumor of the choroid, consisting of mature bone tissue. It has been described to enlarge and evolve at varying rates over time. Here, we report and quantify the progression of a unilateral choroidal osteoma in a 7-year-old boy by fundus photography, and document tumor remodeling by spectral domain optical coherence tomography images. PMID:27175357

  16. Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss.

    PubMed

    Yuan, X; Cao, J; Liu, T; Li, Y-P; Scannapieco, F; He, X; Oursler, M J; Zhang, X; Vacher, J; Li, C; Olson, D; Yang, S

    2015-12-01

    Regulators of G protein signaling (Rgs) have pivotal roles in controlling various cellular processes, such as cell differentiation. How Rgs proteins regulate osteoclast (OC) differentiation, function and bone homeostasis is poorly understood. It was previously demonstrated that Rgs12, the largest protein in the Rgs family, is predominantly expressed in OCs and regulates OC differentiation in vitro. To further understand the role and mechanism of Rgs12 in OC differentiation and bone diseases in vivo, we created OC-targeted Rgs12 knockout mice by using inducible Mx1-Cre and CD11b-Cre. Deletion of Rgs12 in hematopoietic cells or specifically in OC precursors resulted in increased bone mass with decreased OC numbers. Loss of Rgs12 impaired OC differentiation and function with impaired Ca(2+) oscillations and reduced nuclear factor of activated T cells (NFAT) 2 expression. The introduction of wild-type osteoblasts did not rescue the defective osteoclastogenesis. Ectopic expression of NFAT2 rescued defective OC differentiation in CD11b;Rgs12(fl/fl) cells and promoted normal OC differentiation. Moreover, deletion of Rgs12 significantly inhibited pathological osteoclastogenesis and bone destruction in Rgs12-deficient mice that were subjected to ovariectomy and lipodysaccharide for bone loss. Thus our findings demonstrate that Rgs12 is an important regulator in OC differentiation and function and identify Rgs12 as a potential therapeutic target for osteoporosis and inflammation-induced bone loss. PMID:25909889

  17. Bone remodeling during pregnancy and post-partum assessed by metal lead levels and isotopic concentrations.

    PubMed

    Gulson, Brian; Taylor, Alan; Eisman, John

    2016-08-01

    Bone remodeling is normally evaluated using bone turnover markers/indices as indicators of bone resorption and formation. However, during pregnancy and post-partum, there have been inconsistent results between and within biomarkers for bone formation and resorption. These differences may relate to pregnancy-related changes in metabolism and/or hemodilution altering measured marker levels. An alternative approach to evaluating bone remodeling is to use the metal lead (Pb) concentrations and Pb isotopic compositions in blood. These measurements can also provide information on the amount of Pb that is mobilized from the maternal skeleton. Despite some similarities with accepted bone turnover markers, the Pb data demonstrate increased bone resorption throughout pregnancy that further continues post-partum independent of length of breast-feeding, dietary intake and resumption of menses. Furthermore the isotopic measurements are not affected by hemodilution. These data confirm calcium balance studies that indicate increased bone resorption throughout pregnancy and lactation. They also indicate potentially major public health implications of the transfer of maternal Pb burden to the fetus and new born. PMID:27233973

  18. Osteocytes, not Osteoblasts or Lining Cells, are the Main Source of the RANKL Required for Osteoclast Formation in Remodeling Bone

    PubMed Central

    Xiong, Jinhu; Piemontese, Marilina; Onal, Melda; Campbell, Josh; Goellner, Joseph J.; Dusevich, Vladimir; Bonewald, Lynda; Manolagas, Stavros C.; O’Brien, Charles A.

    2015-01-01

    The cytokine receptor activator of nuclear factor kappa B ligand (RANKL), encoded by the Tnfsf11 gene, is essential for osteoclastogenesis and previous studies have shown that deletion of the Tnfsf11 gene using a Dmp1-Cre transgene reduces osteoclast formation in cancellous bone by more than 70%. However, the Dmp1-Cre transgene used in those studies leads to recombination in osteocytes, osteoblasts, and lining cells making it unclear whether one or more of these cell types produce the RANKL required for osteoclast formation in cancellous bone. Because osteoblasts, osteocytes, and lining cells have distinct locations and functions, distinguishing which of these cell types are sources of RANKL is essential for understanding the orchestration of bone remodeling. To distinguish between these possibilities, we have now created transgenic mice expressing the Cre recombinase under the control of regulatory elements of the Sost gene, which is expressed in osteocytes but not osteoblasts or lining cells in murine bone. Activity of the Sost-Cre transgene in osteocytes, but not osteoblast or lining cells, was confirmed by crossing Sost-Cre transgenic mice with tdTomato and R26R Cre-reporter mice, which express tdTomato fluorescent protein or LacZ, respectively, only in cells expressing the Cre recombinase or their descendants. Deletion of the Tnfsf11 gene in Sost-Cre mice led to a threefold decrease in osteoclast number in cancellous bone and increased cancellous bone mass, mimicking the skeletal phenotype of mice in which the Tnfsf11 gene was deleted using the Dmp1-Cre transgene. These results demonstrate that osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling cancellous bone. PMID:26393791

  19. Immunohistochemical localization of tenascin-C in rat periodontal ligament with reference to alveolar bone remodeling.

    PubMed

    Sato, Rei; Fukuoka, Hiroki; Yokohama-Tamaki, Tamaki; Kaku, Masaru; Shibata, Shunichi

    2016-03-01

    We investigated the immunohistochemical localization of tenascin-C in 8-week-old rat periodontal ligaments. Tenascin-C immunoreactivity was detected in zones along with cementum and alveolar bone, and more intensely on the resorption surface of alveolar bone than on the formation surface. On the resorbing surface, tenascin-C immunoreactivity was detected in Howship's lacunae without osteoclasts, and in the interfibrous space of the periodontal ligaments, indicating that this molecule works as an adhesion molecule between bone and fibers of periodontal ligaments. Upon experimental tooth movement by inserting elastic bands (Waldo method), the physiological resorption surface of alveolar bone under compressive force showed enhanced bone resorption and enhanced tenascin-C immunoreactivity. However, on the physiological bone formation surface under compressive force, bone resorption was seen only occasionally, and no enhanced tenascin-C immunoreactivity was noted. In an experiment involving excessive occlusal loading to rat molars, transient bone resorption occurred within interradicular septa, but no enhanced tenascin-C immunoreactivity was seen in the periodontal ligaments. These results indicate that tenascin-C works effectively on the bone resorbing surface of physiological alveolar bone remodeling sites, rather than on the non-physiological transient bone resorbing surface. Fibronectin immunoreactivity was distributed evenly in the periodontal ligaments under experimental conditions. Co-localization of tenascin-C and fibronectin immunoreactivity was observed in many regions, but mutually exclusive expression patterns were also seen in some regions, indicating that fibronectin might not be directly involved in alveolar bone remodeling, but may play a role via interaction with tenascin-C. PMID:25957016

  20. Influence of ingrowth regions on bone remodelling around a cementless hip resurfacing femoral implant.

    PubMed

    Haider, Ifaz T; Speirs, Andrew D; Beaulé, Paul E; Frei, Hanspeter

    2015-01-01

    Hip resurfacing arthroplasty is an alternative to traditional hip replacement that can conserve proximal bone stock and has gained popularity but bone resorption may limit implant survival and remains a clinical concern. The goal of this study was to analyze bone remodelling patterns around an uncemented resurfacing implant and the influence of ingrowth regions on resorption. A computed tomography-derived finite element model of a proximal femur with a virtually implanted resurfacing component was simulated under peak walking loads. Bone ingrowth was simulated by six interface conditions: fully bonded; fully friction; bonded cap with friction stem; a small bonded region at the stem-cup intersection with the remaining surface friction; fully frictional, except for a bonded band along the distal end of the cap and superior half of the cap bonded with the rest frictional. Interface condition had a large influence on remodelling patterns. Bone resorption was minimized when no ingrowth occurred at the bone-implant interface. Bonding only the superior half of the cap increased bone resorption slightly but allowed for a large ingrowth region to improve secondary stability. PMID:24697332

  1. Subchondral bone remodeling: comparing nanofracture with microfracture. An ovine in vivo study

    PubMed Central

    ZEDDE, PIETRO; CUDONI, SEBASTIANO; GIACHETTI, GIACOMO; MANUNTA, MARIA LUCIA; MASALA, GEROLAMO; BRUNETTI, ANTONIO; MANUNTA, ANDREA FABIO

    2016-01-01

    Purpose microfracture, providing direct stimulation of chondrogenic mesenchymal stem cells (MSCs) in the subchondral bone, remains the most frequently used primary cartilage repair technique. However, the newly formed type I collagen-rich fibrocartilaginous tissue has poor biomechanical properties and a tendency to degenerate. To overcome these limitations the nanofracture technique was introduced. Our purpose was to compare subchondral bone remodeling 6 months after microfracture versus nanofracture (subchondral needling) treatment in an ovine model. Methods full-thickness chondral lesions were created in the load-bearing area of the medial femoral condyles in four adult sheep. Each animal was then treated on one side with microfracture and on the contralateral side with nanofracture. Subchondral bone remodeling was assessed by micro-CT using a Bruker® SKYSCAN and CTVOX 2.7 software (Bruker Corp., Billerica, MA, USA) for image reconstruction; trabecular bone density measurements were performed through a color-representation structure thickness analysis. Results at the six-month endpoint, the microfracture-treated samples showed limited perforation depth and cone-shaped channels with large diameters at the joint surface. The channel walls displayed a high degree of regularity with significant trabecular bone compaction leading to a sealing effect with limited communication with the surrounding trabecular canals. Condyles treated with nanofracture showed channels characterized by greater depth and smaller diameters and natural irregularities of the channel walls, absence of trabecular compaction around the perforation, remarkable communication with trabecular canals, and neo-trabecular remodeling inside the channels. Conclusions nanofracture is an effective and innovative repair technique allowing deeper perforation into subchondral bone with less trabecular fragmentation and compaction when compared to microfracture; it results in better restoration of the normal

  2. Strontium-Doped Calcium Phosphate and Hydroxyapatite Granules Promote Different Inflammatory and Bone Remodelling Responses in Normal and Ovariectomised Rats

    PubMed Central

    Xia, Wei; Emanuelsson, Lena; Norlindh, Birgitta; Omar, Omar; Thomsen, Peter

    2013-01-01

    The healing of bone defects may be hindered by systemic conditions such as osteoporosis. Calcium phosphates, with or without ion substitutions, may provide advantages for bone augmentation. However, the mechanism of bone formation with these materials is unclear. The aim of this study was to evaluate the healing process in bone defects implanted with hydroxyapatite (HA) or strontium-doped calcium phosphate (SCP) granules, in non-ovariectomised (non-OVX) and ovariectomised (OVX) rats. After 0 (baseline), six and 28d, bone samples were harvested for gene expression analysis, histology and histomorphometry. Tumour necrosis factor-α (TNF-α), at six days, was higher in the HA, in non-OVX and OVX, whereas interleukin-6 (IL-6), at six and 28d, was higher in SCP, but only in non-OVX. Both materials produced a similar expression of the receptor activator of nuclear factor kappa-B ligand (RANKL). Higher expression of osteoclastic markers, calcitonin receptor (CR) and cathepsin K (CatK), were detected in the HA group, irrespective of non-OVX or OVX. The overall bone formation was comparable between HA and SCP, but with topological differences. The bone area was higher in the defect centre of the HA group, mainly in the OVX, and in the defect periphery of the SCP group, in both non-OVX and OVX. It is concluded that HA and SCP granules result in comparable bone formation in trabecular bone defects. As judged by gene expression and histological analyses, the two materials induced different inflammatory and bone remodelling responses. The modulatory effects are associated with differences in the spatial distribution of the newly formed bone. PMID:24376855

  3. Strontium-doped calcium phosphate and hydroxyapatite granules promote different inflammatory and bone remodelling responses in normal and ovariectomised rats.

    PubMed

    Cardemil, Carina; Elgali, Ibrahim; Xia, Wei; Emanuelsson, Lena; Norlindh, Birgitta; Omar, Omar; Thomsen, Peter

    2013-01-01

    The healing of bone defects may be hindered by systemic conditions such as osteoporosis. Calcium phosphates, with or without ion substitutions, may provide advantages for bone augmentation. However, the mechanism of bone formation with these materials is unclear. The aim of this study was to evaluate the healing process in bone defects implanted with hydroxyapatite (HA) or strontium-doped calcium phosphate (SCP) granules, in non-ovariectomised (non-OVX) and ovariectomised (OVX) rats. After 0 (baseline), six and 28d, bone samples were harvested for gene expression analysis, histology and histomorphometry. Tumour necrosis factor-α (TNF-α), at six days, was higher in the HA, in non-OVX and OVX, whereas interleukin-6 (IL-6), at six and 28d, was higher in SCP, but only in non-OVX. Both materials produced a similar expression of the receptor activator of nuclear factor kappa-B ligand (RANKL). Higher expression of osteoclastic markers, calcitonin receptor (CR) and cathepsin K (CatK), were detected in the HA group, irrespective of non-OVX or OVX. The overall bone formation was comparable between HA and SCP, but with topological differences. The bone area was higher in the defect centre of the HA group, mainly in the OVX, and in the defect periphery of the SCP group, in both non-OVX and OVX. It is concluded that HA and SCP granules result in comparable bone formation in trabecular bone defects. As judged by gene expression and histological analyses, the two materials induced different inflammatory and bone remodelling responses. The modulatory effects are associated with differences in the spatial distribution of the newly formed bone. PMID:24376855

  4. Predicting bone remodeling in response to total hip arthroplasty: computational study using mechanobiochemical model.

    PubMed

    Tavakkoli Avval, Pouria; Klika, Václav; Bougherara, Habiba

    2014-05-01

    Periprosthetic bone loss following total hip arthroplasty (THA) is a serious concern leading to the premature failure of prosthetic implant. Therefore, investigating bone remodeling in response to hip arthroplasty is of paramount for the purpose of designing long lasting prostheses. In this study, a thermodynamic-based theory, which considers the coupling between the mechanical loading and biochemical affinity as stimulus for bone formation and resorption, was used to simulate the femoral density change in response to THA. The results of the numerical simulations using 3D finite element analysis revealed that in Gruen zone 7, after remarkable postoperative bone loss, the bone density started recovering and got stabilized after 9% increase. The most significant periprosthetic bone loss was found in Gruen zone 7 (-17.93%) followed by zone 1 (-13.77%). Conversely, in zone 4, bone densification was observed (+4.63%). The results have also shown that the bone density loss in the posterior region of the proximal metaphysis was greater than that in the anterior side. This study provided a quantitative figure for monitoring the distribution variation of density throughout the femoral bone. The predicted bone density distribution before and after THA agree well with the bone morphology and previous results from the literature. PMID:24509505

  5. [Bone formation and corticotomy-induced accelerated bone remodeling: can alveolar corticotomy induce bone formation?].

    PubMed

    Moreau, Nathan; Charrier, Jean-Baptiste

    2015-03-01

    Current orthodontic treatments must answer an increasing demand for faster yet as efficient treatments, especially in adult patients. These past years, the amelioration of orthodontic, anesthetic and orthognathic surgery techniques have allowed considerable improvement of orthodontico-surgical treatments and of adult orthodontic treatments. Alveolar corticotomy (an example of such techniques) accelerates orthodontic tooth movements by local modifications of bone metabolism, inducing a transient osteopenia. This osteopenia allows greater tooth movements than conventional techniques. Whereas there is a growing understanding of the underlying biological mechanisms of alveolar corticotomies, there is little data regarding the osteogenic potential of such technique. In the present article, we review the literature pertaining to alveolar corticotomies and their underlying biological mechanisms and present a clinical case underlining the osteogenic potential of the technique. PMID:25888047

  6. The role of the gastrointestinal tract in calcium homeostasis and bone remodeling.

    PubMed

    Keller, J; Schinke, T

    2013-11-01

    While skeletal biology was approached in a rather isolated fashion in the past, an increasing understanding of the interplay between extraskeletal organs and bone remodeling has been obtained in recent years. This review will discuss recent advances in the field that have shed light on how the gastrointestinal tract and bone relate to each other. In particular, the importance of the GI tract in maintaining calcium homeostasis and skeletal integrity will be reviewed as impaired gastric acid production represents a major public health problem with possible implications for sufficient calcium absorption. Osteoporosis, the most prevalent bone disease worldwide, is caused not only by intrinsic defects affecting bone cell differentiation and function but also by a large set of extrinsic factors including hormonal disturbances, malnutrition, and iatrogenic drug application. Given the skeletal requirements of calcium, amino acids, and energy for bone turnover and renewal, it is not surprising that the gastrointestinal (GI) tract is of major importance for skeletal integrity. PMID:23536255

  7. Evaluation of bone remodeling in regard to the age of scaphoid non-unions

    PubMed Central

    Rein, Susanne; Hanisch, Uwe; Schaller, Hans-Eberhard; Zwipp, Hans; Rammelt, Stefan; Weindel, Stefan

    2016-01-01

    AIM: To analyse bone remodeling in regard to the age of scaphoid non-unions (SNU) with immunohistochemistry. METHODS: Thirty-six patients with symptomatic SNU underwent surgery with resection of the pseudarthrosis. The resected material was evaluated histologically after staining with hematoxylin-eosin (HE), tartrate resistant acid phosphatase (TRAP), CD 68, osteocalcin (OC) and osteopontin (OP). Histological examination was performed in a blinded fashion. RESULTS: The number of multinuclear osteoclasts in the TRAP-staining correlated with the age of the SNU and was significantly higher in younger SNU (P = 0.034; r = 0.75). A higher number of OP-immunoreactive osteoblasts significantly correlated with a higher number of OC-immunoreactive osteoblasts (P = 0.001; r = 0.55). Furthermore, a greater number of OP-immunoreactive osteoblasts correlated significantly with a higher number of OP-immunoreactive multinuclear osteoclasts (P = 0.008; r = 0.43). SNU older than 6 mo showed a significant decrease of the number of fibroblasts (P = 0.04). Smoking and the age of the patients had no influence on bone remodeling in SNU. CONCLUSION: Multinuclear osteoclasts showed a significant decrease in relation to the age of SNU. However, most of the immunhistochemical findings of bone remodeling do not correlate with the age of the SNU. This indicates a permanent imbalance of bone formation and resorption as indicated by a concurrent increase in both osteoblast and osteoclast numbers. A clear histological differentiation into phases of bone remodeling in SNU is not possible. PMID:27458552

  8. Evaluation of bone remodeling around single dental implants of different lengths: a mechanobiological numerical simulation and validation using clinical data.

    PubMed

    Sotto-Maior, Bruno Salles; Mercuri, Emílio Graciliano Ferreira; Senna, Plinio Mendes; Assis, Neuza Maria Souza Picorelli; Francischone, Carlos Eduardo; Del Bel Cury, Altair Antoninha

    2016-01-01

    Algorithmic models have been proposed to explain adaptive behavior of bone to loading; however, these models have not been applied to explain the biomechanics of short dental implants. Purpose of present study was to simulate bone remodeling around single implants of different lengths using mechanoregulatory tissue differentiation model derived from the Stanford theory, using finite elements analysis (FEA) and to validate the theoretical prediction with the clinical findings of crestal bone loss. Loading cycles were applied on 7-, 10-, or 13-mm-long dental implants to simulate daily mastication and bone remodeling was assessed by changes in the strain energy density of bone after a 3, 6, and 12 months of function. Moreover, clinical findings of marginal bone loss in 45 patients rehabilitated with same implant designs used in the simulation (n = 15) were computed to validate the theoretical results. FEA analysis showed that although the bone density values reduced over time in the cortical bone for all groups, bone remodeling was independent of implant length. Clinical data showed a similar pattern of bone resorption compared with the data generated from mathematical analyses, independent of implant length. The results of this study showed that the mechanoregulatory tissue model could be employed in monitoring the morphological changes in bone that is subjected to biomechanical loads. In addition, the implant length did not influence the bone remodeling around single dental implants during the first year of loading. PMID:26249362

  9. [Effect of dosed diet restriction on physiological remodeling and bioelectric properties of bone].

    PubMed

    Levashov, M I; Ianko, R V; Chaka, E G; Safonov, S L

    2014-07-01

    The effect of dosed diet restriction on the physiological remodeling and bioelectric properties of bone tissue was studied in 48 male Wistar rats 3- and 18-months of age. The rate of bone tissue apposition was studied by the dynamic histomorphometry method (intravital tetracycline labeling). Electric potentials on the periosteal surface of the freshly isolated femurs were recorded. The magnitude of dielectric loss factor was determined to assess the quality of bone tissue. The control rats received a standard diet. The experimental rats received a limited diet (60 % of the standard mass) for 28 days. The magnitude and rate of the bone tissue apposition on the endosteal and periosteal surface of the tibia were less by 38.4% and 122.7% respectively in experimental rats after dosed diet restriction. Electric potential in the metaphyseal-epiphyseal growth zones of the femur was 29.7% lower, and the dielectric loss factor increased by 15.8%. The bone tissue apposition rate and the electric potential magnitude were increased 10 days after completion of the dosed diet restriction. The magnitude of the dielectric loss factor decreased after returning to the standard diet. Key words: dosed diet restriction, bone, remodelling, bioelectric properties. PMID:25669112

  10. Roles of the kidney in the formation, remodeling and repair of bone.

    PubMed

    Wei, Kai; Yin, Zhiwei; Xie, Yuansheng

    2016-06-01

    The relationship between the kidney and bone is highly complex, and the kidney plays an important role in the regulation of bone development and metabolism. The kidney is the major organ involved in the regulation of calcium and phosphate homeostasis, which is essential for bone mineralization and development. Many substances synthesized by the kidney, such as 1,25(OH)2D3, Klotho, bone morphogenetic protein-7, and erythropoietin, are involved in different stages of bone formation, remodeling and repair. In addition, some cytokines which can be affected by the kidney, such as osteoprotegerin, sclerostin, fibroblast growth factor -23 and parathyroid hormone, also play important roles in bone metabolism. In this paper, we summarize the possible effects of these kidney-related cytokines on bone and their possible mechanisms. Most of these cytokines can interact with one another, constituting an intricate network between the kidney and bone. Therefore, kidney diseases should be considered among patients presenting with osteodystrophy and disturbances in bone and mineral metabolism, and treatment for renal dysfunction may accelerate their recovery. PMID:26943181

  11. Moderate-intensity rotating magnetic fields do not affect bone quality and bone remodeling in hindlimb suspended rats.

    PubMed

    Jing, Da; Cai, Jing; Wu, Yan; Shen, Guanghao; Zhai, Mingming; Tong, Shichao; Xu, Qiaoling; Xie, Kangning; Wu, Xiaoming; Tang, Chi; Xu, Xinmin; Liu, Juan; Guo, Wei; Jiang, Maogang; Luo, Erping

    2014-01-01

    Abundant evidence has substantiated the positive effects of pulsed electromagnetic fields (PEMF) and static magnetic fields (SMF) on inhibiting osteopenia and promoting fracture healing. However, the osteogenic potential of rotating magnetic fields (RMF), another common electromagnetic application modality, remains poorly characterized thus far, although numerous commercial RMF treatment devices have been available on the market. Herein the impacts of RMF on osteoporotic bone microarchitecture, bone strength and bone metabolism were systematically investigated in hindlimb-unloaded (HU) rats. Thirty two 3-month-old male Sprague-Dawley rats were randomly assigned to the Control (n = 10), HU (n = 10) and HU with RMF exposure (HU+RMF, n = 12) groups. Rats in the HU+RMF group were subjected to daily 2-hour exposure to moderate-intensity RMF (ranging from 0.60 T to 0.38 T) at 7 Hz for 4 weeks. HU caused significant decreases in body mass and soleus muscle mass of rats, which were not obviously altered by RMF. Three-point bending test showed that the mechanical properties of femurs in HU rats, including maximum load, stiffness, energy absorption and elastic modulus were not markedly affected by RMF. µCT analysis demonstrated that 4-week RMF did not significantly prevent HU-induced deterioration of femoral trabecular and cortical bone microarchitecture. Serum biochemical analysis showed that RMF did not significantly change HU-induced decrease in serum bone formation markers and increase in bone resorption markers. Bone histomorphometric analysis further confirmed that RMF showed no impacts on bone remodeling in HU rats, as evidenced by unchanged mineral apposition rate, bone formation rate, osteoblast numbers and osteoclast numbers in cancellous bone. Together, our findings reveal that RMF do not significantly affect bone microstructure, bone mechanical strength and bone remodeling in HU-induced disuse osteoporotic rats. Our study indicates potentially

  12. Moderate-Intensity Rotating Magnetic Fields Do Not Affect Bone Quality and Bone Remodeling in Hindlimb Suspended Rats

    PubMed Central

    Shen, Guanghao; Zhai, Mingming; Tong, Shichao; Xu, Qiaoling; Xie, Kangning; Wu, Xiaoming; Tang, Chi; Xu, Xinmin; Liu, Juan; Guo, Wei; Jiang, Maogang; Luo, Erping

    2014-01-01

    Abundant evidence has substantiated the positive effects of pulsed electromagnetic fields (PEMF) and static magnetic fields (SMF) on inhibiting osteopenia and promoting fracture healing. However, the osteogenic potential of rotating magnetic fields (RMF), another common electromagnetic application modality, remains poorly characterized thus far, although numerous commercial RMF treatment devices have been available on the market. Herein the impacts of RMF on osteoporotic bone microarchitecture, bone strength and bone metabolism were systematically investigated in hindlimb-unloaded (HU) rats. Thirty two 3-month-old male Sprague-Dawley rats were randomly assigned to the Control (n = 10), HU (n = 10) and HU with RMF exposure (HU+RMF, n = 12) groups. Rats in the HU+RMF group were subjected to daily 2-hour exposure to moderate-intensity RMF (ranging from 0.60 T to 0.38 T) at 7 Hz for 4 weeks. HU caused significant decreases in body mass and soleus muscle mass of rats, which were not obviously altered by RMF. Three-point bending test showed that the mechanical properties of femurs in HU rats, including maximum load, stiffness, energy absorption and elastic modulus were not markedly affected by RMF. µCT analysis demonstrated that 4-week RMF did not significantly prevent HU-induced deterioration of femoral trabecular and cortical bone microarchitecture. Serum biochemical analysis showed that RMF did not significantly change HU-induced decrease in serum bone formation markers and increase in bone resorption markers. Bone histomorphometric analysis further confirmed that RMF showed no impacts on bone remodeling in HU rats, as evidenced by unchanged mineral apposition rate, bone formation rate, osteoblast numbers and osteoclast numbers in cancellous bone. Together, our findings reveal that RMF do not significantly affect bone microstructure, bone mechanical strength and bone remodeling in HU-induced disuse osteoporotic rats. Our study indicates potentially

  13. BREAST CANCER-INDUCED BONE REMODELING, SKELETAL PAIN AND SPROUTING OF SENSORY NERVE FIBERS

    PubMed Central

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

    2011-01-01

    Breast cancer metastasis to bone is frequently accompanied by pain. What remains unclear is why this pain tends to become more severe and difficult to control with disease progression. Here we test the hypothesis that with disease progression sensory nerve fibers that innervate the breast cancer bearing bone undergo a pathological sprouting and reorganization, which in other non-malignant pathologies has been shown to generate and maintain chronic pain. Injection of human breast cancer cells (MDA-MB-231-BO) into the femoral intramedullary space of female athymic nude mice induces sprouting of calcitonin gene-related peptide (CGRP+) sensory nerve fibers. Nearly all CGRP+ nerve fibers that undergo sprouting also co-express tropomyosin receptor kinase A (TrkA+) and growth associated protein-43 (GAP43+). This ectopic sprouting occurs in periosteal sensory nerve fibers that are in close proximity to breast cancer cells, tumor-associated stromal cells and remodeled cortical bone. Therapeutic treatment with an antibody that sequesters nerve growth factor (NGF), administered when the pain and bone remodeling were first observed, blocks this ectopic sprouting and attenuates cancer pain. The present data suggest that the breast cancer cells and tumor-associated stromal cells express and release NGF, which drives bone pain and the pathological reorganization of nearby CGRP+ / TrkA+ / GAP43+ sensory nerve fibers. PMID:21497141

  14. Analyzing bone remodeling patterns after total hip arthroplasty using quantitative computed tomography and patient-specific 3D computational models

    PubMed Central

    Arachchi, Shanika; Pitto, Rocco P.; Anderson, Iain A.

    2015-01-01

    Background Computational models in the form of finite element analysis technique that incorporates bone remodeling theories along with DEXA scans has been extensively used in predicting bone remodeling patterns around the implant. However, majority of such studies used generic models. Therefore, the aim of this study is to develop patient-specific finite element models of total hip replacement patients using their quantitative computed tomography (QCT) scans and accurately analyse bone remodelling patterns after total hip arthroplasty (THA). Methods Patient-specific finite element models have been generated using the patients’ QCT scans from a previous clinical follow-up study. The femur was divided into five regions in proximal-distal direction and then further divided into four quadrants for detailed analysis of bone remodeling patterns. Two types of analysis were performed—inter-patient and intra patient to compare them and then the resulting bone remodeling patterns were quantitatively analyzed. Results Our results show that cortical bone density decrease is higher in diaphyseal region over time and the cancellous bone density decreases significantly in metaphyseal region over time. In metaphyseal region, posterior-medial (P-M) quadrant showed high bone loss while diaphyseal regions show high bone loss in anterior-lateral (A-L) quadrant. Conclusions Our study demonstrated that combining QCT with 3D patient-specific models has the ability of monitoring bone density change patterns after THA in much finer details. Future studies include using these findings for the development of a bone remodelling algorithm capable of predicting surgical outcomes for THA patients. PMID:26435921

  15. Bone morphogenetic protein-2: a potential regulator in scleral remodeling

    PubMed Central

    Hu, Jianmin; Cui, Dongmei; Yang, Xiao; Wang, Shaowei; Hu, Shoulong; Li, Chuanxu

    2008-01-01

    Purpose Bone morphogenetic protein 2 (BMP-2) is a member of the main subgroup of bone morphogenetic proteins within the transforming growth factor-β superfamily. BMP-2 is involved in numerous cellular functions including development, cell proliferation, apoptosis, and extracellular matrix synthesis. We examined BMP-2 expression in human scleral fibroblasts (HSF) and assessed the effects of recombinant human BMP-2 (rhBMP-2) on HSF proliferation, matrix metalloproteinase-2 (MMP-2), and tissue inhibitor of metalloproteinase-2 (TIMP-2). Methods We used confocal fluorescence microscopy (CFM) to study BMP-2 distribution in HSF cells and frozen human scleral sections. The influence of rhBMP-2 on cell proliferation at different concentrations (0 ng/ml, 1 ng/ml, 10 ng/ml, and 100 ng/ml) was evaluated by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. The effects of rhBMP-2 on the cell cycle were investigated with flow cytometric analysis. Reverse transcription polymerase chain reaction (RT–PCR) and enzyme-linked immunosorbent assay (ELISA) were used to examine MMP-2 and TIMP-2 mRNAs and secreted proteins in HSF that were incubated with rhBMP-2. Results BMP-2 protein expression from human sclera was confirmed by CFM. Cell proliferation was significantly increased with 100 ng/ml rhBMP-2 in a time-dependent manner (p<0.05). The HSF cell cycle moved to the S and S+G2M phases after rhBMP-2 stimulation at 100 ng/ml compared to normal cells (p<0.05). TIMP-2 mRNA levels were significantly increased in HSF incubated for 24 h with 100 ng/ml rhBMP-2 (p<0.01). A 48 h incubation with 10 ng/ml or 100 ng/ml rhBMP-2 resulted in significantly increased TIMP-2 mRNA and protein expression and significantly decreased MMP-2 mRNA expression (p<0.01) while MMP-2 protein expression significantly decreased at 100 ng/ml rhBMP-2 (p<0.01). Conclusions Human sclera fibroblasts expressed BMP-2, which promoted cell proliferation, and elicited changes in MMP-2 and TIMP-2

  16. Adaptive Bone Remodeling of the Femoral Bone After Tumor Resection Arthroplasty With an Uncemented Proximally Hydroxyapatite-Coated Stem.

    PubMed

    Andersen, Mikkel R; Petersen, Michael M

    2016-01-01

    Loss of bone stock and stress shielding is a significant challenge in limb salvage surgery. This study investigates the adaptive bone remodeling of the femoral bone after implantation of a tumor prosthesis with an uncemented press fit stem. We performed a prospective 1 yr follow-up of 6 patients (mean age: 55 (26-78) yr, female/male=3/3) who underwent bone tumor resection surgery of the proximal femur (n=3) or distal femur (n=3). Reconstruction was done using a Global Modular Replacement System (Stryker® Orthopaedics, Mahwah, NJ) tumor prosthesis, and all patients received a straight-fluted 125-mm uncemented press-fit titanium alloy stem with hydroxyapatite coating of the proximal part of the stem. Measurements of bone mineral density (BMD; g/cm2) were done postoperatively and after 3, 6, and 12 mo in the part of the femur bone containing the Global Modular Replacement System stem using dual-energy X-ray absorptiometry. BMD was measured in 3 regions of interest (ROIs) in the femur bone. Nonparametric analysis of variance (Friedman test) for evaluation of changes in BMD over time. BMD decreased in all 3 ROIs with time. In ROI 1 (p=0.01), BMD decreased by 10% after 3 mo and ended with a total decrease of 14% after 1 yr. In ROI 2 (p=0.006), BMD was decreased by 6% after 3 and 6 mo; after 1 yr of follow-up, BMD was 9% below the postoperative value. In ROI 3 (p=0.009), BMD decreased by 6% after 3 and 6 mo; after 1 yr of follow-up, BMD was 8% below the postoperative value. A bone loss of 8%-9% during the first postoperative year was seen along the femoral stem, but in the bone containing the hydroxyapatite-coated part of the stem, the decrease in BMD was 14%, thus indicating that stress shielding of this part of the bone may play a role for the adaptive bone remodeling. PMID:25843447

  17. Postextractive implants in aesthetic areas: evaluation of perimplant bone remodeling over time

    PubMed Central

    Figliuzzi, Michele Mario; Giudice, Amerigo; Cristofaro, Maria Giulia; Pacifico, Delfina; Biamonte, Pasquale; Fortunato, Leonzio

    2015-01-01

    Summary Aim The aim of this research was to assess peri-implant bone remodeling of post-extractive implants over 2 years. Material and methods 30 patients meeting pre-established inclusion criteria were enrolled for the study. One implant for each patient was inserted in the post-extraction sockets according to a defined surgical protocol (atramautic extraction, curettage of extraction socket, implant insertion, grafting with collagenated cortico-cancellous porcine bone, and a trimmed collagen membrane to completely cover the socket, suture). A temporary adhesive bridge, with an adequate profile, was bonded to the adjacent teeth. X-ray evaluation with a standardized stent was carried out at different times. Measurements were obtained from the implant edge to the bone peak. The values obtained at time 0 and at 2 years were compared by t-student test. Result Our results showed that after one year 73% of patient had 0 mm of bone reabsorption, 20% of patient had 0 mm ≤ x ≤ 0.5mm, 7% of patient had 0.5 mm ≤ x ≤ 2 mm of bone reabsorption. After two years 62% of patient had 0 mm of bone reabsorption, 24% had 0 mm ≤ x ≤ 0.5mm, 14% had 0.5 mm ≤ x ≤ 2 mm. Conclusions The results showed no significant differences in bone reabsorption in most patients over 2 years. PMID:26161250

  18. Histological Comparison in Rats between Carbonate Apatite Fabricated from Gypsum and Sintered Hydroxyapatite on Bone Remodeling.

    PubMed

    Ayukawa, Yasunori; Suzuki, Yumiko; Tsuru, Kanji; Koyano, Kiyoshi; Ishikawa, Kunio

    2015-01-01

    Carbonate apatite (CO3Ap), the form of apatite found in bone, has recently attracted attention. The purpose of the present study was to histologically evaluate the tissue/cellular response toward the low-crystalline CO3Ap fabricated using a dissolution-precipitation reaction with set gypsum as a precursor. When set gypsum was immersed in a 100°C 1 mol/L Na3PO4 aqueous solution for 24 h, the set gypsum transformed into CO3Ap. Both CO3Ap and sintered hydroxyapatite (s-HAp), which was used as a control, were implanted into surgically created tibial bone defects of rats for histological evaluation. Two and 4 weeks after the implantation, histological sections were created and observed using light microscopy. The CO3Ap granules revealed both direct apposition of the bone matrix by osteoblasts and osteoclastic resorption. In contrast, the s-HAp granules maintained their contour even after 4 weeks following implantation which implied that there was a lack of replacement into the bone. The s-HAp granules were sometimes encapsulated with fibrous tissue, and macrophage polykaryon was occasionally observed directly apposed to the implanted granules. From the viewpoint of bone remodeling, the CO3Ap granules mimicked the bone matrix, suggesting that CO3Ap may be an appropriate bone substitute. PMID:26504813

  19. Effect of sintered silicate-substituted hydroxyapatite on remodelling processes at the bone-implant interface.

    PubMed

    Porter, Alexandra E; Patel, Nelesh; Skepper, Jeremy N; Best, Serena M; Bonfield, William

    2004-07-01

    Phase pure, sintered granules of hydroxyapatite (HA) and silicon-substituted hydroxyapatite (Si-HA) were implanted for 6 and 12 weeks in an ovine model. Samples containing the bone-implant interface were prepared for ultramicrotomy and transmission electron microscopy (TEM) using an anhydrous sample preparation procedure. The results demonstrate that the morphology of apatite deposits and the sequence of events at the interfaces of bone with pure HA and with Si-HA implants, were different. Organised collagen fibrils were first found at the bone/Si-HA interface after 6 weeks, whereas they were found only after 12 weeks around the pure HA implant. Many more nodular aggregates comprised of plate-like apatite crystallites were observed in the vicinity of Si-HA than around the pure HA after 12 weeks in vivo. These findings suggest that the incorporation of silicate ions into HA promotes processes of bone remodelling at the bone/HA interface. TEM observations suggested that the trabecular bone weaves over the Si-HA and that the collagen fibrils form a mechanical interlock with the Si-HA ceramic implants. High-resolution lattice imaging illustrated apatite crystallites contiguous with the Si-HA ceramic and revealed a direct relationship between the bone mineral and the Si-HA ceramic. PMID:14980425

  20. Bone remodelation markers are useful in the management of monoclonal gammopathies.

    PubMed

    Hernández, José M; Suquía, Begoña; Queizan, José A; Fisac, Rosa M; Sanchez, José J; Fernández-Calvo, Francisco J; García-Sanz, Ramón; Olivier, Carmen; Bárez, Abelardo; Calmuntia, María J; García-Frade, Javier; Portero, Juan A; López, Rosa; Aguilera, Carmen; Navajo, Jose A; San-Miguel, Jesús F

    2004-01-01

    The evaluation of bone disease in multiple myeloma (MM) by conventional radiology has low reproducibility. In the last decade, several serum and urine biochemical parameters, for evaluation of bone turnover, have become available. The present study was designed to explore the value of six bone remodelation markers. It was studied in a series of 176 newly diagnosed patients with monoclonal gammopathies (107 MM and 69 monoclonal gammopathies of unknown significance (MGUS)). As control groups we used 25 patients with benign osteoporosis (BO) and 32 healthy individuals (HI). The bone markers analyzed included: bone resorption markers (BRM) (total pyridinoline, total deoxypyridinoline, free deoxypyridinoline and C-terminal telopeptide of collagen I) and bone formation markers (BFM) (bone alkaline phosphatase (bAP) and osteocalcin (OC)). Serum or urinary levels of BRM were significantly higher in MM patients than in MGUS patients, BO patients or HI (P < 0.001, respectively). BRM were higher in MM patients with lytic lesions. However, only C-terminal telopeptide discriminated MM patients without bone lesions from MGUS patients. BFM did not show significant differences in the aforementioned comparisons, although a trend toward higher values of OC and lower values of bAP in patients with early bone affectation was observed. Ratios BRM/BFM that contained bAP exhibited differences that were most significant between the MM group and other entities, as well as between the different MM subgroups. In fact, the ratios BRM/bAP provided discrimination between the MM subgroup without lyses and MGUS group (P < 0.01). BRM and BFM, especially the ratios, are useful in the evaluation of bone lesions in patients with monoclonal gammopathies. PMID:15570289

  1. A histomorphometric study of alveolar bone modeling and remodeling in mice fed a boron-deficient diet

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background and Objective: Emerging evidence indicates that boron (B) plays a role in bone formation and maintenance. Thus, a study was performed to determine whether dietary B-deficiency affects periodontal alveolar bone modeling and remodeling. Material and Methods: Weanling Swiss mice (n=30) were ...

  2. Impaired bone remodeling and its correction by combination therapy in a mouse model of mucopolysaccharidosis-I.

    PubMed

    Kuehn, Sonja C; Koehne, Till; Cornils, Kerstin; Markmann, Sandra; Riedel, Christoph; Pestka, Jan M; Schweizer, Michaela; Baldauf, Christina; Yorgan, Timur A; Krause, Matthias; Keller, Johannes; Neven, Mona; Breyer, Sandra; Stuecker, Ralf; Muschol, Nicole; Busse, Bjoern; Braulke, Thomas; Fehse, Boris; Amling, Michael; Schinke, Thorsten

    2015-12-15

    Mucopolysaccharidosis-I (MPS-I) is a lysosomal storage disease (LSD) caused by inactivating mutations of IDUA, encoding the glycosaminoglycan-degrading enzyme α-l-iduronidase. Although MPS-I is associated with skeletal abnormalities, the impact of IDUA deficiency on bone remodeling is poorly defined. Here we report that Idua-deficient mice progressively develop a high bone mass phenotype with pathological lysosomal storage in cells of the osteoblast lineage. Histomorphometric quantification identified shortening of bone-forming units and reduced osteoclast numbers per bone surface. This phenotype was not transferable into wild-type mice by bone marrow transplantation (BMT). In contrast, the high bone mass phenotype of Idua-deficient mice was prevented by BMT from wild-type donors. At the cellular level, BMT did not only normalize defects of Idua-deficient osteoblasts and osteocytes but additionally caused increased osteoclastogenesis. Based on clinical observations in an individual with MPS-I, previously subjected to BMT and enzyme replacement therapy (ERT), we treated Idua-deficient mice accordingly and found that combining both treatments normalized all histomorphometric parameters of bone remodeling. Our results demonstrate that BMT and ERT profoundly affect skeletal remodeling of Idua-deficient mice, thereby suggesting that individuals with MPS-I should be monitored for their bone remodeling status, before and after treatment, to avoid long-term skeletal complications. PMID:26427607

  3. Diet-induced Obesity Alters Bone Remodeling Leading to Decreased Femoral Trabecular Bone Mass in Mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Body mass derived from an obesity condition may be detrimental to bone health but the mechanism is unknown. This study was to examine changes in bone structure and serum cytokines related to bone metabolism in obese mice induced by a high-fat diet(HFD). Mice fed the HFD were obese and had higher ser...

  4. Bone remodeling markers and bone metastases: From cancer research to clinical implications

    PubMed Central

    Ferreira, Arlindo; Alho, Irina; Casimiro, Sandra; Costa, Luís

    2015-01-01

    Bone metastasis is a frequent finding in the natural history of several types of cancers. However, its anticipated risk, diagnosis and response to therapy are still challenging to assess in clinical practice. Markers of bone metabolism are biochemical by-products that provide insight into the tumor–bone interaction, with potential to enhance the clinical management of patients with bone metastases. In fact, these markers had a cornerstone role in the development of bone-targeted agents; however, its translation to routine practice is still unclear, as reflected by current international guidelines. In this review, we aimed to capture several of the research and clinical translational challenges regarding the use of bone metabolism markers that we consider relevant for future research in bone metastasis. PMID:25908969

  5. Diet-induced obesity alters bone remodeling leading to decreased femoral trabecular bone mass in mice.

    PubMed

    Cao, Jay J; Sun, Li; Gao, Hongwei

    2010-03-01

    Obesity-derived body mass may be detrimental to bone health through not well-defined mechanisms. In this study we determined changes in bone structure and serum cytokines related to bone metabolism in diet-induced obese mice. Mice fed a high-fat diet (HFD) had higher serum tartrate-resistant acid phosphatase (TRAP) and leptin but lower osteocalcin concentrations than those fed the normal-fat diet. The HFD increased multinucleated TRAP-positive osteoclasts in bone marrow compared to the control diet. Despite being much heavier, mice fed the HFD had lower femoral bone volume, trabecular number, and connectivity density and higher trabecular separation than mice on the control diet. These findings suggest that obesity induced by a HFD increases bone resorption that may blunt any positive effects of increased body weight on bone. PMID:20392249

  6. Role of Periostin in Adhesion and Migration of Bone Remodeling Cells

    PubMed Central

    Cobo, Teresa; Viloria, Cristina G.; Solares, Laura; Fontanil, Tania; González-Chamorro, Elena; De Carlos, Félix; Cobo, Juan; Cal, Santiago; Obaya, Alvaro J.

    2016-01-01

    Periostin is an extracellular matrix protein highly expressed in collagen-rich tissues subjected to continuous mechanical stress. Functionally, periostin is involved in tissue remodeling and its altered function is associated to numerous pathological processes. In orthodontics, periostin plays key roles in the maintenance of dental tissues and it is mainly expressed in those areas where tension or pressing forces are taking place. In this regard, high expression of periostin is essential to promote migration and proliferation of periodontal ligament fibroblasts. However little is known about the participation of periostin in migration and adhesion processes of bone remodeling cells. In this work we employ the mouse pre-osteoblastic MC3T3-E1 and the macrophage-like RAW 264.7 cell lines to overexpress periostin and perform different cell-based assays to study changes in cell behavior. Our data indicate that periostin overexpression not only increases adhesion capacity of MC3T3-E1 cells to different matrix proteins but also hampers their migratory capacity. Changes on RNA expression profile of MC3T3-E1 cells upon periostin overexpression have been also analyzed, highlighting the alteration of genes implicated in processes such as cell migration, adhesion or bone metabolism but not in bone differentiation. Overall, our work provides new evidence on the impact of periostin in osteoblasts physiology. PMID:26809067

  7. Prostate cancer specific integrin αvβ3 modulates bone metastatic growth and tissue remodeling

    PubMed Central

    McCabe, NP; De, S; Vasanji, A; Brainard, J; Byzova, TV

    2009-01-01

    The management of pain and morbidity owing to the spreading and growth of cancer within bone remains to be a paramount problem in clinical care. Cancer cells actively transform bone, however, the molecular requirements and mechanisms of this process remain unclear. This study shows that functional modulation of the αvβ3 integrin receptor in prostate cancer cells is required for progression within bone and determines tumor-induced bone tissue transformation. Using histology and quantitative microCT analysis, we show that αvβ3 integrin is required not only for tumor growth within the bone but for tumor-induced bone gain, a response resembling bone lesions in prostate cancer patients. Expression of normal, fully functional αvβ3 enabled tumor growth in bone (incidence: 4/4), whereas αvβ3 (—), inactive or constitutively active mutants of αvβ3 did not (incidence: 0/4, 0/6 and 1/7, respectively) within a 35-day-period. This response appeared to be bone-specific in comparison to the subcutis where tumor incidence was greater than 60% for all groups. Interestingly, bone residing prostate cancer cells expressing normal or dis-regulated αvβ3 (either inactive of constitutively active), but not those lacking β3 promoted bone gain or afforded protection from bone loss in the presence or absence of histologically detectable tumor 35 days following implantation. As bone is replete with ligands for β3 integrin, we next demonstrated that αvβ3 integrin activation on tumor cells is essential for the recognition of key bone-specific matrix proteins. As a result, prostate cancer cells expressing fully functional but not dis-regulated αvβ3 integrin are able to control their own adherence and migration to bone matrix, functions that facilitate tumor growth and control bone lesion development. PMID:17369840

  8. Disease Modification of Breast Cancer–Induced Bone Remodeling by Cannabinoid 2 Receptor Agonists

    PubMed Central

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

    2015-01-01

    Most commonly originating from breast malignancies, metastatic bone cancer causes bone destruction and severe pain. Although novel chemotherapeutic agents have increased life expectancy, patients are experiencing higher incidences of fracture, pain, and drug-induced side effects; furthermore, recent findings suggest that patients are severely undertreated for their cancer pain. Strong analgesics, namely opiates, are first-line therapy in alleviating cancer-related pain despite the severe side effects, including enhanced bone destruction with sustained administration. Bone resorption is primarily treated with bisphosphonates, which are associated with highly undesirable side effects, including nephrotoxicity and osteonecrosis of the jaw. In contrast, cannabinoid receptor 2 (CB2) receptor-specific agonists have been shown to reduce bone loss and stimulate bone formation in a model of osteoporosis. CB2 agonists produce analgesia in both inflammatory and neuropathic pain models. Notably, mixed CB1/CB2 agonists also demonstrate a reduction in ErbB2-driven breast cancer progression. Here we demonstrate for the first time that CB2 agonists reduce breast cancer–induced bone pain, bone loss, and breast cancer proliferation via cytokine/chemokine suppression. Studies used the spontaneously-occurring murine mammary cell line (66.1) implanted into the femur intramedullary space; measurements of spontaneous pain, bone loss, and cancer proliferation were made. The systemic administration of a CB2 agonist, JWH015, for 7 days significantly attenuated bone remodeling, assuaged spontaneous pain, and decreased primary tumor burden. CB2-mediated effects in vivo were reversed by concurrent treatment with a CB2 antagonist/inverse agonist but not with a CB1 antagonist/inverse agonist. In vitro, JWH015 reduced cancer cell proliferation and inflammatory mediators that have been shown to promote pain, bone loss, and proliferation. Taken together, these results suggest CB2 agonists as a

  9. Involvement of the Nonneuronal Cholinergic System in Bone Remodeling in Rat Midpalatal Suture after Rapid Maxillary Expansion

    PubMed Central

    Guo, Jie; Wang, Lue; Miao, Cong; Ge, Lihua; Tian, Zhenchuan; Wang, Jianhong

    2016-01-01

    Few studies sought to analyze the expression and function of the nonneuronal acetylcholine system in bone remodeling in vivo due to the lack of suitable models. We established a rat maxilla expansion model in which the midline palatine suture of the rat was rapidly expanded under mechanical force application, inducing tissue remodeling and new bone formation, which could be a suitable model to investigate the role of the nonneuronal acetylcholine system in bone remodeling in vivo. During the expansion, the expression pattern changes of the nonneuronal cholinergic system components and the mRNA levels of OPG/RANKL were detected by immunohistochemistry or real-time PCR. The value of the RANKL/OPG ratio significantly increased after 1 day of expansion, indicating dominant bone resorption induced by the mechanical stimulation; however after 3 days of expansion, the value of the RANKL/OPG ratio significantly decreased, suggesting a dominant role of the subsequent bone formation process. Increasing expression of Ach was detected after 3 days of expansion which indicated that ACh might play a role in bone formation. The mRNA expression levels of other components also showed observable changes during the expansion which confirmed the involvement of the nonneuronal cholinergic system in the process of bone remodeling in vivo. Further researches are still needed to figure out the detailed functions of the nonneuronal cholinergic system and its components. PMID:27478838

  10. Microarray gene expression profiling of osteoarthritic bone suggests altered bone remodelling, WNT and transforming growth factor-β/bone morphogenic protein signalling

    PubMed Central

    Hopwood, Blair; Tsykin, Anna; Findlay, David M; Fazzalari, Nicola L

    2007-01-01

    Osteoarthritis (OA) is characterized by alterations to subchondral bone as well as articular cartilage. Changes to bone in OA have also been identified at sites distal to the affected joint, which include increased bone volume fraction and reduced bone mineralization. Altered bone remodelling has been proposed to underlie these bone changes in OA. To investigate the molecular basis for these changes, we performed microarray gene expression profiling of bone obtained at autopsy from individuals with no evidence of joint disease (control) and from individuals undergoing joint replacement surgery for either degenerative hip OA, or fractured neck of femur (osteoporosis [OP]). The OP sample set was included because an inverse association, with respect to bone density, has been observed between OA and the low bone density disease OP. Compugen human 19K-oligo microarray slides were used to compare the gene expression profiles of OA, control and OP bone samples. Four sets of samples were analyzed, comprising 10 OA-control female, 10 OA-control male, 10 OA-OP female and 9 OP-control female sample pairs. Print tip Lowess normalization and Bayesian statistical analyses were carried out using linear models for microarray analysis, which identified 150 differentially expressed genes in OA bone with t scores above 4. Twenty-five of these genes were then confirmed to be differentially expressed (P < 0.01) by real-time PCR analysis. A substantial number of the top-ranking differentially expressed genes identified in OA bone are known to play roles in osteoblasts, osteocytes and osteoclasts. Many of these genes are targets of either the WNT (wingless MMTV integration) signalling pathway (TWIST1, IBSP, S100A4, MMP25, RUNX2 and CD14) or the transforming growth factor (TGF)-β/bone morphogenic protein (BMP) signalling pathway (ADAMTS4, ADM, MEPE, GADD45B, COL4A1 and FST). Other differentially expressed genes included WNT (WNT5B, NHERF1, CTNNB1 and PTEN) and TGF-β/BMP (TGFB1, SMAD3

  11. Synchrotron imaging reveals bone healing and remodelling strategies in extinct and extant vertebrates

    PubMed Central

    Anné, Jennifer; Edwards, Nicholas P.; Wogelius, Roy A.; Tumarkin-Deratzian, Allison R.; Sellers, William I.; van Veelen, Arjen; Bergmann, Uwe; Sokaras, Dimosthenis; Alonso-Mori, Roberto; Ignatyev, Konstantin; Egerton, Victoria M.; Manning, Phillip L.

    2014-01-01

    Current understanding of bone healing and remodelling strategies in vertebrates has traditionally relied on morphological observations through the histological analysis of thin sections. However, chemical analysis may also be used in such interpretations, as different elements are known to be absorbed and used by bone for different physiological purposes such as growth and healing. These chemical signatures are beyond the detection limit of most laboratory-based analytical techniques (e.g. scanning electron microscopy). However, synchrotron rapid scanning–X-ray fluorescence (SRS–XRF) is an elemental mapping technique that uniquely combines high sensitivity (ppm), excellent sample resolution (20–100 µm) and the ability to scan large specimens (decimetre scale) approximately 3000 times faster than other mapping techniques. Here, we use SRS–XRF combined with microfocus elemental mapping (2–20 µm) to determine the distribution and concentration of trace elements within pathological and normal bone of both extant and extinct archosaurs (Cathartes aura and Allosaurus fragilis). Results reveal discrete chemical inventories within different bone tissue types and preservation modes. Chemical inventories also revealed detail of histological features not observable in thin section, including fine structures within the interface between pathological and normal bone as well as woven texture within pathological tissue. PMID:24806709

  12. Synchrotron imaging reveals bone healing and remodelling strategies in extinct and extant vertebrates.

    PubMed

    Anné, Jennifer; Edwards, Nicholas P; Wogelius, Roy A; Tumarkin-Deratzian, Allison R; Sellers, William I; van Veelen, Arjen; Bergmann, Uwe; Sokaras, Dimosthenis; Alonso-Mori, Roberto; Ignatyev, Konstantin; Egerton, Victoria M; Manning, Phillip L

    2014-07-01

    Current understanding of bone healing and remodelling strategies in vertebrates has traditionally relied on morphological observations through the histological analysis of thin sections. However, chemical analysis may also be used in such interpretations, as different elements are known to be absorbed and used by bone for different physiological purposes such as growth and healing. These chemical signatures are beyond the detection limit of most laboratory-based analytical techniques (e.g. scanning electron microscopy). However, synchrotron rapid scanning-X-ray fluorescence (SRS-XRF) is an elemental mapping technique that uniquely combines high sensitivity (ppm), excellent sample resolution (20-100 µm) and the ability to scan large specimens (decimetre scale) approximately 3000 times faster than other mapping techniques. Here, we use SRS-XRF combined with microfocus elemental mapping (2-20 µm) to determine the distribution and concentration of trace elements within pathological and normal bone of both extant and extinct archosaurs (Cathartes aura and Allosaurus fragilis). Results reveal discrete chemical inventories within different bone tissue types and preservation modes. Chemical inventories also revealed detail of histological features not observable in thin section, including fine structures within the interface between pathological and normal bone as well as woven texture within pathological tissue. PMID:24806709

  13. The role of midkine in skeletal remodelling

    PubMed Central

    Liedert, A; Schinke, T; Ignatius, A; Amling, M

    2014-01-01

    Bone tissue is subjected to continuous remodelling, replacing old or damaged bone throughout life. In bone remodelling, the coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts ensure the maintenance of bone mass and strength. In early life, the balance of these cellular activities is tightly regulated by various factors, including systemic hormones, the mechanical environment and locally released growth factors. Age-related changes in the activity of these factors in bone remodelling can result in diseases with low bone mass, such as osteoporosis. Osteoporosis is a systemic and age-related skeletal disease characterized by low bone mass and structural degeneration of bone tissue, predisposing the patient to an increased fracture risk. The growth factor midkine (Mdk) plays a key role in bone remodelling and it is expressed during bone formation and fracture repair. Using a mouse deficient in Mdk, our group have identified this protein as a negative regulator of bone formation and mechanically induced bone remodelling. Thus, specific Mdk antagonists might represent a therapeutic option for diseases characterized by low bone mass, such as osteoporosis. Linked Articles This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-4 PMID:24102259

  14. Enhancement of local bone remodeling in osteoporotic rabbits by biomimic multilayered structures on Ti6Al4V implants.

    PubMed

    Huang, Ling; Luo, Zhong; Hu, Yan; Shen, Xinkun; Li, Menghuan; Li, Liqi; Zhang, Yuan; Yang, Weihu; Liu, Peng; Cai, Kaiyong

    2016-06-01

    To enhance long-term survival of titanium implants in patients with osteoporosis, chitosan/gelatin multilayers containing bone morphogenetic protein 2(BMP2) and an antiosteoporotic agent of calcitonin (CT) are deposited on the Ti6Al4V (TC4) implants through layer-by-layer (LBL) electrostatic assembly technique. Here, the obtained titanium alloy implant (TC4/LBL/CT/BMP2) can regulate the release of loaded calcitonin and BMP2 agents in a sustaining manner to accelerate the bone formation and simultaneously inhibit bone resorption. In vitro results show that the bone-related cells on TC4/LBL/CT/BMP2 present the lowest production level of tartrate resistant acid phosphatase (TRAP) but the highest (p < 0.05) level of alkaline phosphatase (ALP) activity, osteocalcin production, mineralization capacity and osteoblast-related gene expression among all groups after treatment for 7 or 21 days, respectively. Besides, in vivo studies of micro-CT analysis, routine histological and immunohistochemical analysis also collectively demonstrate that the TC4/LBL/CT/BMP2 implant can dramatically promote the formation and remodeling of new bone in osteoporotic rabbits after implantation for 30 days and 90 days, respectively. In vivo push-out testing further confirms that the TC4/LBL/CT/BMP2 implant has the highest (p < 0.01) interfacial shear strength and favorable bone-implant osseointegration. Overall, this study establishes a simple and profound methodology to fabricate a biofunctional TC4 implant for the treatment of local osteoporotic fractures in vivo. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1437-1451, 2016. PMID:26822259

  15. Organelle morphogenesis by active membrane remodeling

    NASA Astrophysics Data System (ADS)

    Ramakrishnan, N.; Ipsen, John H.; Rao, Madan; Kumar, P. B. Sunil

    Intracellular organelles are subject to a steady flux of lipids and proteins through active, energy consuming transport processes. Active fission and fusion are promoted by GTPases, e.g., Arf-Coatamer and the Rab-Snare complexes, which both sense and generate local membrane curvature. Here we investigate through Dynamical Triangulation Monte Carlo simulations, the role that these active processes play in determining the morphology and compositional segregation in closed membranes. Our results suggest that the ramified morphologies of organelles observed in-vivo are a consequence of driven nonequilibrium processes rather than equilibrium forces.

  16. Activation of α2A-adrenergic signal transduction in chondrocytes promotes degenerative remodelling of temporomandibular joint.

    PubMed

    Jiao, Kai; Zeng, Guang; Niu, Li-Na; Yang, Hong-Xu; Ren, Gao-Tong; Xu, Xin-Yue; Li, Fei-Fei; Tay, Franklin R; Wang, Mei-Qing

    2016-01-01

    This study tested whether activation of adrenoreceptors in chondrocytes has roles in degenerative remodelling of temporomandibular joint (TMJ) and to determine associated mechanisms. Unilateral anterior crossbite (UAC) was established to induce TMJ degeneration in rats. Saline vehicle, α2- and β-adrenoreceptor antagonists or agonists were injected locally into the TMJ area of UAC rats. Cartilage degeneration, subchondral bone microarchitecture and the expression of adrenoreceptors, aggrecans, matrix metalloproteinases (MMPs) and RANKL by chondrocytes were evaluated. Chondrocytes were stimulated by norepinephrine to investigate signal transduction of adrenoreceptors. Increased α2A-adrenoreceptor expression was observed in condylar cartilage of UAC rats, together with cartilage degeneration and subchondral bone loss. Norepinephrine depresses aggrecans expression but stimulates MMP-3, MMP-13 and RANKL production by chondrocytes through ERK1/2 and PKA pathway; these effects were abolished by an α2A-adrenoreceptor antagonist. Furthermore, inhibition of α2A-adrenoreceptor attenuated degenerative remodelling in the condylar cartilage and subchondral bone, as revealed by increased cartilage thickness, proteoglycans and aggrecan expression, and decreased MMP-3, MMP-13 and RANKL expressions in cartilage, increased BMD, BV/TV, and decreased Tb.Sp in subchondral bone. Conversely, activation of α2A-adrenoreceptor intensified aforementioned degenerative changes in UAC rats. It is concluded that activation of α2A-adrenergic signal in chondrocytes promotes TMJ degenerative remodelling by chondrocyte-mediated pro-catabolic activities. PMID:27452863

  17. Activation of α2A-adrenergic signal transduction in chondrocytes promotes degenerative remodelling of temporomandibular joint

    PubMed Central

    Jiao, Kai; Zeng, Guang; Niu, Li-Na; Yang, Hong-xu; Ren, Gao-tong; Xu, Xin-yue; Li, Fei-fei; Tay, Franklin R.; Wang, Mei-qing

    2016-01-01

    This study tested whether activation of adrenoreceptors in chondrocytes has roles in degenerative remodelling of temporomandibular joint (TMJ) and to determine associated mechanisms. Unilateral anterior crossbite (UAC) was established to induce TMJ degeneration in rats. Saline vehicle, α2- and β-adrenoreceptor antagonists or agonists were injected locally into the TMJ area of UAC rats. Cartilage degeneration, subchondral bone microarchitecture and the expression of adrenoreceptors, aggrecans, matrix metalloproteinases (MMPs) and RANKL by chondrocytes were evaluated. Chondrocytes were stimulated by norepinephrine to investigate signal transduction of adrenoreceptors. Increased α2A-adrenoreceptor expression was observed in condylar cartilage of UAC rats, together with cartilage degeneration and subchondral bone loss. Norepinephrine depresses aggrecans expression but stimulates MMP-3, MMP-13 and RANKL production by chondrocytes through ERK1/2 and PKA pathway; these effects were abolished by an α2A-adrenoreceptor antagonist. Furthermore, inhibition of α2A-adrenoreceptor attenuated degenerative remodelling in the condylar cartilage and subchondral bone, as revealed by increased cartilage thickness, proteoglycans and aggrecan expression, and decreased MMP-3, MMP-13 and RANKL expressions in cartilage, increased BMD, BV/TV, and decreased Tb.Sp in subchondral bone. Conversely, activation of α2A-adrenoreceptor intensified aforementioned degenerative changes in UAC rats. It is concluded that activation of α2A-adrenergic signal in chondrocytes promotes TMJ degenerative remodelling by chondrocyte-mediated pro-catabolic activities. PMID:27452863

  18. Various effects of antidepressant drugs on bone microarchitectecture, mechanical properties and bone remodeling

    SciTech Connect

    Bonnet, N. . E-mail: nicolas.bonnet15@wanadoo.fr; Bernard, P.; Beaupied, H; Bizot, J.C.; Trovero, F.; Courteix, D.; Benhamou, C.L.

    2007-05-15

    The aim of this study was to evaluate the effects of various drugs which present antidepressant properties: selective serotonin-reuptake inhibitors (SSRIs, fluoxetine), serotonin and noradrenaline-reuptake inhibitors (Desipramine) and phosphodiesterase inhibitors (PDE, rolipram and tofisopam) on bone microarchitecture and biomechanical properties. Twelve female mice were studied per group starting at an age of 10 weeks. During 4 weeks, they received subcutaneously either placebo or 20 mg kg{sup -1} day{sup -1} of desipramine, fluoxetine or 10 mg kg{sup -1} day{sup -1} of rolipram or tofisopam. Serum Osteocalcin and CTx were evaluated by ELISA. Bone microarchitecture of the distal femur was characterized by X-ray microCT (Skyscan1072). Mechanical properties were assessed by three-point bending test (Instron 4501) and antidepressant efficacy by forced swimming and open field tests. Fluoxetine displayed lower TbTh (- 6.1%, p < 0.01) and tofisopam higher TbTh (+ 5.0%, p < 0.05) versus placebo. Rolipram and tofisopam treatments induced higher BV/TV than placebo (+ 23.8% and + 18.3% respectively). Desipramine group had significantly higher cortical area (+ 4.8%, p < 0.01) and fluoxetine lower cortical area (- 6.1%, p < 0.01) compared to placebo. The stiffness and Young's modulus were lower in the fluoxetine group (77 {+-} 13 N mm{sup -1}, 6431 {+-} 1182 MPa) than in placebo (101 {+-} 9 N mm{sup -1}, 8441 {+-} 1180 MPa). Bone markers indicated a significantly higher bone formation in tofisopam (+ 8.6%) and a lower in fluoxetine (- 56.1%) compared to placebo. These data suggest deleterious effects for SSRIs, both on trabecular and cortical bone and a positive effect of PDE inhibitors on trabecular bone. Furthermore tofisopam anabolic effect in terms of bone markers, suggests a potential therapeutic effect of the PDE inhibitors on bone.

  19. Using PET/CT Bone Scan Dynamic Data to Evaluate Tibia Remodeling When a Taylor Spatial Frame Is Used: Short and Longer Term Differences

    PubMed Central

    Lundblad, Henrik; Maguire, Gerald Q.; Karlsson-Thur, Charlotte; Jonsson, Cathrine; Noz, Marilyn E.; Zeleznik, Michael P.; Jacobsson, Hans; Weidenhielm, Lars

    2015-01-01

    Eighteen consecutive patients, treated with a Taylor Spatial Frame for complex tibia conditions, gave their informed consent to undergo Na18F− PET/CT bone scans. We present a Patlak-like analysis utilizing an approximated blood time-activity curve eliminating the need for blood aliquots. Additionally, standardized uptake values (SUV) derived from dynamic acquisitions were compared to this Patlak-like approach. Spherical volumes of interest (VOIs) were drawn to include broken bone, other (normal) bone, and muscle. The SUVm(t) (m = max, mean) and a series of slopes were computed as (SUVm(ti) − SUVm(tj))/(ti − tj), for pairs of time values ti and tj. A Patlak-like analysis was performed for the same time values by computing ((VOIp(ti)/VOIe(ti))−(VOIp(tj)/VOIe(tj)))/(ti − tj), where p = broken bone, other bone, and muscle and e = expected activity in a VOI. Paired comparisons between Patlak-like and SUVm slopes showed good agreement by both linear regression and correlation coefficient analysis (r = 84%, rs = 78%-SUVmax, r = 92%, and rs = 91%-SUVmean), suggesting static scans could substitute for dynamic studies. Patlak-like slope differences of 0.1 min−1 or greater between examinations and SUVmax differences of ~5 usually indicated good remodeling progress, while negative Patlak-like slope differences of −0.06 min−1 usually indicated poor remodeling progress in this cohort. PMID:26436093

  20. Numerical model of bone remodeling sensitive to loading frequency through a poroelastic behavior and internal fluid movements.

    PubMed

    Malachanne, Etienne; Dureisseix, David; Jourdan, Franck

    2011-08-01

    In this article, a phenomenological numerical model of bone remodeling is proposed. This model is based on the poroelasticity theory in order to take into account the effects of fluid movements in bone adaptation. Moreover, the proposed remodeling law is based on the classical 'Stanford' law, enriched in order to take into account the loading frequency, through fluid movements. This coupling is materialized by a quadratic function of Darcy velocity. The numerical model is carried out, using a finite element method, and calibrated using experimental results at macroscopic level, from the literature. First results concern cyclic loadings on a mouse ulna, at different frequencies between 1 Hz and 30 Hz, for a force amplitude of 1.5 N and 2 N. Experimental results exhibit a sensitivity to the loading frequency, with privileged frequency for bone remodeling between 5 Hz and 10 Hz, for the force amplitude of 2 N. For the force amplitude of 1.5 N, no privileged frequencies for bone remodeling are highlighted. This tendency is reproduced by the proposed numerical computations. The model is identified on a single case (one frequency and one force amplitude) and validated on the other ones. The second experimental validation deals with a different loading regime, an internal fluid pressure at 20 Hz on a turkey ulna. The same framework is applied, and the numerical and experimental data are still matching in terms of gain in bone mass density. PMID:21616466

  1. Experiment K-310: The effect of space flight on ostenogenesis and dentinogenesis in the mandible of rats. Supplement 1: The effects of space flight on alveolar bone modeling and remodeling in the rat mandible

    NASA Technical Reports Server (NTRS)

    Van, P. T.; Vignery, A.; Bacon, R.

    1981-01-01

    The histomorphometric study of alveolar bone, a non-weight-bearing bone submitted mainly to the mechanical stimulations of mastication, showed that space flight decreases the remodeling activity but does not induce a negative balance between resorption and formation. The most dramatic effect of space flight has been observed along the periosteal surface, and especially in areas not covered with masticatory muscles, where bone formation almost stopped completely during the flight period. This bone, having been submitted to the same mechanical forces in the flight animals and the controls, leads to the conclusion that factors other than mechanical loading might be involved in the decreased bone formation during flight.

  2. The effects of 1,25-dihydroxycholecalciferol, parathyroid hormone, and thyroxine on trabecular bone remodeling in adult dogs. A histomorphometric study.

    PubMed Central

    High, W. B.; Capen, C. C.; Black, H. E.

    1981-01-01

    The effects of 1,25-dihydroxycholecalciferol (1,25-(OH)2D3), parathyroid hormone (PTH), and L-thyroxine (T4) on trabecular bone remodeling were evaluated by histomorphometric methods in adult female beagle dogs. Intravenous 1,25-(OH)2D3 (1.25 micrograms/day in equally divided doses) was administered intermittently for 6 days and withdrawn 14 days for three complete cycles. PTH was administered intravenously (2.5 U/kg/day) in divided doses 6 hours apart for 60 days. Thyroxine was given orally (1.0 mg/kg/day) in divided doses for a similar interval. Static and dynamic changes were evaluated using tetracycline and DCAF (2,4 BIS) N, N', Di (carboxymethyl) (amino methyl fluorescein) in vivo double labeling of bone from the iliac crest taken before treatment and after 60 days. The intermittent administration of 1,25-(OH)2D3 stimulated the bone resorption rate and depressed the formation rate. 1,25-(OH)2D3 increased trabecular resorption surfaces; osteoid surface, volume, and thickness; mineralization lag time; and osteoblast number but decreased the bone volume. Multiple small daily doses of PTH resulted in an overall negative balance in trabecular bone. This was associated with an increased trabecular surface-to-volume ratio, bone resorption and formation rates, active forming surfaces, osteoid volume and surface, life span of bone forming and resorbing sites, and the number of osteoclast nuclei. Thyroxine appeared to increase bone mass by enhancing the switch-over from the resorptive to the formative phase of remodeling. Coupling between osteoid apposition and mineralization was increased by recruiting more forming sites and prolonging their life span. Thyroxine increased bone resorption and formation rates, trabecular bone volume and balance, number of osteoclast nuclei, and life span of bone forming sites. The osteoid seam thickness and mineralization lag time were decreased. The present study demonstrated that 1,25-(OH)2D3, PTH, and thyroxine at the dose and

  3. Morphology of bone development and bone remodeling in embryonic chick limbs.

    PubMed

    Pechak, D G; Kujawa, M J; Caplan, A I

    1986-01-01

    Staged embryos from White Leghorn chicken eggs were used to assemble a detailed morphological sequence of events occurring in long bone development from Hamburger-Hamilton stage 32 through stage 44 and 2 days post hatching. The detailed patterning of osteoblasts, osteoid, mineral, and vasculature were observed at the mid-diaphysis of the tibia. At stage 32, the cartilage core is composed of hypertrophic chondrocytes and is surrounded by a continuous ring of mineralized osteoid on which osteoblasts and vasculature reside. At stage 35, the vasculature and associated cell types invade the cartilage core region. By stage 37, marrow occupies the entire cartilage core region at the mid-diaphysis. Anastamosing channels, containing vasculature, interconnect with each other and the marrow region to the inside and the periosteal region to the outside. Clearly, the cartilage is replaced by marrow, not bone. Mineral deposition at the periosteal surface continues through stage 44 as does mineral resorption on the endosteal surface, although the rate of mineral deposition and resorption varies at different developmental stages. Vasculature plays an important role in the pattern formation of the trabeculae and their channels as can be seen in the developmental sequence within one bone (the tibia) or comparisons between two bones (the tibia and fibula). A model is presented which considers the possibility that osteoprogenitor cells are formed as early as the chondroprogenitor cells. This model also emphasizes the observation that cartilage is not replaced by bone but is replaced by marrow. PMID:3801237

  4. Long-Term Administration of High-Fat Diet Corrects Abnormal Bone Remodeling in the Tibiae of Interleukin-6-Deficient Mice.

    PubMed

    Feng, Wei; Liu, Bo; Liu, Di; Hasegawa, Tomoka; Wang, Wei; Han, Xiuchun; Cui, Jian; Yimin; Oda, Kimimitsu; Amizuka, Norio; Li, Minqi

    2016-01-01

    In this study, we aimed to evaluate the influence of diet-induced obesity on IL-6 deficiency-induced bone remodeling abnormality. Seven-week-old IL-6(-/-) mice and their wild type (WT) littermates were fed a standard diet (SD) or high-fat diet (HFD) for 25 weeks. Lipid formation and bone metabolism in mice tibiae were investigated by histochemical analysis. Both IL-6(-/-) and WT mice fed the HFD showed notable body weight gain, thickened cortical bones, and adipose accumulation in the bone marrow. Notably, the HFD normalized the bone phenotype of IL-6(-/-) mice to that of their WT counterpart, as characterized by a decrease in bone mass and the presence of an obliquely arranged, plate-like morphology in the trabecular bone. Alkaline phosphatase and osteocalcin expressions were attenuated in both genotypes after HFD feeding, especially for the IL-6(-/-) mice. Meanwhile, tartrate-resistant acid phosphatase staining was inhibited, osteoclast apoptosis rate down-regulated (revealed by TUNEL assay), and the proportion of cathepsin K (CK)-positive osteoclasts significantly increased in IL-6(-/-) mice on a HFD as compared with IL-6(-/-) mice on standard chow. Our results demonstrate that HFD-induced obesity reverses IL-6 deficiency-associated bone metabolic disorders by suppressing osteoblast activity, upregulating osteoclastic activity, and inhibiting osteoclast apoptosis. PMID:26416243

  5. Senataxin controls meiotic silencing through ATR activation and chromatin remodeling

    PubMed Central

    Yeo, Abrey J; Becherel, Olivier J; Luff, John E; Graham, Mark E; Richard, Derek; Lavin, Martin F

    2015-01-01

    Senataxin, defective in ataxia oculomotor apraxia type 2, protects the genome by facilitating the resolution of RNA–DNA hybrids (R-loops) and other aspects of RNA processing. Disruption of this gene in mice causes failure of meiotic recombination and defective meiotic sex chromosome inactivation, leading to male infertility. Here we provide evidence that the disruption of Setx leads to reduced SUMOylation and disruption of protein localization across the XY body during meiosis. We demonstrate that senataxin and other DNA damage repair proteins, including ataxia telangiectasia and Rad3-related protein-interacting partner, are SUMOylated, and a marked downregulation of both ataxia telangiectasia and Rad3-related protein-interacting partner and TopBP1 leading to defective activation and signaling through ataxia telangiectasia and Rad3-related protein occurs in the absence of senataxin. Furthermore, chromodomain helicase DNA-binding protein 4, a component of the nucleosome remodeling and deacetylase chromatin remodeler that interacts with both ataxia telangiectasia and Rad3-related protein and senataxin was not recruited efficiently to the XY body, triggering altered histone acetylation and chromatin conformation in Setx−/− pachytene-staged spermatocytes. These results demonstrate that senataxin has a critical role in ataxia telangiectasia and Rad3-related protein- and chromodomain helicase DNA-binding protein 4-mediated transcriptional silencing and chromatin remodeling during meiosis providing greater insight into its critical role in gene regulation to protect against neurodegeneration. PMID:27462424

  6. One carbon metabolism and bone homeostasis and remodeling: A review of experimental research and population studies.

    PubMed

    Feigerlova, Eva; Demarquet, Lea; Guéant, Jean-Louis

    2016-07-01

    Homocysteine (HCY) is a degradation product of the methionine pathway. The B vitamins, in particular vitamin B12 and folate, are the primary nutritional determinant of HCY levels and therefore their deficiencies result in hyperhomocysteinaemia (HHCY). Prevalence of hyperhomocysteinemia (HHCY) and related dietary deficiencies in B vitamins and folate increase with age and have been related to osteoporosis and abnormal development of epiphyseal cartilage and bone in rodents. Here we provide a review of experimental and population studies. The negative effects of HHCY and/or B vitamins and folate deficiencies on bone formation and remodeling are documented by cell models, including primary osteoblasts, osteoclast and bone progenitor cells as well as by animal and human studies. However, underlying pathophysiological mechanisms are complex and remain poorly understood. Whether these associations are the direct consequences of impaired one carbon metabolism is not clarified and more studies are still needed to translate these findings to human population. To date, the evidence is limited and somewhat conflicting, however further trials in groups most vulnerable to impaired one carbon metabolism are required. PMID:27086080

  7. Effect of cyclical forces on the periodontal ligament and alveolar bone remodeling during orthodontic tooth movement

    PubMed Central

    Kalajzic, Zana; Peluso, Elizabeth Blake; Utreja, Achint; Dyment, Nathaniel; Nihara, Jun; Xu, Manshan; Chen, Jing; Uribe, Flavio; Wadhwa, Sunil

    2014-01-01

    Objective To investigate the effect of externally applied cyclical (vibratory) forces on the rate of tooth movement, the structural integrity of the periodontal ligament, and alveolar bone remodeling. Methods Twenty-six female Sprague-Dawley rats (7 weeks old) were divided into four groups: CTRL (unloaded), VBO (molars receiving a vibratory stimulus only), TMO (molars receiving an orthodontic spring only), and TMO+VB (molars receiving an orthodontic spring and the additional vibratory stimulus). In TMO and TMO+VB groups, the rat first molars were moved mesially for 2 weeks using Nickel-Titanium coil spring delivering 25 g of force. In VBO and TMO+VB groups, cyclical forces at 0.4 N and 30 Hz were applied occlusally twice a week for 10 minutes. Microfocus X-ray computed tomography analysis and tooth movement measurements were performed on the dissected rat maxillae. Tartrate-resistant acid phosphatase staining and collagen fiber assessment were performed on histological sections. Results Cyclical forces significantly inhibited the amount of tooth movement. Histological analysis showed marked disorganization of the collagen fibril structure of the periodontal ligament during tooth movement. Tooth movement caused a significant increase in osteoclast parameters on the compression side of alveolar bone and a significant decrease in bone volume fraction in the molar region compared to controls. Conclusions Tooth movement was significantly inhibited by application of cyclical forces. PMID:23937517

  8. Effects of different loading patterns on the trabecular bone morphology of the proximal femur using adaptive bone remodeling.

    PubMed

    Banijamali, S Mohammad Ali; Oftadeh, Ramin; Nazarian, Ara; Goebel, Ruben; Vaziri, Ashkan; Nayeb-Hashemi, Hamid

    2015-01-01

    In this study, the changes in the bone density of human femur model as a result of different loadings were investigated. The model initially consisted of a solid shell representing cortical bone encompassing a cubical network of interconnected rods representing trabecular bone. A computationally efficient program was developed that iteratively changed the structure of trabecular bone by keeping the local stress in the structure within a defined stress range. The stress was controlled by either enhancing existing beam elements or removing beams from the initial trabecular frame structure. Analyses were performed for two cases of homogenous isotropic and transversely isotropic beams.Trabecular bone structure was obtained for three load cases: walking, stair climbing and stumbling without falling. The results indicate that trabecular bone tissue material properties do not have a significant effect on the converged structure of trabecular bone. In addition, as the magnitude of the loads increase, the internal structure becomes denser in critical zones. Loading associated with the stumbling results in the highest density;whereas walking, considered as a routine daily activity, results in the least internal density in different regions. Furthermore, bone volume fraction at the critical regions of the converged structure is in good agreement with previously measured data obtained from combinations of dual X-ray absorptiometry (DXA) and computed tomography (CT). The results indicate that the converged bone architecture consisting of rods and plates are consistent with the natural bone morphology of the femur. The proposed model shows a promising means to understand the effects of different individual loading patterns on the bone density. PMID:25392856

  9. X-ray image review of the bone remodeling around an osseointegrated trans-femoral implant and a finite element simulation case study.

    PubMed

    Xu, Wei; Robinson, Kingsley

    2008-03-01

    The insertion of an implant into a bone leads to stress/strain redistribution, hence bone remodeling occurs adjacent to the implant. The study of the bone remodeling around the osseointegration implants can predict the long-term clinical success of the implant. The clinical medial-lateral X-rays of 11 patients were reviewed. To eliminate geometrical distortion of different X-rays, they were converted into a digital format and geometrical correction was carried out. Furthermore, the finite element (FE) method was used to investigate how the bone remodeling was affected by the stress/strain distribution in the femur. The review of clinical X-rays showed cortical bone growth around the proximal end of the implant and absorbtion at the distal end of the femur. The FE simulation revealed the stress/strain distribution in the femur of a selected patient. This provided a biomechanical interpretation of the bone remodeling. The existing bone remodeling theories such as minimal strain and strain rate theories were unable to offer satisfactory explanation for the cortical bone growth at the implant side of the proximal femur, where the stress/strain level was much lower than the one in the intact side of the femur. The study established the correlation between stress/strain distribution obtained from FE simulations and the bone remodeling of the clinical review. The cortical bone growth was initiated by the stress/strain gradient in the bone. Through the review of clinical X-rays and FE simulations, the study confirmed that the bone remodeling in a femur with an implant was influenced by the stress/strain redistribution. The strain level and stress gradient hypothesis is presented to offer an explanation for the implanted cortical bone remodeling observed in this study. PMID:18197477

  10. Development of the lateral line canal system through a bone remodeling process in zebrafish.

    PubMed

    Wada, Hironori; Iwasaki, Miki; Kawakami, Koichi

    2014-08-01

    The lateral line system of teleost fish is composed of mechanosensory receptors (neuromasts), comprising superficial receptors and others embedded in canals running under the skin. Canal diameter and size of the canal neuromasts are correlated with increasing body size, thus providing a very simple system to investigate mechanisms underlying the coordination between organ growth and body size. Here, we examine the development of the trunk lateral line canal system in zebrafish. We demonstrated that trunk canals originate from scales through a bone remodeling process, which we suggest is essential for the normal growth of canals and canal neuromasts. Moreover, we found that lateral line cells are required for the formation of canals, suggesting the existence of mutual interactions between the sensory system and surrounding connective tissues. PMID:24836859

  11. Crosstalk of osteoblast and osteoclast precursors on mineralized collagen--towards an in vitro model for bone remodeling.

    PubMed

    Bernhardt, A; Thieme, S; Domaschke, H; Springer, A; Rösen-Wolff, A; Gelinsky, M

    2010-12-01

    Bone remodeling and, therefore, integration of implant materials require the coordinated regulation of osteoblast and osteoclast activity. This is why the in vitro evaluation of biomaterials for bone regeneration should involve not only the analysis of osteoblast differentiation but also the formation and differentiation of osteoclasts. In the present study, we applied a material made of mineralized collagen I that mimics extracellular bone matrix to establish a culture system, which allows the cocultivation of human monocytes and human mesenchymal stem cells (hMSCs), which were differentiated into osteoclast-like cells and osteoblasts, respectively. Both cell types were cultivated on membrane-like structures from mineralized collagen. Transwell inserts were used to spatially separate the cell types but allowed exchange of soluble factors. The osteoclastogenesis and osteogenic differentiation were evaluated by analysis of gene expression, determination of alkaline phosphatase (ALP), and tartrate-resistant acidic phosphatase (TRAP) activity. Furthermore, cell morphology was studied using scanning electron and transmission electron microscopy. Osteogenically induced hMSC showed an increased specific ALP activity as well as increased gene expression of gene coding for alkaline phosphatase (ALPL), when cocultivated with differentiating osteoclasts. Adipogenic differentiation of hMSCs was suppressed by the presence of osteoclasts as indicated by a major decrease in adipocyte cell number and a decrease in gene expression of adipogenic markers. The formation of multinucleated osteoclasts seems to be decreased in the presence of osteogenically induced hMSC as indicated by electron microscopic evaluation and determination of TRAP activity. However, gene expression of osteoclast markers was not decreased in coculture with osteogenically induced hMSC. PMID:20824694

  12. Pleiotropic activity of lysophosphatidic acid in bone metastasis.

    PubMed

    Peyruchaud, Olivier; Leblanc, Raphael; David, Marion

    2013-01-01

    Bone is a common metastatic site for solid cancers. Bone homeostasis is tightly regulated by intimate cross-talks between osteoblast (bone forming cells) and osteoclasts (bone resorbing cells). Once in the bone microenvironment, metastatic cells do not alter bone directly but instead perturb the physiological balance of the bone remodeling process controlled by bone cells. Tumor cells produce growth factors and cytokines stimulating either osteoclast activity leading to osteolytic lesions or osteoblast function resulting in osteoblastic metastases. Growth factors, released from the resorbed bone matrix or throughout osteoblastic bone formation, sustain tumor growth. Therefore, bone metastases are the sites of vicious cycles wherein tumor growth and bone metabolism sustain each other. Lysophosphatidic acid (LPA) promotes the growth of primary tumors and metastatic dissemination of cancer cells. We have shown that by acting on cancer cells via the contribution of blood platelets and the LPA-producing enzyme Autotaxin (ATX), LPA promotes the progression of osteolytic bone metastases in animal models. In the light of recent reports it would appear that the role of LPA in the context of bone metastases is complex involving multiple sources of lipid combined with direct and indirect effects on target cells. This review will present our current knowledge on the LPA/ATX axis involvement in osteolytic and osteoblastic skeletal metastases and will discuss the potential activity of LPA upstream and downstream metastasis seeding of cancer cells to bone as well as its implication in cancer induced bone pain. This article is part of a Special Issue entitled Advances in Lysophospholipid Research. PMID:22710393

  13. Chromatin Remodeling Inactivates Activity Genes and Regulates Neural Coding

    PubMed Central

    Hill, Kelly K.; Hemberg, Martin; Reddy, Naveen C.; Cho, Ha Y.; Guthrie, Arden N.; Oldenborg, Anna; Heiney, Shane A.; Ohmae, Shogo; Medina, Javier F.; Holy, Timothy E.; Bonni, Azad

    2016-01-01

    Activity-dependent transcription influences neuronal connectivity, but the roles and mechanisms of inactivation of activity-dependent genes have remained poorly understood. Genome-wide analyses in the mouse cerebellum revealed that the nucleosome remodeling and deacetylase (NuRD) complex deposits the histone variant H2A.z at promoters of activity-dependent genes, thereby triggering their inactivation. Purification of translating mRNAs from synchronously developing granule neurons (Sync-TRAP) showed that conditional knockout of the core NuRD subunit Chd4 impairs inactivation of activity-dependent genes when neurons undergo dendrite pruning. Chd4 knockout or expression of NuRD-regulated activity genes impairs dendrite pruning. Imaging of behaving mice revealed hyperresponsivity of granule neurons to sensorimotor stimuli upon Chd4 knockout. Our findings define an epigenetic mechanism that inactivates activity-dependent transcription and regulates dendrite patterning and sensorimotor encoding in the brain. PMID:27418512

  14. Role of Cbl-PI3K Interaction during Skeletal Remodeling in a Murine Model of Bone Repair.

    PubMed

    Scanlon, Vanessa; Soung, Do Yu; Adapala, Naga Suresh; Morgan, Elise; Hansen, Marc F; Drissi, Hicham; Sanjay, Archana

    2015-01-01

    Mice in which Cbl is unable to bind PI3K (YF mice) display increased bone volume due to enhanced bone formation and repressed bone resorption during normal bone homeostasis. We investigated the effects of disrupted Cbl-PI3K interaction on fracture healing to determine whether this interaction has an effect on bone repair. Mid-diaphyseal femoral fractures induced in wild type (WT) and YF mice were temporally evaluated via micro-computed tomography scans, biomechanical testing, histological and histomorphometric analyses. Imaging analyses revealed no change in soft callus formation, increased bony callus formation, and delayed callus remodeling in YF mice compared to WT mice. Histomorphometric analyses showed significantly increased osteoblast surface per bone surface and osteoclast numbers in the calluses of YF fractured mice, as well as increased incorporation of dynamic bone labels. Furthermore, using laser capture micro-dissection of the fracture callus we found that cells lacking Cbl-PI3K interaction have higher expression of Osterix, TRAP, and Cathepsin K. We also found increased expression of genes involved in propagating PI3K signaling in cells isolated from the YF fracture callus, suggesting that the lack of Cbl-PI3K interaction perhaps results in enhanced PI3K signaling, leading to increased bone formation, but delayed remodeling in the healing femora. PMID:26393915

  15. Numerical evaluation of bone remodelling associated with trans-femoral osseointegration implant--A 68 month follow-up study.

    PubMed

    Xu, D H; Crocombe, A D; Xu, W

    2016-02-01

    Osseointegrated trans-femoral implant is a relatively new orthopaedic anchoring method for connecting a stump with a prosthesis. Through a follow-up study of a patient over six years, significant bone remodelling has been observed. Finite element (FE) simulations were carried out to investigate the relationship between the bone remodelling and the strain re-distribution around the trans-femoral osseointegrated implant system. An initial FE model representing the original status of the femur-implant assembly was created from CT scans of the subject prior to osseointegration. Follow-up X-ray images were acquired at various stages post-surgery, which allowed the changes in bone wall thickness to be measured. By updating the bone thickness in the initial model, a series of follow-up FE models were created. Representative load associated with the subject's body weight was applied to the models, and the strain re-distributions were calculated. The results showed that in order to minimise the adverse effect of bone remodelling, an osseointegration implant made by functionally gradient materials are preferred over homogeneous materials. PMID:26776932

  16. Mid-term study of bone remodeling after femoral cemented stem implantation: comparison between DXA and finite element simulation.

    PubMed

    Herrera, Antonio; Rebollo, Sarai; Ibarz, Elena; Mateo, Jesús; Gabarre, Sergio; Gracia, Luis

    2014-01-01

    This five-year prospective study was designed to investigate periprosthetic bone remodeling associated with two cemented stem models, ABG-II (Stryker) and VerSys (Zimmer), randomly implanted in patients older than 75 years. The sample consisted of 64 cases (32, ABG-II; 32, VerSys). Inclusion criterion was diagnosis of osteoarthritis recommended for cemented total hip arthroplasty. Besides clinical study, Finite Element (FE) simulation was used to analyze biomechanical changes caused by hip arthroplasty. Bone Mineral Density (BMD) measurements showed a progressive increase in bone mass throughout the entire follow-up period for both stems, well correlated with FE results except in Gruen zones 4, 5, 6 for ABG-II and in zones 4, 5 for VerSys, denoting that remodeling in those zones does not depend on mechanical factors but rather on biological or physiological ones. PMID:23725926

  17. Changes of cell-vascular complex in zones of adaptive remodeling of the bone tissue under microgravity conditions

    NASA Astrophysics Data System (ADS)

    Rodionova, N. V.; Oganov, V. S.

    2003-10-01

    We examined the peculiarities of the structure of the blood-vascular bed and perivascular cells in zones of osteogenesis in the epiphyses and metaphises of femoral bones of rats, flown aboard the US laboratory SLS-2 for two weeks by electron microscopy and histochemistry. In zones of bone remodeling, there was a tendency for a reduction of sinusoid capillary specific volume. Endotheliocytes preserve the typical structure. In the population of perivascular cells, we discovered differentiating osteogenic cells that contained alkaline phosphomonoesterase as well as cells that don't contain this enzyme and differentiate into fibroblasts. The fibroblasts genesis in zones of adaptive remodeling of spongy bones leads to a further development of fibrous tissue that is not subject to mineralization.

  18. Effects of Resveratrol Supplementation on Bone Growth in Young Rats and Microarchitecture and Remodeling in Ageing Rats

    PubMed Central

    Lee, Alice M. C.; Shandala, Tetyana; Nguyen, Long; Muhlhausler, Beverly S.; Chen, Ke-Ming; Howe, Peter R.; Xian, Cory J.

    2014-01-01

    Osteoporosis is a highly prevalent skeletal disorder in the elderly that causes serious bone fractures. Peak bone mass achieved at adolescence has been shown to predict bone mass and osteoporosis related risk fracture later in life. Resveratrol, a natural polyphenol compound, may have the potential to promote bone formation and reduce bone resorption. However, it is unclear whether it can aid bone growth and bone mass accumulation during rapid growth and modulate bone metabolism during ageing. Using rat models, the current study investigated the potential effects of resveratrol supplementation during the rapid postnatal growth period and in late adulthood (early ageing) on bone microarchitecture and metabolism. In the growth trial, 4-week-old male hooded Wistar rats on a normal chow diet were given resveratrol (2.5 mg/kg/day) or vehicle control for 5 weeks. In the ageing trial, 6-month-old male hooded Wistar rats were treated with resveratrol (20 mg/kg/day) or vehicle for 3 months. Treatment effects in the tibia were examined by μ-computer tomography (μ-CT) analysis, bone histomorphometric measurements and reverse transcription-polymerase chain reaction (RT-PCR) gene expression analysis. Resveratrol treatment did not affect trabecular bone volume and bone remodeling indices in the youth animal model. Resveratrol supplementation in the early ageing rats tended to decrease trabecular bone volume, Sirt1 gene expression and increased expression of adipogenesis-related genes in bone, all of which were statistically insignificant. However, it decreased osteocalcin expression (p = 0.03). Furthermore, serum levels of bone resorption marker C-terminal telopeptides type I collagen (CTX-1) were significantly elevated in the resveratrol supplementation group (p = 0.02) with no changes observed in serum levels of bone formation marker alkaline phosphatase (ALP). These results in rat models suggest that resveratrol supplementation does not significantly affect bone volume

  19. Effects of particle size and porosity on in vivo remodeling of settable allograft bone/polymer composites.

    PubMed

    Prieto, Edna M; Talley, Anne D; Gould, Nicholas R; Zienkiewicz, Katarzyna J; Drapeau, Susan J; Kalpakci, Kerem N; Guelcher, Scott A

    2015-11-01

    Established clinical approaches to treat bone voids include the implantation of autograft or allograft bone, ceramics, and other bone void fillers (BVFs). Composites prepared from lysine-derived polyurethanes and allograft bone can be injected as a reactive liquid and set to yield BVFs with mechanical strength comparable to trabecular bone. In this study, we investigated the effects of porosity, allograft particle size, and matrix mineralization on remodeling of injectable and settable allograft/polymer composites in a rabbit femoral condyle plug defect model. Both low viscosity and high viscosity grafts incorporating small (<105 μm) particles only partially healed at 12 weeks, and the addition of 10% demineralized bone matrix did not enhance healing. In contrast, composite grafts with large (105-500 μm) allograft particles healed at 12 weeks postimplantation, as evidenced by radial μCT and histomorphometric analysis. This study highlights particle size and surface connectivity as influential parameters regulating the remodeling of composite bone scaffolds. PMID:25581686

  20. Computational simulation of the bone remodeling using the finite element method: an elastic-damage theory for small displacements

    PubMed Central

    2013-01-01

    Background The resistance of the bone against damage by repairing itself and adapting to environmental conditions is its most important property. These adaptive changes are regulated by physiological process commonly called the bone remodeling. Better understanding this process requires that we apply the theory of elastic-damage under the hypothesis of small displacements to a bone structure and see its mechanical behavior. Results The purpose of the present study is to simulate a two dimensional model of a proximal femur by taking into consideration elastic-damage and mechanical stimulus. Here, we present a mathematical model based on a system of nonlinear ordinary differential equations and we develop the variational formulation for the mechanical problem. Then, we implement our mathematical model into the finite element method algorithm to investigate the effect of the damage. Conclusion The results are consistent with the existing literature which shows that the bone stiffness drops in damaged bone structure under mechanical loading. PMID:23663260

  1. Regulators of G protein signaling 12 (Rgs12) promotes osteoclastogenesis in bone remodeling and pathologic bone loss

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Calcium (Ca2+) signaling plays a pivotal role in controlling various cellular processes such as secretion, differentiation, proliferation, motility, and cell death through the release of Ca2+ from internal stores and entry from extracellular fluid. In bone, receptor activator of NF-kB ligand (RANKL)...

  2. Osteoporosis and alzheimer pathology: Role of cellular stress response and hormetic redox signaling in aging and bone remodeling

    PubMed Central

    Cornelius, Carolin; Koverech, Guido; Crupi, Rosalia; Di Paola, Rosanna; Koverech, Angela; Lodato, Francesca; Scuto, Maria; Salinaro, Angela T.; Cuzzocrea, Salvatore; Calabrese, Edward J.; Calabrese, Vittorio

    2014-01-01

    Alzheimer’s disease (AD) and osteoporosis are multifactorial progressive degenerative disorders. Increasing evidence shows that osteoporosis and hip fracture are common complication observed in AD patients, although the mechanisms underlying this association remain poorly understood. Reactive oxygen species (ROS) are emerging as intracellular redox signaling molecules involved in the regulation of bone metabolism, including receptor activator of nuclear factor-κB ligand-dependent osteoclast differentiation, but they also have cytotoxic effects that include lipoperoxidation and oxidative damage to proteins and DNA. ROS generation, which is implicated in the regulation of cellular stress response mechanisms, is an integrated, highly regulated, process under control of redox sensitive genes coding for redox proteins called vitagenes. Vitagenes, encoding for proteins such as heat shock proteins (Hsps) Hsp32, Hsp70, the thioredoxin, and the sirtuin protein, represent a systems controlling a complex network of intracellular signaling pathways relevant to life span and involved in the preservation of cellular homeostasis under stress conditions. Consistently, nutritional anti-oxidants have demonstrated their neuroprotective potential through a hormetic-dependent activation of vitagenes. The biological relevance of dose–response affects those strategies pointing to the optimal dosing to patients in the treatment of numerous diseases. Thus, the heat shock response has become an important hormetic target for novel cytoprotective strategies focusing on the pharmacological development of compounds capable of modulating stress response mechanisms. Here we discuss possible signaling mechanisms involved in the activation of vitagenes which, relevant to bone remodeling and through enhancement of cellular stress resistance provide a rationale to limit the deleterious consequences associated to homeostasis disruption with consequent impact on the aging process. PMID:24959146

  3. Preoperative bone quality as a factor in dual-energy X-ray absorptiometry analysis comparing bone remodelling between two implant types

    PubMed Central

    Rahmy, Ali; Grimm, Bernd; Heyligers, Ide; Tonino, Alphons

    2006-01-01

    Recently it was shown that the design changes from the ABG-I to ABG-II hip stem resulted in a better, although not significant, proximal bone preservation. Our hypothesis was that by matching patients for preoperative bone quality, statistical power would increase and that the trend of better proximal bone preservation in ABG-II might become significant. Twenty-four ABG-II patients were compared to two different ABG-I groups: (1) 25 patients from our earlier prospective study and (2) a group of 24 patients selected to perfectly match the ABG-II group regarding gender, age and preoperative bone quality. Postoperative changes in periprosthetic bone mineral density (BMD) were quantified at 2 years postoperatively using DEXA scanning. Bone preservation (less BMD loss) was better for the ABG-II than the ABG-I (all two groups) in the proximal zones 1 and 7. In Gruen zone 7, a statistically significant difference was found for group B (p = 0.03). By matching patients for preoperative bone quality and gender, a statistical significant difference was found in proximal bone preservation in favour of ABG-II. In future comparative bone remodelling studies using DEXA, patients should be matched for preoperative bone quality and gender. PMID:17086429

  4. Comprehensive profiling analysis of actively resorbing osteoclasts identifies critical signaling pathways regulated by bone substrate

    PubMed Central

    Purdue, P. Edward; Crotti, Tania N.; Shen, Zhenxin; Swantek, Jennifer; Li, Jun; Hill, Jonathan; Hanidu, Adedayo; Dimock, Janice; Nabozny, Gerald; Goldring, Steven R.; McHugh, Kevin P.

    2014-01-01

    As the only cells capable of efficiently resorbing bone, osteoclasts are central mediators of both normal bone remodeling and pathologies associates with excessive bone resorption. However, despite the clear evidence of interplay between osteoclasts and the bone surface in vivo, the role of the bone substrate in regulating osteoclast differentiation and activation at a molecular level has not been fully defined. Here, we present the first comprehensive expression profiles of osteoclasts differentiated on authentic resorbable bone substrates. This analysis has identified numerous critical pathways coordinately regulated by osteoclastogenic cytokines and bone substrate, including the transition from proliferation to differentiation, and sphingosine-1-phosphate signaling. Whilst, as expected, much of this program is dependent upon integrin beta 3, the pre-eminent mediator of osteoclast-bone interaction, a surprisingly significant portion of the bone substrate regulated expression signature is independent of this receptor. Together, these findings identify an important hitherto underappreciated role for bone substrate in osteoclastogenesis. PMID:25534583

  5. Targeted gene correction in the mdx mouse using short DNA fragments: towards application with bone marrow-derived cells for autologous remodeling of dystrophic muscle.

    PubMed

    Kapsa, R M; Quigley, A F; Vadolas, J; Steeper, K; Ioannou, P A; Byrne, E; Kornberg, A J

    2002-06-01

    In muscle, mutant genes can be targeted and corrected directly by intramuscular (i.m.) injection of corrective DNA, or by ex vivo delivery of DNA to myogenic cells, followed by cell transplantation. Short fragment homologous replacement (SFHR) has been used to repair the exon 23 nonsense transition at the Xp21.1 dys locus in cultured cells and also, directly in tibialis anterior from male mdx mice. Whilst mdx dys locus correction can be achieved in up to 20% of cells in culture, much lower efficiency is evident by i.m. injection. The major consideration for application of targeted gene correction to muscle is delivery throughout relevant tissues. Systemically injected bone marrow (BM)-derived cells from wt C57BL/10 ScSn mice are known to remodel mdx muscle when injected into the systemic route. Provided that non muscle-derived cell types most capable of muscle remodeling activity can be more specifically identified, isolated and expanded, cell therapy seems presently the most favorable vehicle by which to deliver gene correction throughout muscle tissues. Using wt bone marrow as a model, this study investigates systemic application of bone marrow-derived cells as potential vehicles to deliver corrected (ie wt) dys locus to dystrophic muscle. Intravenous (i.v.) and intraperitoneal (i.p.) injections of wt BM were given to lethally and sub-lethally irradiated mdx mice. Despite both i.v. and surviving i.p. groups containing wt dys loci in 100% and less than 1% of peripheral blood nuclei, respectively, both groups displayed equivalent levels of wt dys transcript in muscle RNA. These results suggest that the muscle remodeling activity observed in systemically injected BM cells is not likely to be found in the hemopoietic fraction. PMID:12032690

  6. Bioprinting Organotypic Hydrogels with Improved Mesenchymal Stem Cell Remodeling and Mineralization Properties for Bone Tissue Engineering.

    PubMed

    Duarte Campos, Daniela Filipa; Blaeser, Andreas; Buellesbach, Kate; Sen, Kshama Shree; Xun, Weiwei; Tillmann, Walter; Fischer, Horst

    2016-06-01

    3D-manufactured hydrogels with precise contours and biological adhesion motifs are interesting candidates in the regenerative medicine field for the culture and differentiation of human bone-marrow-derived mesenchymal stem cells (MSCs). 3D-bioprinting is a powerful technique to approach one step closer the native organization of cells. This study investigates the effect of the incorporation of collagen type I in 3D-bioprinted polysaccharide-based hydrogels to the modulation of cell morphology, osteogenic remodeling potential, and mineralization. By combining thermo-responsive agarose hydrogels with collagen type I, the mechanical stiffness and printing contours of printed constructs can be improved compared to pure collagen hydrogels which are typically used as standard materials for MSC osteogenic differentiation. The results presented here show that MSC not only survive the 3D-bioprinting process but also maintain the mesenchymal phenotype, as proved by live/dead staining and immunocytochemistry (vimentin positive, CD34 negative). Increased solids concentrations of collagen in the hydrogel blend induce changes in cell morphology, namely, by enhancing cell spreading, that ultimately contribute to enhanced and directed MSC osteogenic differentiation. 3D-bioprinted agarose-collagen hydrogels with high-collagen ratio are therefore feasible for MSC osteogenic differentiation, contrarily to low-collagen blends, as proved by two-photon microscopy, Alizarin Red staining, and real-time polymerase chain reaction. PMID:27072652

  7. The influence of different loads on the remodeling process of a bone and bioresorbable material mixture with voids

    NASA Astrophysics Data System (ADS)

    Giorgio, Ivan; Andreaus, Ugo; Madeo, Angela

    2016-03-01

    A model of a mixture of bone tissue and bioresorbable material with voids was used to numerically analyze the physiological balance between the processes of bone growth and resorption and artificial material resorption in a plate-like sample. The adopted model was derived from a theory for the behavior of porous solids in which the matrix material is linearly elastic and the interstices are void of material. The specimen—constituted by a region of bone living tissue and one of bioresorbable material—was acted by different in-plane loading conditions, namely pure bending and shear. Ranges of load magnitudes were identified within which physiological states become possible. Furthermore, the consequences of applying different loading conditions are examined at the end of the remodeling process. In particular, maximum value of bone and material mass densities, and extensions of the zones where bone is reconstructed were identified and compared in the two different load conditions. From the practical view point, during surgery planning and later rehabilitation, some choice of the following parameters is given: porosity of the graft, material characteristics of the graft, and adjustment of initial mixture tissue/bioresorbable material and later, during healing and remodeling, optimal loading conditions.

  8. Biochemical Assays for Analyzing Activities of ATP-dependent Chromatin Remodeling Enzymes

    PubMed Central

    Chen, Lu; Ooi, Soon-Keat; Conaway, Joan W.; Conaway, Ronald C.

    2014-01-01

    Members of the SNF2 family of ATPases often function as components of multi-subunit chromatin remodeling complexes that regulate nucleosome dynamics and DNA accessibility by catalyzing ATP-dependent nucleosome remodeling. Biochemically dissecting the contributions of individual subunits of such complexes to the multi-step ATP-dependent chromatin remodeling reaction requires the use of assays that monitor the production of reaction products and measure the formation of reaction intermediates. This JOVE protocol describes assays that allow one to measure the biochemical activities of chromatin remodeling complexes or subcomplexes containing various combinations of subunits. Chromatin remodeling is measured using an ATP-dependent nucleosome sliding assay, which monitors the movement of a nucleosome on a DNA molecule using an electrophoretic mobility shift assay (EMSA)-based method. Nucleosome binding activity is measured by monitoring the formation of remodeling complex-bound mononucleosomes using a similar EMSA-based method, and DNA- or nucleosome-dependent ATPase activity is assayed using thin layer chromatography (TLC) to measure the rate of conversion of ATP to ADP and phosphate in the presence of either DNA or nucleosomes. Using these assays, one can examine the functions of subunits of a chromatin remodeling complex by comparing the activities of the complete complex to those lacking one or more subunits. The human INO80 chromatin remodeling complex is used as an example; however, the methods described here can be adapted to the study of other chromatin remodeling complexes. PMID:25407555

  9. Uncemented Total Hip Replacement Stem Loosening after Long Term Compressive Stress Application: A Simulated FEA Study of Cortical Bone Remodeling

    NASA Astrophysics Data System (ADS)

    Jung, Duk-Young; Tsutsumi, Sadami; Nakai, Ryusuke; Ikeuchi, Ken; Sekel, Ron

    The purpose of this study is to predict with the use of FEA, the differing predisposition to cortical bone resorption and subsequent distal migration of an un-cemented femoral hip replacement stem subjected to long term biomechanical high compressive stresses, while varying the load angles, the material properties of the stem, and the stem length. A two-dimensional hip model was constructed to estimate the minimum principle stresses (P3) and migration magnitudes. Bone remodeling at the interface between the bone and the prosthesis was performed by comparison of the local compressive stress to physiological stress values governing bone resorption. With respect to load angles, migrations of the hip prosthesis did not occur with load angles between 63° and 74° load angle in relation to the longitudinal axis of the bony femur, as the compressive stress generated on the cortical bone was under the criteria threshold for bone resorption (-50MPa). In addition, the magnitude of migration (17%decrease) was relatively more sensitive to changes in stem length than those (92%decrease) of changes of material properties. In conclusion, using an FEA model for bone remodeling, based on the high compressive stresses exerted on distal cortical bone, it is possible to estimate migration magnitudes of cementless hip prostheses in the long term. The load angles have been shown to be an important parameter affecting the migration magnitudes and furthermore, it can be demonstrated that the stiffer materials and reduction of stem length can decrease the migration of cementless hip prosthesis in the long term.

  10. Effects of vitamin E on bone remodeling in perimenopausal women: mini review.

    PubMed

    Guralp, Onur

    2014-12-01

    Vitamin E is known to be the most important antioxidant in the body, protecting against the effects of toxic radicals. The main idea behind the studies on vitamin E and bone metabolism stems from the concept that oxidative stress may interfere with the bone formation activity of osteoblasts which in turn can lead to osteoporosis. This mini-review, summarizes the studies on the effects of vitamin E on bone mineral density, fracture risk, bone formation, and resorption markers in perimenopausal women. Current evidence does not the support daily use of vitamin E for protection against osteoporosis and hip fracture risk in perimenopausal women. However some benefit has been shown in some observational studies. Low vitamin E (>6.2mg/day) intake seems to be associated with an OR of 3.0 of hip fracture in current smokers. Compared with the highest quintile of alpha-tocopherol intake, the lowest quintile of intake conferred a multivariable-adjusted HR of 1.86 for hip fracture and 1.20 for any fracture. Alpha-tocopherol supplementation may alter the alpha-tocopherol/gamma-tocopherol ratio; which in turn may be associated with decreased osteoblastic activity. Interventional studies, especially randomized controlled trials (RCT), evaluating a possible causal relationship between serum vitamin E levels and BMD and hip fracture risk in perimenopausal women are needed. PMID:25248856

  11. Osteoimmunology: the expanding role of immunoreceptors in osteoclasts and bone remodeling

    PubMed Central

    Long, Courtney L; Humphrey, Mary Beth

    2012-01-01

    The study of bone and immunology (termed osteoimmunology) has led to the discovery of many important similarities between the two systems including shared niches, mechanisms, cytokines and receptors. The bone marrow provides a niche for hematopoietic cells including those of the lymphoid and myeloid lineage. Osteoclasts, specialized polykarons arising from myeloid precursors, bind to bone and resorb the organic and inorganic components through secretion of acid and proteases. Osteoclasts are differentiated and activated by cytokines that can be produced by immune cells and osteoclast activity can be dysregulated in states of autoimmunity or high inflammation. Similar to B and T cells, osteoclasts require coordinated co-stimulation of signaling pathways provided in the form of receptor-associated immunoreceptor tyrosine-based activation motif adaptor proteins, DAP12 and FcRγ, to drive differentiation and activation. In this review, we will cover the differentiation process of osteoclasts from the earliest precursors shown to have differentiation potential and the signals needed to drive these cells into osteoclast commitment and activation. PMID:23789115

  12. Impaired differentiation of macrophage lineage cells attenuates bone remodeling and inflammatory angiogenesis in Ndrg1 deficient mice

    PubMed Central

    Watari, Kosuke; Shibata, Tomohiro; Nabeshima, Hiroshi; Shinoda, Ai; Fukunaga, Yuichi; Kawahara, Akihiko; Karasuyama, Kazuyuki; Fukushi, Jun-ichi; Iwamoto, Yukihide; Kuwano, Michihiko; Ono, Mayumi

    2016-01-01

    N-myc downstream regulated gene 1 (NDRG1) is a responsible gene for a hereditary motor and sensory neuropathy-Lom (Charcot–Marie–Tooth disease type 4D). This is the first study aiming to assess the contribution of NDRG1 to differentiation of macrophage lineage cells, which has important implications for bone remodeling and inflammatory angiogenesis. Ndrg1 knockout (KO) mice exhibited abnormal curvature of the spine, high trabecular bone mass, and reduced number of osteoclasts. We observed that serum levels of macrophage colony-stimulating factor (M-CSF) and macrophage-related cytokines were markedly decreased in KO mice. Differentiation of bone marrow (BM) cells into osteoclasts, M1/M2-type macrophages and dendritic cells was all impaired. Furthermore, KO mice also showed reduced tumor growth and angiogenesis by cancer cells, accompanied by decreased infiltration of tumor-associated macrophages. The transfer of BM-derived macrophages from KO mice into BM-eradicated wild type (WT) mice induced much less tumor angiogenesis than observed in WT mice. Angiogenesis in corneas in response to inflammatory stimuli was also suppressed with decreased infiltration of macrophages. Taken together, these results indicate that NDRG1 deficiency attenuates the differentiation of macrophage lineage cells, suppressing bone remodeling and inflammatory angiogenesis. This study strongly suggests the crucial role of NDRG1 in differentiation process for macrophages. PMID:26778110

  13. Bone Marrow-Derived Cell-Specific Chemokine (C-C motif) Receptor-2 Expression is Required for Arteriolar Remodeling

    PubMed Central

    Nickerson, Meghan M.; Song, Ji; Meisner, Joshua K.; Bajikar, Sameer; Burke, Caitlin W.; Shuptrine, Casey W.; Owens, Gary K.; Skalak, Thomas C.; Price, Richard J.

    2009-01-01

    Objective Bone marrow-derived cells (BMCs) and inflammatory chemokine receptors regulate arteriogenesis and angiogenesis. Here, we tested whether arteriolar remodeling in response to an inflammatory stimulus is dependent on BMC-specific chemokine (C-C motif) receptor 2 (CCR2) expression and whether this response involves BMC transdifferentiation into smooth muscle. Methods and Results Dorsal skinfold window chambers were implanted into C57Bl/6 wild-type (WT) mice, as well as the following bone marrow chimeras (donor-host): WT-WT, CCR2−/−-WT, WT-CCR2−/−, and EGFP+-WT. One day after implantation, tissue MCP-1 levels rose from “undetectable” to 463pg/mg, and the number of EGFP+ cells increased more than 4-fold, indicating marked inflammation. A 66% (28μm) increase in maximum arteriolar diameter was observed over 7 days in WT-WT mice. This arteriolar remodeling response was completely abolished in CCR2−/−-WT mice but largely rescued in WT-CCR2−/− mice. EGFP+ BMCs were numerous throughout the tissue, but we found no evidence that EGFP+ BMCs transdifferentiate into smooth muscle, based on examination of >800 arterioles and venules. Conclusions BMC-specific CCR2 expression is required for injury/inflammation-associated arteriolar remodeling, but this response is not characterized by the differentiation of BMCs into smooth muscle. PMID:19734197

  14. A second gradient continuum model accounting for some effects of micro-structure on reconstructed bone remodelling

    NASA Astrophysics Data System (ADS)

    Madeo, Angela; George, D.; Lekszycki, T.; Nierenberger, Mathieu; Rémond, Yves

    2012-08-01

    We propose a second gradient, two-solids, continuum mixture model with variable masses to describe the effect of micro-structure on mechanically-driven remodelling of bones grafted with bio-resorbable materials. A one-dimensional numerical simulation is addressed showing the potentialities of the proposed generalized continuum model. In particular, we show that the used second gradient model allows for the description of some micro-structure-related size effects which are known to be important in hierarchically heterogeneous materials like reconstructed bones. Moreover, the influence of the introduced second gradient parameters on the final percentages of replacement of artificial bio-material with natural bone tissue is presented and discussed.

  15. Remodeling and Tenacity of Inhibitory Synapses: Relationships with Network Activity and Neighboring Excitatory Synapses

    PubMed Central

    Rubinski, Anna; Ziv, Noam E.

    2015-01-01

    Glutamatergic synapse size remodeling is governed not only by specific activity forms but also by apparently stochastic processes with well-defined statistics. These spontaneous remodeling processes can give rise to skewed and stable synaptic size distributions, underlie scaling of these distributions and drive changes in glutamatergic synapse size “configurations”. Where inhibitory synapses are concerned, however, little is known on spontaneous remodeling dynamics, their statistics, their activity dependence or their long-term consequences. Here we followed individual inhibitory synapses for days, and analyzed their size remodeling dynamics within the statistical framework previously developed for glutamatergic synapses. Similar to glutamatergic synapses, size distributions of inhibitory synapses were skewed and stable; at the same time, however, sizes of individual synapses changed considerably, leading to gradual changes in synaptic size configurations. The suppression of network activity only transiently affected spontaneous remodeling dynamics, did not affect synaptic size configuration change rates and was not followed by the scaling of inhibitory synapse size distributions. Comparisons with glutamatergic synapses within the same dendrites revealed a degree of coupling between nearby inhibitory and excitatory synapse remodeling, but also revealed that inhibitory synapse size configurations changed at considerably slower rates than those of their glutamatergic neighbors. These findings point to quantitative differences in spontaneous remodeling dynamics of inhibitory and excitatory synapses but also reveal deep qualitative similarities in the processes that control their sizes and govern their remodeling dynamics. PMID:26599330

  16. Time-resolved microrheology of actively remodeling actomyosin networks

    NASA Astrophysics Data System (ADS)

    Silva, Marina Soares e.; Stuhrmann, Björn; Betz, Timo; Koenderink, Gijsje H.

    2014-07-01

    Living cells constitute an extraordinary state of matter since they are inherently out of thermal equilibrium due to internal metabolic processes. Indeed, measurements of particle motion in the cytoplasm of animal cells have revealed clear signatures of nonthermal fluctuations superposed on passive thermal motion. However, it has been difficult to pinpoint the exact molecular origin of this activity. Here, we employ time-resolved microrheology based on particle tracking to measure nonequilibrium fluctuations produced by myosin motor proteins in a minimal model system composed of purified actin filaments and myosin motors. We show that the motors generate spatially heterogeneous contractile fluctuations, which become less frequent with time as a consequence of motor-driven network remodeling. We analyze the particle tracking data on different length scales, combining particle image velocimetry, an ensemble analysis of the particle trajectories, and finally a kymograph analysis of individual particle trajectories to quantify the length and time scales associated with active particle displacements. All analyses show clear signatures of nonequilibrium activity: the particles exhibit random motion with an enhanced amplitude compared to passive samples, and they exhibit sporadic contractile fluctuations with ballistic motion over large (up to 30 μm) distances. This nonequilibrium activity diminishes with sample age, even though the adenosine triphosphate level is held constant. We propose that network coarsening concentrates motors in large clusters and depletes them from the network, thus reducing the occurrence of contractile fluctuations. Our data provide valuable insight into the physical processes underlying stress generation within motor-driven actin networks and the analysis framework may prove useful for future microrheology studies in cells and model organisms.

  17. A multiscale mechanobiological model of bone remodelling predicts site-specific bone loss in the femur during osteoporosis and mechanical disuse.

    PubMed

    Lerebours, C; Buenzli, P R; Scheiner, S; Pivonka, P

    2016-02-01

    We propose a multiscale mechanobiological model of bone remodelling to investigate the site-specific evolution of bone volume fraction across the midshaft of a femur. The model includes hormonal regulation and biochemical coupling of bone cell populations, the influence of the microstructure on bone turnover rate, and mechanical adaptation of the tissue. Both microscopic and tissue-scale stress/strain states of the tissue are calculated from macroscopic loads by a combination of beam theory and micromechanical homogenisation. This model is applied to simulate the spatio-temporal evolution of a human midshaft femur scan subjected to two deregulating circumstances: (i) osteoporosis and (ii) mechanical disuse. Both simulated deregulations led to endocortical bone loss, cortical wall thinning and expansion of the medullary cavity, in accordance with experimental findings. Our model suggests that these observations are attributable to a large extent to the influence of the microstructure on bone turnover rate. Mechanical adaptation is found to help preserve intracortical bone matrix near the periosteum. Moreover, it leads to non-uniform cortical wall thickness due to the asymmetry of macroscopic loads introduced by the bending moment. The effect of mechanical adaptation near the endosteum can be greatly affected by whether the mechanical stimulus includes stress concentration effects or not. PMID:26239380

  18. Chromatin remodeling during Saccharomyces cerevisiae ADH2 gene activation.

    PubMed

    Verdone, L; Camilloni, G; Di Mauro, E; Caserta, M

    1996-05-01

    We have analyzed at both low and high resolution the distribution of nucleosomes over the Saccharomyces cerevisiae ADH2 promoter region in its chromosomal location, both under repressing (high-glucose) conditions and during derepression. Enzymatic treatments (micrococcal nuclease and restriction endonucleases) were used to probe the in vivo chromatin structure during ADH2 gene activation. Under glucose-repressed conditions, the ADH2 promoter was bound by a precise array of nucleosomes, the principal ones positioned at the RNA initiation sites (nucleosome +1), at the TATA box (nucleosome -1), and upstream of the ADR1-binding site (UAS1) (nucleosome -2). The UAS1 sequence and the adjacent UAS2 sequence constituted a nucleosome-free region. Nucleosomes -1 and +1 were destabilized soon after depletion of glucose and had become so before the appearance of ADH2 mRNA. When the transcription rate was high, nucleosomes -2 and +2 also underwent rearrangement. When spheroplasts were prepared from cells grown in minimal medium, detection of this chromatin remodeling required the addition of a small amount of glucose. Cells lacking the ADR1 protein did not display any of these chromatin modifications upon glucose depletion. Since the UAS1 sequence to which Adr1p binds is located immediately upstream of nucleosome -1, Adr1p is presumably required for destabilization of this nucleosome and for aiding the TATA-box accessibility to the transcription machinery. PMID:8628264

  19. The remodeling pattern of human mandibular alveolar bone during prenatal formation from 19 to 270mm CRL.

    PubMed

    Radlanski, Ralf J; Renz, Herbert; Tsengelsaikhan, Nyamdorj; Schuster, Felix; Zimmermann, Camilla A

    2016-05-01

    The underlying mechanisms of human bone morphogenesis leading to a topologically specific shape remain unknown, despite increasing knowledge of the basic molecular aspects of bone formation and its regulation. The formation of the alveolar bone, which houses the dental primordia, and later the dental roots, may serve as a model to approach general questions of bone formation. Twenty-five heads of human embryos and fetuses (Radlanski-Collection, Berlin) ranging from 19mm to 270mm (crown-rump-length) CRL were prepared as histological serial sections. For each stage, virtual 3D-reconstructions were made in order to study the morphogenesis of the mandibular molar primordia with their surrounding bone. Special focus was given to recording the bone-remodeling pattern, as diagnosed from the histological sections. In early stages (19-31mm CRL) developing bone was characterized by appositional only. At 41, in the canine region, mm CRL bony extensions were found forming on the bottom of the trough. Besides general apposition, regions with resting surfaces were also found. At a fetal size of 53mm CRL, septa have developed and led to a compartment for canine development. Furthermore, one shared compartment for the incisor primordia and another shared compartment for the molars also developed. Moreover, the inner surfaces of the dental crypts showed resorption of bone. From this stage on, a general pattern became established such that the compartmentalizing ridges and septa between all of the dental primordia and the brims of the crypts were noted, and were due to appositional growth of bone, while the crypts enlarged on their inner surfaces by resorption. By 160mm CRL, the dental primordia were larger, and all of the bony septa had become reduced in size. The primordia for the permanent teeth became visible at 225mm CRL and shared the crypts of their corresponding deciduous primordia. PMID:26921449

  20. Bone morphogenic protein-2 regulates the myogenic differentiation of PMVECs in CBDL rat serum-induced pulmonary microvascular remodeling.

    PubMed

    Liu, Chang; Chen, Lin; Zeng, Jing; Cui, Jian; Ning, Jiao-Nin; Wang, Guan-Song; Belguise, Karine; Wang, Xiaobo; Qian, Gui-Sheng; Lu, Kai-Zhi; Yi, Bin

    2015-08-01

    Hepatopulmonary syndrome (HPS) is characterized by an arterial oxygenation defect induced by intrapulmonary vasodilation (IPVD) that increases morbidity and mortality. In our previous study, it was determined that both the proliferation and the myogenic differentiation of pulmonary microvascular endothelial cells (PMVECs) play a key role in the development of IPVD. However, the molecular mechanism underlying the relationship between IPVD and the myogenic differentiation of PMVECs remains unknown. Additionally, it has been shown that bone morphogenic protein-2 (BMP2), via the control of protein expression, may regulate cell differentiation including cardiomyocyte differentiation, neuronal differentiation and odontoblastic differentiation. In this study, we observed that common bile duct ligation (CBDL)-rat serum induced the upregulation of the expression of several myogenic proteins (SM-α-actin, calponin, SM-MHC) and enhanced the expression levels of BMP2 mRNA and protein in PMVECs. We also observed that both the expression levels of Smad1/5 and the activation of phosphorylated Smad1/5 were significantly elevated in PMVECs following exposure to CBDL-rat serum, which was accompanied by the down-regulation of Smurf1. The blockage of the BMP2/Smad signaling pathway with Noggin inhibited the myogenic differentiation of PMVECs, a process that was associated with relatively low expression levels of both SM-α-actin and calponin in the setting of CBDL-rat serum exposure, although SM-MHC expression was not affected. These findings suggested that the BMP2/Smad signaling pathway is involved in the myogenic differentiation of the PMVECs. In conclusion, our data highlight the pivotal role of BMP2 in the CBDL-rat serum-induced myogenic differentiation of PMVECs via the activation of both Smad1 and Smad5 and the down-regulation of Smurf1, which may represent a potential therapy for HPS-induced pulmonary vascular remodeling. PMID:26071935

  1. Monitoring in vivo (re)modeling: a computational approach using 4D microCT data to quantify bone surface movements.

    PubMed

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

    2015-06-01

    Bone undergoes continual damage repair and structural adaptation to changing external loads with the aim of maintaining skeletal integrity throughout life. The ability to monitor bone (re)modeling would allow for a better understanding in how various pathologies and interventions affect bone turnover and subsequent bone strength. To date, however, current methods to monitor bone (re)modeling over time and in space are limited. We propose a novel method to visualize and quantify bone turnover, based on in vivo microCT imaging and a 4D computational approach. By in vivo tracking of spatially correlated formation and resorption sites over time it classifies bone restructuring into (re)modeling sequences, the spatially and temporally linked sequences of formation, resorption and quiescent periods on the bone surface. The microCT based method was validated using experimental data from an in vivo mouse tibial loading model and ex vivo data of the mouse tibia. In this application, the method allows the visualization of time-resolved cortical (re)modeling and the quantification of short-term and long-term modeling on the endocortical and periosteal surface at the mid-diaphysis of loaded and control mice tibiae. Both short-term and long-term modeling processes, independent formation and resorption events, could be monitored and modeling (spatially not correlated formation and resorption) and remodeling (resorption followed by new formation at the same site) could be distinguished on the bone surface. This novel method that combines in vivo microCT with a computational approach is a powerful tool to monitor bone turnover in animal models now and is waiting to be applied to human patients in the near future. PMID:25746796

  2. Tooth Eruption Results from Bone Remodelling Driven by Bite Forces Sensed by Soft Tissue Dental Follicles: A Finite Element Analysis

    PubMed Central

    Sarrafpour, Babak; Swain, Michael; Li, Qing; Zoellner, Hans

    2013-01-01

    Intermittent tongue, lip and cheek forces influence precise tooth position, so we here examine the possibility that tissue remodelling driven by functional bite-force-induced jaw-strain accounts for tooth eruption. Notably, although a separate true ‘eruptive force’ is widely assumed, there is little direct evidence for such a force. We constructed a three dimensional finite element model from axial computerized tomography of an 8 year old child mandible containing 12 erupted and 8 unerupted teeth. Tissues modelled included: cortical bone, cancellous bone, soft tissue dental follicle, periodontal ligament, enamel, dentine, pulp and articular cartilage. Strain and hydrostatic stress during incisive and unilateral molar bite force were modelled, with force applied via medial and lateral pterygoid, temporalis, masseter and digastric muscles. Strain was maximal in the soft tissue follicle as opposed to surrounding bone, consistent with follicle as an effective mechanosensor. Initial numerical analysis of dental follicle soft tissue overlying crowns and beneath the roots of unerupted teeth was of volume and hydrostatic stress. To numerically evaluate biological significance of differing hydrostatic stress levels normalized for variable finite element volume, ‘biological response units’ in Nmm were defined and calculated by multiplication of hydrostatic stress and volume for each finite element. Graphical representations revealed similar overall responses for individual teeth regardless if incisive or right molar bite force was studied. There was general compression in the soft tissues over crowns of most unerupted teeth, and general tension in the soft tissues beneath roots. Not conforming to this pattern were the unerupted second molars, which do not erupt at this developmental stage. Data support a new hypothesis for tooth eruption, in which the follicular soft tissues detect bite-force-induced bone-strain, and direct bone remodelling at the inner surface of

  3. Isolation of an activator-dependent, promoter-specific chromatin remodeling factor

    PubMed Central

    Ehrensberger, Andreas H.; Kornberg, Roger D.

    2011-01-01

    Repressed PHO5 gene chromatin, isolated from yeast in the native state, was remodeled by yeast extract in a gene activator-dependent, ATP-dependent manner. The product of the reaction bore the hallmark of the process in vivo, the selective removal of promoter nucleosomes, without effect on open reading frame nucleosomes. Fractionation of the extract identified a single protein, chromodomain helicase DNA binding protein 1 (Chd1), capable of the remodeling activity. Deletion of the CHD1 gene in an isw1Δ pho80Δ strain abolished PHO5 gene expression, demonstrating the relevance of the remodeling reaction in vitro to the process in vivo. PMID:21646535

  4. Isolation of an activator-dependent, promoter-specific chromatin remodeling factor.

    PubMed

    Ehrensberger, Andreas H; Kornberg, Roger D

    2011-06-21

    Repressed PHO5 gene chromatin, isolated from yeast in the native state, was remodeled by yeast extract in a gene activator-dependent, ATP-dependent manner. The product of the reaction bore the hallmark of the process in vivo, the selective removal of promoter nucleosomes, without effect on open reading frame nucleosomes. Fractionation of the extract identified a single protein, chromodomain helicase DNA binding protein 1 (Chd1), capable of the remodeling activity. Deletion of the CHD1 gene in an isw1Δ pho80Δ strain abolished PHO5 gene expression, demonstrating the relevance of the remodeling reaction in vitro to the process in vivo. PMID:21646535

  5. Cross-Talk Between Human Tenocytes and Bone Marrow Stromal Cells Potentiates Extracellular Matrix Remodeling In Vitro

    PubMed Central

    Ekwueme, Emmanuel C.; Shah, Jay V.; Mohiuddin, Mahir; Ghebes, Corina A.; Crispim, João F.; Saris, Daniël B.F.; Fernandes, Hugo A.M.; Freeman, Joseph W.

    2016-01-01

    Tendon and ligament (T/L) pathologies account for a significant portion of musculoskeletal injuries and disorders. Tissue engineering has emerged as a promising solution in the regeneration of both tissues. Specifically, the use of multipotent human mesenchymal stromal cells (hMSC) has shown great promise to serve as both a suitable cell source for tenogenic regeneration and a source of trophic factors to induce tenogenesis. Using four donor sets, we investigated the bidirectional paracrine tenogenic response between human hamstring tenocytes (hHT) and bone marrow-derived hMSC. Cell metabolic assays showed that only one hHT donor experienced sustained notable increases in cell metabolic activity during co-culture. Histological staining confirmed that co-culture induced elevated collagen protein levels in both cell types at varying time-points in two of four donor sets assessed. Gene expression analysis using qPCR showed the varied up-regulation of anabolic and catabolic markers involved in extracellular matrix maintenance for hMSC and hHT. Furthermore, analysis of hMSC/hHT co-culture secretome using a reporter cell line for TGF-β, a potent inducer of tenogenesis, revealed a trend of higher TGF-β bioactivity in hMSC secretome compared to hHT. Finally, hHT cytoskeletal immunostaining confirmed that both cell types released soluble factors capable of inducing favorable tenogenic morphology, comparable to control levels of soluble TGF-β1. These results suggest a potential for TGF-β-mediated signaling mechanism that is involved during the paracrine interplay between the two cell types that is reminiscent of T/L matrix remodeling/ turnover. These findings have significant implications in the clinical use of hMSC for common T/L pathologies. PMID:26308651

  6. Effects of long term treatment with high doses of odanacatib on bone mass, bone strength, and remodeling/modeling in newly ovariectomized monkeys.

    PubMed

    Duong, L T; Pickarski, M; Cusick, T; Chen, C M; Zhuo, Y; Scott, K; Samadfam, R; Smith, S Y; Pennypacker, B L

    2016-07-01

    The objectives here were to evaluate the effects of odanacatib (ODN) at doses exceeding the clinical exposure on biomechanical properties of lumbar vertebrae (LV), hip and central femur (CF), and compare ODN to alendronate (ALN) on bone remodeling/modeling in ovariectomized (OVX) monkeys. Ten days post-surgery, animals were treated with vehicle (VEH), ODN-L (2mg/kg/day, p.o.), ODN-H (8/4mg/kg/day), or ALN (30μg/kg/week, s.c.) for 20months. An intact group was also included. ODN-L provided systemic exposures of 1.8-fold of clinical exposure. ODN-H started at 20-fold for 5.5months, and then reduced to 7.8-fold of clinical exposure, compared to ALN at approximated clinical exposure. From cross sectional analyses, LV density and peak load in ODN at both doses or ALN were not different from VEH or Intact. However, cortical thickness of femoral neck (FN) and CF in ODN were higher (21-34%, p<0.05) than VEH, due to smaller endocortical (Ec) perimeter of FN (10-11%; p<0.05) and CF (9-12%; ODN-L, p<0.05), and larger CF periosteal (Ps) perimeter (2-12%; ODN-H, p<0.001) versus VEH. ODN groups also showed slightly higher cortical porosity and Ps non-lamellar bone in CF. ODN-H treatment resulted in higher CF peak load (p<0.05) versus VEH. For all bone sites analyzed, a positive, linear relationship (r(2)=0.46-0.69, p<0.0001) of peak load to density or structural parameters was demonstrated. No treatment-related differences in the derived intrinsic strength properties were evidenced as compared between groups. ALN reduced all remodeling surfaces without affecting Ps modeling. Trabecular and intracortical remodeling were reduced in ODN groups, similar to ALN. Ec mineralizing surface in ODN-H trended to be lower than VEH by month 20, but Ec bone formation indices in ODN groups generally were not different from VEH. Ps modeling in ODN groups was significantly higher than other treatment groups. This study overall demonstrated the bone safety profile of ODN and its unique mechanism

  7. Histochemical examination of the effects of high-dose 1,25(OH)2D3 on bone remodeling in young growing rats.

    PubMed

    Sun, Jing; Sun, Bao; Wang, Wei; Han, Xiuchun; Liu, Hongrui; Du, Juan; Feng, Wei; Liu, Bo; Amizuka, Norio; Li, Minqi

    2016-08-01

    Vitamin D has an anabolic effect on bone developmental processes and is involved in maintaining skeletal integrity. In recent years, pediatric cases of vitamin D intoxication have attracted attention. Therefore, the aim of this study was to investigate the influence of long-term administration of physiologically-high-dose calcitriol (1,25(OH)2D3) on bone remodeling in young developing rats. Neonatal rats received once-daily subcutaneous injection of calcitriol (250 ng/kg body weight), or PBS only as a control, for 3 weeks. At 1, 2 and 4 weeks' post-administration, rats were sacrificed and fixed by transcardial perfusion with 4 % paraformaldehyde, following which tibiae were extracted for histochemical analysis. Compared with the control group, the number of tartrate-resistant acid phosphatase- and Cathepsin K-positive osteoclasts were significantly increased, and the expression of alkaline phosphatase in osteoblasts was decreased in trabecular bone of rats administered high-dose 1,25(OH)2D3, leading to decreased trabecular bone volume. In addition, the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) was increased, while that of osteoprotegerin was weaker in osteoblasts in the experimental group compared with the control group. Moreover, there was weaker immunoreactivity for EphrinB2 in osteoclasts and EphB4 in osteoblasts of trabecular bone in the experimental group compared with the control group. These findings suggest that long-term use of physiologically-high dose calcitriol may result in bone loss through RANKL/RANK/osteoprotegerin and EphrinB2-EphB4 signaling pathways, and that these negative effects could continue after drug withdrawal. Therefore, optimal limits for vitamin D administration need to be established for children and adolescents. PMID:27255234

  8. Changes of vessel-cells complex in zones of adaptive remodeling of the bone tissue under microgravity conditions

    NASA Astrophysics Data System (ADS)

    Rodionova, N.; Oganov, V.; Nosova, L.

    The development and differentiation of osteogenic cells in organism happen in closely topographical and functional connection with blood capillaries. We formerly proofed, that small-differentiated cells, which are in the population of perivascular cells are osteogenic cells -precursors . At the present time it is actually to clear up, how these biostructures react on conditions of less of biomechanical load on skeleton bones. We researched peculiarities of blood-bed structure and perivascular cells in metaphises of thighbones and tibial bones in rats, which were onboard the American space station SLS-2 and in experiments of modeling hypokinesia. There were used methods of cytochemistry, histology and electron microscopy. We established, that under the support and functional load decreasing in zones of bones adaptive remodeling, comparatively to control, on histosections the own volume of sinusoid capillaries reduces. The small vessels prevail here. The spaces of sinusoid capillaries are limited by 1 2 cells of the endothelia. Endotheliocytes in- general have the typical ultrastructure. Basal membranes are expressed not-distinctly. Perivascular cells don't create the unbroken layer. The population of these cells is not-homogeneous. It includes enclosed to endothelia small-differentiated forms and separating cells with sings of fibroblastic differentiation (the own volume of rough endoplasmic reticulum in cytoplasm induces). The part of these cells reacts on the alkaline phosphatase (the marker of the osteogenic differentiation). Under the conditions of support load decreasing (especially under the microgravity) there is a tendency to reducing of separating osteogenic cells number. We noted the priority of differentiating fibroblasts. It leads to further development in zones of bone remodeling of hearths of fibrous tissue, that doesn't mineralize. The obtained data are seen as one of mechanisms of osteoporosis and osteopenia development under the deficite of support

  9. The use of biochemical markers of bone remodeling in multiple myeloma: a report of the International Myeloma Working Group.

    PubMed

    Terpos, E; Dimopoulos, M A; Sezer, O; Roodman, D; Abildgaard, N; Vescio, R; Tosi, P; Garcia-Sanz, R; Davies, F; Chanan-Khan, A; Palumbo, A; Sonneveld, P; Drake, M T; Harousseau, J-L; Anderson, K C; Durie, B G M

    2010-10-01

    Lytic bone disease is a frequent complication of multiple myeloma (MM). Lytic lesions rarely heal and X-rays are of limited value in monitoring bone destruction during anti-myeloma or anti-resorptive treatment. Biochemical markers of bone resorption (amino- and carboxy-terminal cross-linking telopeptide of type I collagen (NTX and CTX, respectively) or CTX generated by matrix metalloproteinases (ICTP)) and bone formation provide information on bone dynamics and reflect disease activity in bone. These markers have been investigated as tools for evaluating the extent of bone disease, risk of skeletal morbidity and response to anti-resorptive treatment in MM. Urinary NTX, serum CTX and serum ICTP are elevated in myeloma patients with osteolytic lesions and correlate with advanced disease stage. Furthermore, urinary NTX and serum ICTP correlate with risk for skeletal complications, disease progression and overall survival. Bone markers have also been used for the early diagnosis of bone lesions. This International Myeloma Working Group report summarizes the existing data for the role of bone markers in assessing the extent of MM bone disease and in monitoring bone turnover during anti-myeloma therapies and provides information on novel markers that may be of particular interest in the near future. PMID:20811404

  10. Cybernetic aspects of bone modeling and remodeling, with special reference to osteoporosis and whole-bone strength.

    PubMed

    Frost, H M

    2001-01-01

    Assume mythical physiologists were taught that renal physiology and its disorders depend on "kidney cells" and their regulation by nonmechanical factors, but were taught nothing about nephrons. For decades they "knew" that idea was correct, just as Ptolemy "knew" the universe centers on our planet. But then others began to describe nephrons, their roles in renal physiology and disorders, and problems they revealed in former views, so doubts and controversies began. Today real physiologists encounter a similar situation for bone health and its disorders. A 1960 paradigm attributed such things to bone's effector cells (osteoblasts and osteoclasts) and their regulation by nonmechanical factors, without "nephron-equivalent" or biomechanical input. But both mechanical and nonmechanical factors regulate bone's nephron equivalents. Adding features of those equivalents to the 1960 views led to the Utah paradigm, which suggests problems in former views and better explanations for "osteoporosis," whole-bone strength, and other bone disorders. Such things incited controversies among current skeletal physiologists. Cybernetics concerns the relationships, mechanisms, signals, and message traffic that help to control the behavior and other features of dynamic systems. A cybernetic analysis of the bone physiology in the Utah paradigm can add many features to the 1960 paradigm that help to understand osteoporoses, other bone disorders, and whole-bone strength (and bone mass). The added features also show new and pertinent targets for the related research. PMID:11460869

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

    PubMed

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

    1986-05-17

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

  12. 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.

  13. Bone morphogenic protein-2 regulates the myogenic differentiation of PMVECs in CBDL rat serum-induced pulmonary microvascular remodeling

    SciTech Connect

    Liu, Chang; Chen, Lin; Zeng, Jing; Cui, Jian; Ning, Jiao-nin; Wang, Guan-song; Belguise, Karine; Wang, Xiaobo; Qian, Gui-sheng; Lu, Kai-zhi; Yi, Bin

    2015-08-01

    Hepatopulmonary syndrome (HPS) is characterized by an arterial oxygenation defect induced by intrapulmonary vasodilation (IPVD) that increases morbidity and mortality. In our previous study, it was determined that both the proliferation and the myogenic differentiation of pulmonary microvascular endothelial cells (PMVECs) play a key role in the development of IPVD. However, the molecular mechanism underlying the relationship between IPVD and the myogenic differentiation of PMVECs remains unknown. Additionally, it has been shown that bone morphogenic protein-2 (BMP2), via the control of protein expression, may regulate cell differentiation including cardiomyocyte differentiation, neuronal differentiation and odontoblastic differentiation. In this study, we observed that common bile duct ligation (CBDL)-rat serum induced the upregulation of the expression of several myogenic proteins (SM-α-actin, calponin, SM-MHC) and enhanced the expression levels of BMP2 mRNA and protein in PMVECs. We also observed that both the expression levels of Smad1/5 and the activation of phosphorylated Smad1/5 were significantly elevated in PMVECs following exposure to CBDL-rat serum, which was accompanied by the down-regulation of Smurf1. The blockage of the BMP2/Smad signaling pathway with Noggin inhibited the myogenic differentiation of PMVECs, a process that was associated with relatively low expression levels of both SM-α-actin and calponin in the setting of CBDL-rat serum exposure, although SM-MHC expression was not affected. These findings suggested that the BMP2/Smad signaling pathway is involved in the myogenic differentiation of the PMVECs. In conclusion, our data highlight the pivotal role of BMP2 in the CBDL-rat serum-induced myogenic differentiation of PMVECs via the activation of both Smad1 and Smad5 and the down-regulation of Smurf1, which may represent a potential therapy for HPS-induced pulmonary vascular remodeling. - Highlights: • CBDL-rat serum promotes the myogenic

  14. Long-Term Relationships between Synaptic Tenacity, Synaptic Remodeling, and Network Activity

    PubMed Central

    Minerbi, Amir; Kahana, Roni; Goldfeld, Larissa; Kaufman, Maya; Marom, Shimon; Ziv, Noam E.

    2009-01-01

    Synaptic plasticity is widely believed to constitute a key mechanism for modifying functional properties of neuronal networks. This belief implicitly implies, however, that synapses, when not driven to change their characteristics by physiologically relevant stimuli, will maintain these characteristics over time. How tenacious are synapses over behaviorally relevant time scales? To begin to address this question, we developed a system for continuously imaging the structural dynamics of individual synapses over many days, while recording network activity in the same preparations. We found that in spontaneously active networks, distributions of synaptic sizes were generally stable over days. Following individual synapses revealed, however, that the apparently static distributions were actually steady states of synapses exhibiting continual and extensive remodeling. In active networks, large synapses tended to grow smaller, whereas small synapses tended to grow larger, mainly during periods of particularly synchronous activity. Suppression of network activity only mildly affected the magnitude of synaptic remodeling, but dependence on synaptic size was lost, leading to the broadening of synaptic size distributions and increases in mean synaptic size. From the perspective of individual neurons, activity drove changes in the relative sizes of their excitatory inputs, but such changes continued, albeit at lower rates, even when network activity was blocked. Our findings show that activity strongly drives synaptic remodeling, but they also show that significant remodeling occurs spontaneously. Whereas such spontaneous remodeling provides an explanation for “synaptic homeostasis” like processes, it also raises significant questions concerning the reliability of individual synapses as sites for persistently modifying network function. PMID:19554080

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

    PubMed

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

    2016-01-25

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

  16. Influence of Exercise on Bone Remodeling-Related Hormones and Cytokines in Ovariectomized Rats: A Model of Postmenopausal Osteoporosis

    PubMed Central

    Li, Lihui; Chen, Xi; Lv, Shuang; Dong, Miaomiao; Zhang, Li; Tu, Jiaheng; Yang, Jie; Zhang, Lingli; Song, Yinan; Xu, Leiting; Zou, Jun

    2014-01-01

    This study aims to explore the effects of exercise on postmenopausal osteoporosis and the mechanisms by which exercise affects bone remodeling. Sixty-three Wistar female rats were randomly divided into five groups: (1) control group, (2) sham-operated group, (3) OVX (Ovariectomy) group, (4) DES-OVX (Diethylstilbestrol-OVX) group, and (5) Ex-OVX (Exercise-OVX) group. The rat osteoporosis model was established through ovariectomy. The Ex-OVX rats were made to run 251.2 meters every day, 6 d/wk for 3 months in a running wheel. Trabecular bone volume (TBV%), total resorption surface (TRS%), trabecular formation surface (TFS%), mineralization rate (MAR), bone cortex mineralization rate (mAR), and osteoid seam width (OSW) were determined by bone histomorphometry. The mRNA and protein levels of interleukin-1β (IL-1β2), interleukin-6 (IL-6), and cyclooxygenase-2 (Cox-2) were determined by in situ hybridization and immunohistochemistry, respectively. Serum levels of estrogen estradiol (E2), calcitonin (CT), osteocalcin (BGP), and parathyroid hormone (PTH) were determined by ELISA assays. The investigation revealed that compared to the control and the sham-operated groups, the OVX group showed significantly lower levels of TBV%, E2, and CT, but much higher levels of TRS%, TFS%, MAR, OSW, BGP, and PTH. The Ex-OVX group showed increased TBV% and serum levels of E2 and CT compared to the OVX group. Ovariectomy also led to a significant increase in IL-1β mRNA and protein levels in the bone marrow and IL-6 and Cox-2 protein levels in tibias. In addition, the Ex-OVX group showed lower levels of IL-1 mRNA and protein, IL-6 mRNA, and Cox-2 mRNA and protein than those in the OVX group. The upshot of the study suggests that exercise can significantly increase bone mass in postmenopausal osteoporosis rat models by inhibiting bone resorption and increasing bone formation, especially in trabecular bones. PMID:25393283

  17. FACT Assists Base Excision Repair by Boosting the Remodeling Activity of RSC

    PubMed Central

    Ouararhni, Khalid; Roulland, Yohan; Ben Simon, Elsa; Kundu, Tapas; Hamiche, Ali; Angelov, Dimitar; Dimitrov, Stefan

    2016-01-01

    FACT, in addition to its role in transcription, is likely implicated in both transcription-coupled nucleotide excision repair and DNA double strand break repair. Here, we present evidence that FACT could be directly involved in Base Excision Repair and elucidate the chromatin remodeling mechanisms of FACT during BER. We found that, upon oxidative stress, FACT is released from transcription related protein complexes to get associated with repair proteins and chromatin remodelers from the SWI/SNF family. We also showed the rapid recruitment of FACT to the site of damage, coincident with the glycosylase OGG1, upon the local generation of oxidized DNA. Interestingly, FACT facilitates uracil-DNA glycosylase in the removal of uracil from nucleosomal DNA thanks to an enhancement in the remodeling activity of RSC. This discloses a novel property of FACT wherein it has a co-remodeling activity and strongly enhances the remodeling capacity of the chromatin remodelers. Altogether, our data suggest that FACT may acts in concert with RSC to facilitate excision of DNA lesions during the initial step of BER. PMID:27467129

  18. FACT Assists Base Excision Repair by Boosting the Remodeling Activity of RSC.

    PubMed

    Charles Richard, John Lalith; Shukla, Manu Shubhdarshan; Menoni, Hervé; Ouararhni, Khalid; Lone, Imtiaz Nisar; Roulland, Yohan; Papin, Christophe; Ben Simon, Elsa; Kundu, Tapas; Hamiche, Ali; Angelov, Dimitar; Dimitrov, Stefan

    2016-07-01

    FACT, in addition to its role in transcription, is likely implicated in both transcription-coupled nucleotide excision repair and DNA double strand break repair. Here, we present evidence that FACT could be directly involved in Base Excision Repair and elucidate the chromatin remodeling mechanisms of FACT during BER. We found that, upon oxidative stress, FACT is released from transcription related protein complexes to get associated with repair proteins and chromatin remodelers from the SWI/SNF family. We also showed the rapid recruitment of FACT to the site of damage, coincident with the glycosylase OGG1, upon the local generation of oxidized DNA. Interestingly, FACT facilitates uracil-DNA glycosylase in the removal of uracil from nucleosomal DNA thanks to an enhancement in the remodeling activity of RSC. This discloses a novel property of FACT wherein it has a co-remodeling activity and strongly enhances the remodeling capacity of the chromatin remodelers. Altogether, our data suggest that FACT may acts in concert with RSC to facilitate excision of DNA lesions during the initial step of BER. PMID:27467129

  19. Effects of remifemin treatment on bone integrity and remodeling in rats with ovariectomy-induced osteoporosis.

    PubMed

    Cui, Guangxia; Leng, Huijie; Wang, Ke; Wang, Jianwei; Zhu, Sainan; Jia, Jing; Chen, Xing; Zhang, Weiguang; Qin, Lihua; Bai, Wenpei

    2013-01-01

    This study aims to evaluate the effects of Remifemin (isopropanolic extract of Cimicifuga Racemosa) on postmenopausal osteoporosis. 120 female Sprague-Dawley rats were randomly assigned to four groups: sham surgery with vehicle, ovariectomy with vehicle, ovariectomy with estradiol valerate, or ovariectomy with Remifemin. Daily oral administrations of the vehicle, estradiol valerate, or Remifemin began 2 weeks after surgery and lasted to 4, 8, or 12 weeks. Ten rats in each group were sacrificed at each timestep with assessment of bone mineral density, trabecular bone structure, and biomechanical parameters of the femur and lumbar vertebra. Bone turnover markers were evaluated 12 weeks after surgery. Both drugs prevented bone density loss in the distal end of the femur and preserved the trabecular bone structure in both the lumbar vertebra and distal end of the femur following ovariectomy. Both drugs protected bone stiffness at the tested regions and reduced bone reabsorption in ovariectomized rats. The preventive effects of Remifemin against bone-loss can rival those of estradiol valerate if treatment duration is adequately extended. In conclusion, Remifemin may demonstrate equivalent effects to estradiol valerate in terms of preventing postmenopausal osteoporosis. PMID:24349369

  20. Effects of Remifemin Treatment on Bone Integrity and Remodeling in Rats with Ovariectomy-Induced Osteoporosis

    PubMed Central

    Wang, Ke; Wang, Jianwei; Zhu, Sainan; Jia, Jing; Chen, Xing; Zhang, Weiguang; Qin, Lihua; Bai, Wenpei

    2013-01-01

    This study aims to evaluate the effects of Remifemin (isopropanolic extract of Cimicifuga Racemosa) on postmenopausal osteoporosis. 120 female Sprague-Dawley rats were randomly assigned to four groups: sham surgery with vehicle, ovariectomy with vehicle, ovariectomy with estradiol valerate, or ovariectomy with Remifemin. Daily oral administrations of the vehicle, estradiol valerate, or Remifemin began 2 weeks after surgery and lasted to 4, 8, or 12 weeks. Ten rats in each group were sacrificed at each timestep with assessment of bone mineral density, trabecular bone structure, and biomechanical parameters of the femur and lumbar vertebra. Bone turnover markers were evaluated 12 weeks after surgery. Both drugs prevented bone density loss in the distal end of the femur and preserved the trabecular bone structure in both the lumbar vertebra and distal end of the femur following ovariectomy. Both drugs protected bone stiffness at the tested regions and reduced bone reabsorption in ovariectomized rats. The preventive effects of Remifemin against bone-loss can rival those of estradiol valerate if treatment duration is adequately extended. In conclusion, Remifemin may demonstrate equivalent effects to estradiol valerate in terms of preventing postmenopausal osteoporosis. PMID:24349369

  1. In Vivo Hypobaric Hypoxia Performed During the Remodeling Process Accelerates Bone Healing in Mice

    PubMed Central

    Durand, Marjorie; Collombet, Jean-Marc; Frasca, Sophie; Begot, Laurent; Lataillade, Jean-Jacques; Le Bousse-Kerdilès, Marie-Caroline

    2014-01-01

    We investigated the effects of respiratory hypobaric hypoxia on femoral bone-defect repair in mice because hypoxia is believed to influence both mesenchymal stromal cell (MSC) and hematopoietic stem cell mobilization, a process involved in the bone-healing mechanism. To mimic conditions of non-weight-bearing limb immobilization in patients suffering from bone trauma, our hypoxic mouse model was further subjected to hind-limb unloading. A hole was drilled in the right femur of adult male C57/BL6J mice. Four days after surgery, mice were subjected to hind-limb unloading for 1 week. Seven days after surgery, mice were either housed for 4 days in a hypobaric room (FiO2 at 10%) or kept under normoxic conditions. Unsuspended control mice were housed in either hypobaric or normoxic conditions. Animals were sacrificed on postsurgery day 11 to allow for collection of both contralateral and lesioned femurs, blood, and spleen. As assessed by microtomography, delayed hypoxia enhanced bone-healing efficiency by increasing the closing of the cortical defect and the newly synthesized bone volume in the cavity by +55% and +35%, respectively. Proteome analysis and histomorphometric data suggested that bone-repair improvement likely results from the acceleration of the natural bone-healing process rather than from extended mobilization of MSC-derived osteoprogenitors. Hind-limb unloading had hardly any effect beyond delayed hypoxia-enhanced bone-healing efficiency. PMID:24944208

  2. Nucleolin is a histone chaperone with FACT-like activity and assists remodeling of nucleosomes

    PubMed Central

    Angelov, Dimitar; Bondarenko, Vladimir A; Almagro, Sébastien; Menoni, Hervé; Mongélard, Fabien; Hans, Fabienne; Mietton, Flore; Studitsky, Vasily M; Hamiche, Ali; Dimitrov, Stefan; Bouvet, Philippe

    2006-01-01

    Remodeling machines play an essential role in the control of gene expression, but how their activity is regulated is not known. Here we report that the nuclear protein nucleolin possesses a histone chaperone activity and that this factor greatly enhances the activity of the chromatin remodeling machineries SWI/SNF and ACF. Interestingly, nucleolin is able to induce the remodeling by SWI/SNF of macroH2A, but not of H2ABbd nucleosomes, which are otherwise resistant to remodeling. This new histone chaperone promotes the destabilization of the histone octamer, helping the dissociation of a H2A–H2B dimer, and stimulates the SWI/SNF-mediated transfer of H2A–H2B dimers. Furthermore, nucleolin facilitates transcription through the nucleosome, which is reminiscent of the activity of the FACT complex. This work defines new functions for histone chaperones in chromatin remodeling and regulation of transcription and explains how nucleolin could act on transcription. PMID:16601700

  3. Activation of GLP-1 Receptor Promotes Bone Marrow Stromal Cell Osteogenic Differentiation through β-Catenin

    PubMed Central

    Meng, Jingru; Ma, Xue; Wang, Ning; Jia, Min; Bi, Long; Wang, Yunying; Li, Mingkai; Zhang, Huinan; Xue, Xiaoyan; Hou, Zheng; Zhou, Ying; Yu, Zhibin; He, Gonghao; Luo, Xiaoxing

    2016-01-01

    Summary Glucagon-like peptide 1 (GLP-1) plays an important role in regulating bone remodeling, and GLP-1 receptor agonist shows a positive relationship with osteoblast activity. However, GLP-1 receptor is not found in osteoblast, and the mechanism of GLP-1 receptor agonist on regulating bone remodeling is unclear. Here, we show that the GLP-1 receptor agonist exendin-4 (Ex-4) promoted bone formation and increased bone mass and quality in a rat unloading-induced bone loss model. These functions were accompanied by an increase in osteoblast number and serum bone formation markers, while the adipocyte number was decreased. Furthermore, GLP-1 receptor was detected in bone marrow stromal cells (BMSCs), but not in osteoblast. Activation of GLP-1 receptor by Ex-4 promoted the osteogenic differentiation and inhibited BMSC adipogenic differentiation through regulating PKA/β-catenin and PKA/PI3K/AKT/GSK3β signaling. These findings reveal that GLP-1 receptor regulates BMSC osteogenic differentiation and provide a molecular basis for therapeutic potential of GLP-1 against osteoporosis. PMID:26947974

  4. Impairment of osteoclastic bone resorption in rapidly growing female p47phox knockout mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bone formation is dependent on the activity and differentiation of osteoblasts; whereas resorption of preexisting mineralized bone matrix by osteoclasts is necessary not only for bone development but also for regeneration and remodeling. Bone remodeling is a process in which osteoblasts and osteocla...

  5. TDAG8 activation inhibits osteoclastic bone resorption.

    PubMed

    Hikiji, Hisako; Endo, Daisuke; Horie, Kyoji; Harayama, Takeshi; Akahoshi, Noriyuki; Igarashi, Hidemitsu; Kihara, Yasuyuki; Yanagida, Keisuke; Takeda, Junji; Koji, Takehiko; Shimizu, Takao; Ishii, Satoshi

    2014-02-01

    Although the roles of acids in bone metabolism are well characterized, the function of proton-sensing receptors in bone metabolism remains to be explored. In this study, we evaluated the role of proton-sensing receptor T-cell death-associated gene 8 (TDAG8) in osteoclastic activity during bone loss after ovariectomy. Through observations of bone mineral content, we found that pathological bone resorption was significantly exacerbated in mice homozygous for a gene trap mutation in the Tdag8 gene. Furthermore, osteoclasts from the homozygous mutant mice resorbed calcium in vitro more than the osteoclasts from the heterozygous mice did. Impaired osteoclast formation under acidic conditions was ameliorated in cultures of bone marrow cells by Tdag8 gene mutation. Extracellular acidification changed the cell morphology of osteoclasts via the TDAG8-Rho signaling pathway. These results suggest that the enhancement of TDAG8 function represents a new strategy for preventing bone resorption diseases, such as osteoporosis. PMID:24221084

  6. In vivo micro-CT analysis of bone remodeling in a rat calvarial defect model

    NASA Astrophysics Data System (ADS)

    Umoh, Joseph U.; Sampaio, Arthur V.; Welch, Ian; Pitelka, Vasek; Goldberg, Harvey A.; Underhill, T. Michael; Holdsworth, David W.

    2009-04-01

    The rodent calvarial defect model is commonly used to investigate bone regeneration and wound healing. This study presents a micro-computed tomography (micro-CT) methodology for measuring the bone mineral content (BMC) in a rat calvarial defect and validates it by estimating its precision error. Two defect models were implemented. A single 6 mm diameter defect was created in 20 rats, which were imaged in vivo for longitudinal experiments. Three 5 mm diameter defects were created in three additional rats, which were repeatedly imaged ex vivo to determine precision. Four control rats and four rats treated with bone morphogenetic protein were imaged at 3, 6, 9 and 12 weeks post-surgery. Scan parameters were 80 kVp, 0.45 mA and 180 mAs. Images were reconstructed with an isotropic resolution of 45 µm. At 6 weeks, the BMC in control animals (4.37 ± 0.66 mg) was significantly lower (p < 0.05) than that in treated rats (11.29 ± 1.01 mg). Linear regression between the BMC and bone fractional area, from 20 rats, showed a strong correlation (r2 = 0.70, p < 0.0001), indicating that the BMC can be used, in place of previous destructive analysis techniques, to characterize bone growth. The high precision (2.5%) of the micro-CT methodology indicates its utility in detecting small BMC changes in animals.

  7. Study of bone remodeling of two models of femoral cementless stems by means of DEXA and finite elements

    PubMed Central

    2010-01-01

    Background A hip replacement with a cemented or cementless femoral stem produces an effect on the bone called adaptive remodelling, attributable to mechanical and biological factors. All of the cementless prostheses designs try to achieve an optimal load transfer in order to avoid stress-shielding, which produces an osteopenia. Long-term densitometric studies taken after implanting ABG-I and ABG-II stems confirm that the changes made to the design and alloy of the ABG-II stem help produce less proximal atrophy of the femur. The simulation with FE allowed us to study the biomechanical behaviour of two stems. The aim of this study was, if possible, to correlate the biological and mechanical findings. Methods Both models with prostheses ABG-I and II have been simulated in five different moments of time which coincide with the DEXA measurements: postoperative, 6 months, 1, 3 and 5 years, in addition to the healthy femur as the initial reference. For the complete comparative analysis of both stems, all of the possible combinations of bone mass (group I and group II of pacients in two controlled studies for ABG-I and II stems, respectively), prosthetic geometry (ABG-I and ABG-II) and stem material (Wrought Titanium or TMZF) were simulated. Results and Discussion In both groups of bone mass an increase of stress in the area of the cancellous bone is produced, which coincides with the end of the HA coating, as a consequence of the bottleneck effect which is produced in the transmission of loads, and corresponds to Gruen zones 2 and 6, where no osteopenia can be seen in contrast to zones 1 and 7. Conclusions In this study it is shown that the ABG-II stem is more effective than the ABG-I given that it generates higher tensional values on the bone, due to which proximal bone atrophy diminishes. This biomechanical behaviour with an improved transmission of loads confirmed by means of FE simulation corresponds to the biological findings obtained with Dual-Energy X

  8. Genetic and Hormonal Control of Bone Volume, Architecture, and Remodeling in XXY Mice

    PubMed Central

    Liu, Peter Y; Kalak, Robert; Lue, YanHe; Jia, Yue; Erkkila, Krista; Zhou, Hong; Seibel, Markus J; Wang, Christina; Swerdloff, Ronald S; Dunstan, Colin R

    2010-01-01

    Klinefelter syndrome is the most common chromosomal aneuploidy in men (XXY karyotype, 1 in 600 live births) and results in testicular (infertility and androgen deficiency) and nontesticular (cognitive impairment and osteoporosis) deficits. The extent to which skeletal changes are due to testosterone deficiency or arise directly from gene overdosage cannot be determined easily in humans. To answer this, we generated XXY mice through a four-generation breeding scheme. Eight intact XXY and 9 XY littermate controls and 8 castrated XXY mice and 8 castrated XY littermate controls were euthanized at 1 year of age. Castration occurred 6 months prior to killing. A third group of 9 XXY and 11 XY littermates were castrated and simultaneously implanted with a 1-cm Silastic testosterone capsule 8 weeks prior to sacrifice. Tibias were harvested from all three groups and examined by micro–computed tomography and histomorphometry. Blood testosterone concentration was assayed by radioimmunoassay. Compared with intact XY controls, intact androgen-deficient XXY mice had lower bone volume (6.8% ± 1.2% versus8.8% ± 1.7%, mean ± SD, p = .01) and thinner trabeculae (50 ± 4 µm versus 57 ± 5 µm, p = .007). Trabecular separation (270 ± 20 µm versus 270 ± 20 µm) or osteoclast number relative to bone surface (2.4 ± 1.0/mm2 versus 2.7 ± 1.5/mm2) did not differ significantly. Testosterone-replaced XXY mice continued to show lower bone volume (5.5% ± 2.4% versus 8.1% ± 3.5%, p = .026). They also exhibited greater trabecular separation (380 ± 69 µm versus 324 ± 62 µm, p = .040) but equivalent blood testosterone concentrations (6.3 ± 1.8 ng/mL versus 8.2 ± 4.2 ng/mL, p = .28) compared with testosterone-replaced XY littermates. In contrast, castration alone drastically decreased bone volume (p < .001), trabecular thickness (p = .05), and trabecular separation (p < .01) to such a great extent that differences between XXY and XY mice were undetectable. In conclusion, XXY mice

  9. Cartilage Repair and Subchondral Bone Remodeling in Response to Focal Lesions in a Mini-Pig Model: Implications for Tissue Engineering

    PubMed Central

    Fisher, Matthew B.; Belkin, Nicole S.; Milby, Andrew H.; Henning, Elizabeth A.; Bostrom, Marc; Kim, Minwook; Pfeifer, Christian; Meloni, Gregory; Dodge, George R.; Burdick, Jason A.; Schaer, Thomas P.; Steinberg, David R.

    2015-01-01

    Objective: Preclinical large animal models are essential for evaluating new tissue engineering (TE) technologies and refining surgical approaches for cartilage repair. Some preclinical animal studies, including the commonly used minipig model, have noted marked remodeling of the subchondral bone. However, the mechanisms underlying this response have not been well characterized. Thus, our objective was to compare in-vivo outcomes of chondral defects with varied injury depths and treatments. Design: Trochlear chondral defects were created in 11 Yucatan minipigs (6 months old). Groups included an untreated partial-thickness defect (PTD), an untreated full-thickness defect (FTD), and FTDs treated with microfracture, autologous cartilage transfer (FTD-ACT), or an acellular hyaluronic acid hydrogel. Six weeks after surgery, micro-computed tomography (μCT) was used to quantitatively assess defect fill and subchondral bone remodeling. The quality of cartilage repair was assessed using the ICRS-II histological scoring system and immunohistochemistry for type II collagen. A finite element model (FEM) was developed to assess load transmission. Results: Using μCT, substantial bone remodeling was observed for all FTDs, but not for the PTD group. The best overall histological scores and greatest type II collagen staining was found for the FTD-ACT and PTD groups. The FEM confirmed that only the FTD-ACT group could initially restore appropriate transfer of compressive loads to the underlying bone. Conclusions: The bony remodeling observed in this model system appears to be a biological phenomena and not a result of altered mechanical loading, with the depth of the focal chondral defect (partial vs. full thickness) dictating the bony remodeling response. The type of cartilage injury should be carefully controlled in studies utilizing this model to evaluate TE approaches for cartilage repair. PMID:25318414

  10. Suppressive effect of compact bone-derived mesenchymal stem cells on chronic airway remodeling in murine model of asthma.

    PubMed

    Ogulur, Ismail; Gurhan, Gulben; Aksoy, Ayca; Duruksu, Gokhan; Inci, Cigdem; Filinte, Deniz; Kombak, Faruk Erdem; Karaoz, Erdal; Akkoc, Tunc

    2014-05-01

    New therapeutic strategies are needed in the treatment of asthma besides vaccines and pharmacotherapies. For the development of novel therapies, the use of mesenchymal stem cells (MSCs) is a promising approach in regenerative medicine. Delivery of compact bone (CB) derived MSCs to the injured lungs is an alternative treatment strategy for chronic asthma. In this study, we aimed to isolate highly enriched population of MSCs from mouse CB with regenerative capacity, and to investigate the impact of these cells in airway remodeling and inflammation in experimental ovalbumin-induced mouse model of chronic asthma. mCB-MSCs were isolated, characterized, labeled with GFP and then transferred into mice with chronic asthma developed by ovalbumin (OVA) provocation. Histopathological changes including basement membrane, epithelium, subepithelial smooth thickness and goblet cell hyperplasia, and MSCs migration to lung tissues were evaluated. These histopathological alterations were increased in ovalbumin-treated mice compared to PBS group (P<0.001). Intravenous administration of mCB-MSC significantly reduced these histopathological changes in both distal and proximal airways (P<0.001). We showed that GFP-labeled MSCs were located in the lungs of OVA group 2weeks after intravenous induction. mCB-MSCs also significantly promoted Treg response in ovalbumin-treated mice (OVA+MSC group) (P<0.037). Our studies revealed that mCB-MSCs migrated to lung tissue and suppressed histopathological changes in murine model of asthma. The results reported here provided evidence that mCB-MSCs may be an alternative strategy for the treatment of remodeling and inflammation associated with chronic asthma. PMID:24613203

  11. Small body size and extreme cortical bone remodeling indicate phyletic dwarfism in Magyarosaurus dacus (Sauropoda: Titanosauria)

    PubMed Central

    Stein, Koen; Csiki, Zoltan; Rogers, Kristina Curry; Weishampel, David B.; Redelstorff, Ragna; Carballido, Jose L.; Sander, P. Martin

    2010-01-01

    Sauropods were the largest terrestrial tetrapods (>105 kg) in Earth's history and grew at rates that rival those of extant mammals. Magyarosaurus dacus, a titanosaurian sauropod from the Upper Cretaceous (Maastrichtian) of Romania, is known exclusively from small individuals (<103 kg) and conflicts with the idea that all sauropods were massive. The diminutive M. dacus was a classical example of island dwarfism (phyletic nanism) in dinosaurs, but a recent study suggested that the small Romanian titanosaurs actually represent juveniles of a larger-bodied taxon. Here we present strong histological evidence that M. dacus was indeed a dwarf (phyletic nanoid). Bone histological analysis of an ontogenetic series of Magyarosaurus limb bones indicates that even the smallest Magyarosaurus specimens exhibit a bone microstructure identical to fully mature or old individuals of other sauropod taxa. Comparison of histologies with large-bodied sauropods suggests that Magyarosaurus had an extremely reduced growth rate, but had retained high basal metabolic rates typical for sauropods. The uniquely decreased growth rate and diminutive body size in Magyarosaurus were adaptations to life on a Cretaceous island and show that sauropod dinosaurs were not exempt from general ecological principles limiting body size. PMID:20435913

  12. Activation of AMPK Prevents Monocrotaline-Induced Extracellular Matrix Remodeling of Pulmonary Artery

    PubMed Central

    Li, Shaojun; Han, Dong; Zhang, Yonghong; Xie, Xinming; Ke, Rui; Zhu, Yanting; Liu, Lu; Song, Yang; Yang, Lan; Li, Manxiang

    2016-01-01

    Background The current study was performed to investigate the effect of adenosine monophosphate (AMP) – activated protein kinase (AMPK) activation on the extracellular matrix (ECM) remodeling of pulmonary arteries in pulmonary arterial hypertension (PAH) and to address its potential mechanisms. Material/Methods PAH was induced by a single intraperitoneal injection of monocrotaline (MCT) into Sprague-Dawley rats. Metformin (MET) was administered to activate AMPK. Immunoblotting was used to determine the phosphorylation and expression of AMPK and expression of tissue inhibitor of metalloproteinase-1 (TIMP-1). Gelatin zymography was performed to determine the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9. Results Activation of AMPK by MET significantly reduced the right ventricle systolic pressure and the right ventricular hypertrophy in MCT-induced rat PAH model, and partially inhibited the ECM remodeling of pulmonary arteries. These effects were coupled with the decrease of MMP-2/9 activity and TIMP-1 expression. Conclusions This study suggests that activation of AMPK benefits PAH by inhibiting ECM remodeling of pulmonary arteries. Enhancing AMPK activity might have potential value in clinical treatment of PAH. PMID:26978596

  13. In vivo bone tunnel remodeling in symptomatic patients after ACL reconstruction: a retrospective comparison of articular and extra-articular fixation

    PubMed Central

    Mathis, Dominic T.; Rasch, Helmut; Hirschmann, Michael T.

    2015-01-01

    Summary Background there is only a paucity of studies dealing with bone remodeling within the tunnels after anterior cruciate ligament (ACL) reconstruction. The objective of this study was to evaluate the influence of tendon graft type and surgical fixation technique on bone tunnel remodeling in patients with symptomatic knees after ACL reconstruction. Methods in a retrospective study 99mTc-HDP bone tracer uptake (BTU) in SPECT/CT of 57 knees with symptoms of pain and/or instability after ACL reconstruction was investigated. All 57 knees were subdivided according their anatomy (femur and tibia), fixation (articular versus extra-articular fixation) and graft types into eight groups: femoral-articular versus extra-articular fixation using bone-patellar tendon-bone (BPTB) and hamstring autografts; tibial-articular versus extra-articular fixation using patellar tendon and hamstring autografts; BTU grading for each area of the localisation scheme were recorded. Tunnel diameter and length was measured in the CT scans. Results BTU was higher for the articular fixation in the femur and for the extra-articular fixation in the tibial tunnel. Patellar tendon graft fixation showed a significantly higher BTU in the superior-lateral and posterior-central area of the tibia, meaning the areas of the tibial tunnel near the entrance into the joint. Tunnel enlargement correlated significantly with increased BTU (p<0.05). Conclusion assessment of in vivo bone tunnel remodelling in symptomatic patients after ACL reconstruction revealed different patterns of BTU with regards to graft and fixation method. PMID:26958543

  14. Effect of Cervus and Cucumis Peptides on Osteoblast Activity and Fracture Healing in Osteoporotic Bone

    PubMed Central

    Wang, Ai-Yuan; Tian, Yue; Yuan, Mei; Zhang, Li; Chen, Ji-Feng; Xu, Wen-Jing; Meng, Hao-Ye; Yu, Xiao-Ming; Wang, Yao-Qin; Guo, Quan-Yi; Lu, Shi-Bi; Peng, Jiang; Wang, Yu

    2014-01-01

    Osteoporosis is associated with delayed and/or reduced fracture healing. As cervus and cucumis are the traditional Chinese treatments for rheumatoid arthritis, we investigated the effect of supplementation of these peptides (CCP) on bone fracture healing in ovariectomized (OVX) osteoporotic rats in vitro and in vivo. CCP enhanced osteoblast proliferation and increased alkaline phosphatase activity, matrix mineralization, and expression of runt-related transcription factor 2 (Runx2), bone morphogenetic protein 4 (BMP4), and osteopontin. In vivo, female Sprague-Dawley rats underwent ovariectomy and the right femora were fractured and fixed by intramedullary nailing 3 months later. Rats received intraperitoneal injections of either CCP (1.67 mg/kg) or physiological saline every day for 30 days. Fracture healing and callus formation were evaluated by radiography, micro-CT, biomechanical testing, and histology. At 12 weeks after fracture, calluses in CCP-treated bones showed significantly higher torsional strength and greater stiffness than control-treated bones. Bones in CCP-treated rats reunified and were thoroughly remodeled, while two saline-treated rats showed no bone union and incomplete remodeling. Taken together, these results indicate that use of CCP after fracture in osteoporotic rats accelerates mineralization and osteogenesis and improves fracture healing. PMID:25525453

  15. Re"modeling" College Algebra: An Active Learning Approach

    ERIC Educational Resources Information Center

    Pinzon, D.; Pinzon, K.; Stackpole, M.

    2016-01-01

    In this paper, we discuss active learning in College Algebra at Georgia Gwinnett College. This approach has been used in more than 20 sections of College Algebra taught by the authors in the past four semesters. Students work in small, structured groups on guided inquiry activities after watching 15-20 minutes of videos before class. We discuss a…

  16. Mitochondrial Biogenesis and Proteome Remodeling Promote One-Carbon Metabolism for T Cell Activation.

    PubMed

    Ron-Harel, Noga; Santos, Daniel; Ghergurovich, Jonathan M; Sage, Peter T; Reddy, Anita; Lovitch, Scott B; Dephoure, Noah; Satterstrom, F Kyle; Sheffer, Michal; Spinelli, Jessica B; Gygi, Steven; Rabinowitz, Joshua D; Sharpe, Arlene H; Haigis, Marcia C

    2016-07-12

    Naive T cell stimulation activates anabolic metabolism to fuel the transition from quiescence to growth and proliferation. Here we show that naive CD4(+) T cell activation induces a unique program of mitochondrial biogenesis and remodeling. Using mass spectrometry, we quantified protein dynamics during T cell activation. We identified substantial remodeling of the mitochondrial proteome over the first 24 hr of T cell activation to generate mitochondria with a distinct metabolic signature, with one-carbon metabolism as the most induced pathway. Salvage pathways and mitochondrial one-carbon metabolism, fed by serine, contribute to purine and thymidine synthesis to enable T cell proliferation and survival. Genetic inhibition of the mitochondrial serine catabolic enzyme SHMT2 impaired T cell survival in culture and antigen-specific T cell abundance in vivo. Thus, during T cell activation, mitochondrial proteome remodeling generates specialized mitochondria with enhanced one-carbon metabolism that is critical for T cell activation and survival. PMID:27411012

  17. Spatiotemporal regulation of chemical reaction kinetics of cell surface molecules by active remodeling of cortical actin

    NASA Astrophysics Data System (ADS)

    Bhattacharyya, Bhaswati; Chaudhuri, Abhishek; Gowrishankar, Kripa; Mayor, Satyajit; Rao, Madan

    2010-03-01

    Cell surface proteins such as lipid tethered GPI-anchored proteins and Ras-proteins are distributed as monomers and nanoclusters on the surface of living cells. Recent work from our laboratory suggests that the spatial distribution and dynamics of formation and breakup of these nanoclusters is controlled by the active remodeling dynamics of the underlying cortical actin. To explain these observations, we propose a novel mechanism of nanoclustering, involving the transient binding to and advection along constitutively occuring ``asters'' of cortical actin. Here we study the consequences of such active actin based clustering, in the context of chemical reactions involving conformational changes of cell surface proteins. We find that active remodeling of cortical actin, can give rise to a dramatic increase in the reaction efficiency and output levels. In general, such actin driven clustering of membrane proteins could be a cellular mechanism to spatiotemporally regulate and amplify local chemical reaction rates, in the context of signalling and endocytosis.

  18. Application of an anisotropic bone-remodelling model based on a damage-repair theory to the analysis of the proximal femur before and after total hip replacement.

    PubMed

    Doblaré, M; García, J M

    2001-09-01

    In this work, a new model for internal anisotropic bone remodelling is applied to the study of the remodelling behaviour of the proximal femur before and after total hip replacement (THR). This model considers bone remodelling under the scope of a general damage-repair theory following the principles of continuum damage mechanics. A "damage-repair" tensor is defined in terms of the apparent density and Cowin's "fabric tensor", respectively, associated with porosity and directionality of the trabeculae. The different elements of a thermodynamically consistent damage theory are established, including resorption and apposition criteria, evolution law and rate of remodelling. All of these elements were introduced and discussed in detail in a previous paper (García, J. M., Martinez, M. A., Doblaré, M., 2001. An anisotrophic internal-external bone adaptation model based on a combination of CAO and continuum damage mechanics technologies. Computer Methods in Biomechanics and Biomedical Engineering 4(4), 355-378.), including the definition of the proposed mechanical stimulus and the qualitative properties of the model. In this paper, the fundamentals of the proposed model are briefly reviewed and the computational aspects of its implementation are discussed. This model is then applied to the analysis of the remodelling behaviour of the intact femur obtaining densities and mass principal values and directions very close to the experimental data. The second application involved the proximal femoral extremity after THR and the inclusion of an Exeter prosthesis. As a result of the simulation process, some well-known features previously detected in medical clinics were recovered, such as the stress yielding effect in the proximal part of the implant or the enlargement of the cortical layer at the distal part of the implant. With respect to the anisotropic properties, bone microstructure and local stiffness are known to tend to align with the stress principal directions. This

  19. Activation of Calpain-2 by Mediators in Pulmonary Vascular Remodeling of Pulmonary Arterial Hypertension.

    PubMed

    Kovacs, Laszlo; Han, Weihong; Rafikov, Ruslan; Bagi, Zsolt; Offermanns, Stefan; Saido, Takaomi C; Black, Stephen M; Su, Yunchao

    2016-03-01

    Calpain mediates collagen synthesis and cell proliferation and plays an important role in pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). In the present study, we investigated whether and how calpain is activated by PAH mediators in pulmonary artery smooth muscle cells (PASMCs). These data show that smooth muscle-specific knockout of calpain attenuated and knockout of calpastatin potentiated pulmonary vascular remodeling and pulmonary hypertension. Treatment of PASMCs with the PAH mediators platelet-derived growth factor (PDGF), serotonin, H2O2, endothelin-1, and IL-6 caused significant increases in calpain activity, cell proliferation, and collagen-I protein level without changes in protein levels of calpain-1 and -2. The calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA/AM) did not affect calpain activation, but the extracellular signal-regulated kinase (ERK) 1/2 inhibitor PD98059 and knocking down of calpain-2 prevented calpain activation in PAH mediator-treated PASMCs. Mass spectrometry data showed that the phosphorylation of calpain-2 at serine (Ser) 50 was increased and the phosphorylation of calpain-2 at Ser369 was decreased in PDGF-treated PASMCs. The PDGF-induced increase in Ser50 phosphorylation of calpain-2 was prevented by PD98059, whereas dephosphorylation of calpain-2 at Ser369 was blocked by the protein phosphatase 2A inhibitor fostriecin. Furthermore, smooth muscle of pulmonary arteries in PAH animal models and patients with PAH showed higher levels of phospho-Ser50-calpain-2 (P-Ser50) and lower levels of phospho-Ser369-calpain-2 (P-Ser369). These data support that calpain modulates pulmonary vascular remodeling in PAH. PAH mediator-induced activation of calpain is caused by ERK1/2-dependent phosphorylation of calpain-2 at Ser50 and protein phosphatase 2A-dependent dephosphorylation of calpain-2 at Ser369 in pulmonary vascular remodeling of PAH. PMID:26248159

  20. Physical Activity and Bone Density in Women

    NASA Technical Reports Server (NTRS)

    Bowley, Susan M.; Whalen, R. T.

    2000-01-01

    A mathematical model of bone density regulation as a function of the daily tissue "effective" stress has been derived. Using the model, the influence of daily activity in the form of a daily loading history has been related to bone density of the calcaneus. The theory incorporates a stress exponent m to account for differences in the importance of magnitude and number of load cycles experienced during daily activity. We have derived a parameter from the model, the "Bone Density Index" (BDI). We have developed a method of collecting daily habitual loading histories using an insole force sensor interfaced to a portable digital data logger carried in a fanny pack. Our goal for this study was to determine a stress exponent, m, relating GRFz history to Calcaneal Bone Mineral Density (CBMD).

  1. Increased Diels-Alderase activity through backbone remodeling guided by Foldit players.

    PubMed

    Eiben, Christopher B; Siegel, Justin B; Bale, Jacob B; Cooper, Seth; Khatib, Firas; Shen, Betty W; Players, Foldit; Stoddard, Barry L; Popovic, Zoran; Baker, David

    2012-02-01

    Computational enzyme design holds promise for the production of renewable fuels, drugs and chemicals. De novo enzyme design has generated catalysts for several reactions, but with lower catalytic efficiencies than naturally occurring enzymes. Here we report the use of game-driven crowdsourcing to enhance the activity of a computationally designed enzyme through the functional remodeling of its structure. Players of the online game Foldit were challenged to remodel the backbone of a computationally designed bimolecular Diels-Alderase to enable additional interactions with substrates. Several iterations of design and characterization generated a 24-residue helix-turn-helix motif, including a 13-residue insertion, that increased enzyme activity >18-fold. X-ray crystallography showed that the large insertion adopts a helix-turn-helix structure positioned as in the Foldit model. These results demonstrate that human creativity can extend beyond the macroscopic challenges encountered in everyday life to molecular-scale design problems. PMID:22267011

  2. Shape remodeling and blebbing of active cytoskeletal vesicles

    PubMed Central

    Loiseau, Etienne; Schneider, Jochen A. M.; Keber, Felix C.; Pelzl, Carina; Massiera, Gladys; Salbreux, Guillaume; Bausch, Andreas R.

    2016-01-01

    Morphological transformations of living cells, such as shape adaptation to external stimuli, blebbing, invagination, or tethering, result from an intricate interplay between the plasma membrane and its underlying cytoskeleton, where molecular motors generate forces. Cellular complexity defies a clear identification of the competing processes that lead to such a rich phenomenology. In a synthetic biology approach, designing a cell-like model assembled from a minimal set of purified building blocks would allow the control of all relevant parameters. We reconstruct actomyosin vesicles in which the coupling of the cytoskeleton to the membrane, the topology of the cytoskeletal network, and the contractile activity can all be precisely controlled and tuned. We demonstrate that tension generation of an encapsulated active actomyosin network suffices for global shape transformation of cell-sized lipid vesicles, which are reminiscent of morphological adaptations in living cells. The observed polymorphism of our cell-like model, such as blebbing, tether extrusion, or faceted shapes, can be qualitatively explained by the protein concentration dependencies and a force balance, taking into account the membrane tension, the density of anchoring points between the membrane and the actin network, and the forces exerted by molecular motors in the actin network. The identification of the physical mechanisms for shape transformations of active cytoskeletal vesicles sets a conceptual and quantitative benchmark for the further exploration of the adaptation mechanisms of cells. PMID:27152328

  3. Shape remodeling and blebbing of active cytoskeletal vesicles.

    PubMed

    Loiseau, Etienne; Schneider, Jochen A M; Keber, Felix C; Pelzl, Carina; Massiera, Gladys; Salbreux, Guillaume; Bausch, Andreas R

    2016-04-01

    Morphological transformations of living cells, such as shape adaptation to external stimuli, blebbing, invagination, or tethering, result from an intricate interplay between the plasma membrane and its underlying cytoskeleton, where molecular motors generate forces. Cellular complexity defies a clear identification of the competing processes that lead to such a rich phenomenology. In a synthetic biology approach, designing a cell-like model assembled from a minimal set of purified building blocks would allow the control of all relevant parameters. We reconstruct actomyosin vesicles in which the coupling of the cytoskeleton to the membrane, the topology of the cytoskeletal network, and the contractile activity can all be precisely controlled and tuned. We demonstrate that tension generation of an encapsulated active actomyosin network suffices for global shape transformation of cell-sized lipid vesicles, which are reminiscent of morphological adaptations in living cells. The observed polymorphism of our cell-like model, such as blebbing, tether extrusion, or faceted shapes, can be qualitatively explained by the protein concentration dependencies and a force balance, taking into account the membrane tension, the density of anchoring points between the membrane and the actin network, and the forces exerted by molecular motors in the actin network. The identification of the physical mechanisms for shape transformations of active cytoskeletal vesicles sets a conceptual and quantitative benchmark for the further exploration of the adaptation mechanisms of cells. PMID:27152328

  4. The effects of a systemic single dose of zoledronic acid on post-implantation bone remodelling and inflammation in an ovariectomised rat model.

    PubMed

    Cardemil, Carina; Omar, Omar M; Norlindh, Birgitta; Wexell, Cecilia L; Thomsen, Peter

    2013-02-01

    Bisphosphonates reverse the negative effects of ovariectomy on bone, but they have also been associated with adverse processes in human jawbone. The molecular events determining bone regeneration and implant integration in osteoporotic conditions, with and without bisphosphonate treatment, are unclear. In this study, ovariectomised rats, to which a single dose of saline (NaCl) or zoledronic acid (Zol) was administered, received titanium alloy implants in their tibiae and mandibles. An enzyme-linked immunosorbent assay, gene expression analysis and histomorphometry were performed. The results show that ovariectomy, per se, upregulated the expression of genes denoting bone formation in the tibia, bone remodelling in the mandible and apoptosis in the tibia and mandible. Zoledronic acid administration resulted in lower levels of a remodelling marker in serum and downregulated gene expression for inflammation, bone formation, angiogenesis and apoptosis, mainly in the mandible, after 28 d of healing. Histomorphometry revealed improved bone-to-implant contact in the tibia, while the opposite was observed in the mandible. The present data show that a systemic single dose of zoledronic acid, in ovariectomised animals, results in site-specific differences in the regulation of genes involved in bone healing and regeneration in association with implant installation. These events occur in parallel with site-specific differences in the rate of osseointegration, indicating diverse tissue responses in the tibia and mandible after zoledronic acid treatment. The zoledronic acid effect on gene expression, during the late phase of healing in the mandible, suggests negative effects by the anti-resorptive agent on osseointegration at that particular site. PMID:23182921

  5. Depression Increases Sympathetic Activity and Exacerbates Myocardial Remodeling after Myocardial Infarction: Evidence from an Animal Experiment

    PubMed Central

    Liu, Tao; Yuan, Xiaoran; Ruan, Bing; Sun, Lifang; Tang, Yanhong; Yang, Bo; Hu, Dan; Huang, Congxin

    2014-01-01

    Depression is an independent risk factor for cardiovascular events and mortality in patients with myocardial infarction (MI). Excessive sympathetic activation and serious myocardial remodeling may contribute to this association. The aim of this study was to discuss the effect of depression on sympathetic activity and myocardial remodeling after MI. Wild-type (WT) rats were divided into a sham group (Sham), a myocardial infarction group (MI), a depression group (D), and a myocardial infarction plus depression group (MI+D). Compared with controls, the MI+D animals displayed depression-like behaviors and attenuated body weight gain. The evaluation of sympathetic activity showed an increased level in plasma concentrations of epinephrine and norepinephrine and higher expression of myocardial tyrosine hydroxylase in the MI+D group than the control groups (p<0.05 for all). Cardiac function and morphologic analyses revealed a decreased fractional shortening accompanied by increased left ventricular dimensions, thinning myocardium wall, and reduced collagen repair in the MI+D group compared with the MI group (p<0.05 for all). Frequent premature ventricular contractions, prolonged QT duration and ventricular repolarization duration, shorted effective refractory period, and increased susceptibility to ventricular arrhythmia were displayed in MI+D rats. These results indicate that sympathetic hyperactivation and exacerbated myocardial remodeling may be a plausible mechanism linking depression to an adverse prognosis after MI. PMID:25036781

  6. Opposing ISWI- and CHD-class chromatin remodeling activities orchestrate heterochromatic DNA repair

    PubMed Central

    Klement, Karolin; Luijsterburg, Martijn S.; Pinder, Jordan B.; Cena, Chad S.; Del Nero, Victor; Wintersinger, Christopher M.; Dellaire, Graham; van Attikum, Haico

    2014-01-01

    Heterochromatin is a barrier to DNA repair that correlates strongly with elevated somatic mutation in cancer. CHD class II nucleosome remodeling activity (specifically CHD3.1) retained by KAP-1 increases heterochromatin compaction and impedes DNA double-strand break (DSB) repair requiring Artemis. This obstruction is alleviated by chromatin relaxation via ATM-dependent KAP-1S824 phosphorylation (pKAP-1) and CHD3.1 dispersal from heterochromatic DSBs; however, how heterochromatin compaction is actually adjusted after CHD3.1 dispersal is unknown. In this paper, we demonstrate that Artemis-dependent DSB repair in heterochromatin requires ISWI (imitation switch)-class ACF1–SNF2H nucleosome remodeling. Compacted chromatin generated by CHD3.1 after DNA replication necessitates ACF1–SNF2H–mediated relaxation for DSB repair. ACF1–SNF2H requires RNF20 to bind heterochromatic DSBs, underlies RNF20-mediated chromatin relaxation, and functions downstream of pKAP-1–mediated CHD3.1 dispersal to enable DSB repair. CHD3.1 and ACF1–SNF2H display counteractive activities but similar histone affinities (via the plant homeodomains of CHD3.1 and ACF1), which we suggest necessitates a two-step dispersal and recruitment system regulating these opposing chromatin remodeling activities during DSB repair. PMID:25533843

  7. Opposing ISWI- and CHD-class chromatin remodeling activities orchestrate heterochromatic DNA repair.

    PubMed

    Klement, Karolin; Luijsterburg, Martijn S; Pinder, Jordan B; Cena, Chad S; Del Nero, Victor; Wintersinger, Christopher M; Dellaire, Graham; van Attikum, Haico; Goodarzi, Aaron A

    2014-12-22

    Heterochromatin is a barrier to DNA repair that correlates strongly with elevated somatic mutation in cancer. CHD class II nucleosome remodeling activity (specifically CHD3.1) retained by KAP-1 increases heterochromatin compaction and impedes DNA double-strand break (DSB) repair requiring Artemis. This obstruction is alleviated by chromatin relaxation via ATM-dependent KAP-1S824 phosphorylation (pKAP-1) and CHD3.1 dispersal from heterochromatic DSBs; however, how heterochromatin compaction is actually adjusted after CHD3.1 dispersal is unknown. In this paper, we demonstrate that Artemis-dependent DSB repair in heterochromatin requires ISWI (imitation switch)-class ACF1-SNF2H nucleosome remodeling. Compacted chromatin generated by CHD3.1 after DNA replication necessitates ACF1-SNF2H-mediated relaxation for DSB repair. ACF1-SNF2H requires RNF20 to bind heterochromatic DSBs, underlies RNF20-mediated chromatin relaxation, and functions downstream of pKAP-1-mediated CHD3.1 dispersal to enable DSB repair. CHD3.1 and ACF1-SNF2H display counteractive activities but similar histone affinities (via the plant homeodomains of CHD3.1 and ACF1), which we suggest necessitates a two-step dispersal and recruitment system regulating these opposing chromatin remodeling activities during DSB repair. PMID:25533843

  8. Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells

    PubMed Central

    Florencio-Silva, Rinaldo; Sasso, Gisela Rodrigues da Silva; Sasso-Cerri, Estela; Simões, Manuel Jesus; Cerri, Paulo Sérgio

    2015-01-01

    Bone tissue is continuously remodeled through the concerted actions of bone cells, which include bone resorption by osteoclasts and bone formation by osteoblasts, whereas osteocytes act as mechanosensors and orchestrators of the bone remodeling process. This process is under the control of local (e.g., growth factors and cytokines) and systemic (e.g., calcitonin and estrogens) factors that all together contribute for bone homeostasis. An imbalance between bone resorption and formation can result in bone diseases including osteoporosis. Recently, it has been recognized that, during bone remodeling, there are an intricate communication among bone cells. For instance, the coupling from bone resorption to bone formation is achieved by interaction between osteoclasts and osteoblasts. Moreover, osteocytes produce factors that influence osteoblast and osteoclast activities, whereas osteocyte apoptosis is followed by osteoclastic bone resorption. The increasing knowledge about the structure and functions of bone cells contributed to a better understanding of bone biology. It has been suggested that there is a complex communication between bone cells and other organs, indicating the dynamic nature of bone tissue. In this review, we discuss the current data about the structure and functions of bone cells and the factors that influence bone remodeling. PMID:26247020

  9. Can Na18F PET/CT Be Used to Study Bone Remodeling in the Tibia When Patients Are Being Treated with a Taylor Spatial Frame?

    PubMed Central

    Lundblad, Henrik; Maguire, Gerald Q.; Olivecrona, Henrik; Jonsson, Cathrine; Jacobsson, Hans; Noz, Marilyn E.; Zeleznik, Michael P.; Weidenhielm, Lars; Sundin, Anders

    2014-01-01

    Monitoring and quantifying bone remodeling are of interest, for example, in correction osteotomies, delayed fracture healing pseudarthrosis, bone lengthening, and other instances. Seven patients who had operations to attach an Ilizarov-derived Taylor Spatial Frame to the tibia gave informed consent. Each patient was examined by Na18F PET/CT twice, at approximately six weeks and three months after the operation. A validated software tool was used for the following processing steps. The first and second CT volumes were aligned in 3D and the respective PET volumes were aligned accordingly. In the first PET volume spherical volumes of interest (VOIs) were delineated for the crural fracture and normal bone and transferred to the second PET volume for SUVmax evaluation. This method potentially provides clinical insight into questions such as, when has the bone remodeling progressed well enough to safely remove the TSF? and when is intervention required, in a timelier manner than current methods? For example, in two patients who completed treatment, the SUVmax between the first and second PET/CT examination decreased by 42% and 13%, respectively. Further studies in a larger patient population are needed to verify these preliminary results by correlating regional Na18F PET measurements to clinical and radiological findings. PMID:24778581

  10. The osteocyte: key player in regulating bone turnover

    PubMed Central

    Goldring, Steven R

    2015-01-01

    Osteocytes are the most abundant cell type in bone and are distributed throughout the mineralised bone matrix forming an interconnected network that ideally positions them to sense and to respond to local biomechanical and systemic stimuli to regulate bone remodelling and adaptation. The adaptive process is dependent on the coordinated activity of osteoclasts and osteoblasts that form a so called bone multicellular unit that remodels cortical and trabecular bone through a process of osteoclast-mediated bone resorption, followed by a phase of bone formation mediated by osteoblasts. Osteocytes mediate their effects on bone remodelling via both cell–cell interactions with osteoclasts and osteoblasts, but also via signaling through the release of soluble mediators. The remodelling process provides a mechanism for adapting the skeleton to local biomechanical factors and systemic hormonal influences and for replacing bone that has undergone damage from repetitive mechanical loading. PMID:26557372

  11. Regional differences in oxidative metabolism and mitochondrial activity among cortical bone osteocytes.

    PubMed

    Frikha-Benayed, Dorra; Basta-Pljakic, Jelena; Majeska, Robert J; Schaffler, Mitchell B

    2016-09-01

    Metabolic oxidative stress has been implicated as a cause of osteocyte apoptosis, an essential step in triggering bone remodeling. However, little is known about the oxidative behavior of osteocytes in vivo. We assessed the redox status and distribution of total and active mitochondria in osteocytes of mouse metatarsal cortical bone in situ. Multiphoton microscopy (MPM) was used to measure fluorescence of reduced pyridine nucleotides (NADH) under normoxic conditions and acutely following extreme (postmortem) hypoxic stress. Under non-hypoxic conditions, osteocytes exhibited no detectable fluorescence, indicating rapid NADH re-oxidation. With hypoxia, NADH levels peaked and returned to near baseline levels over 3h. Cells near the periosteal surface reached maximum NADH levels twice as rapidly as osteocytes near the mid-cortex, due to the time required to initiate NADH accumulation; once started, NADH accumulation followed a similar exponential relationship at all sites. Osteocytes near periosteal and endosteal bone surfaces also had higher mitochondrial content than those in mid-cortex based on immunohistochemical staining for mitochondrial ATPase-5A (Complex V ATPase). The content of active mitochondria, assessed in situ using the potentiometric dye TMRM, was also high in osteocytes near periosteum, but low in osteocytes near endocortical surfaces, similar to levels in mid-cortex. These results demonstrate that cortical osteocytes maintain normal oxidative status utilizing mainly aerobic (mitochondrial) pathways but respond to hypoxic stress differently depending on their location in the cortex, a difference linked to mitochondrial content. An apparently high proportion of poorly functional mitochondria in osteocytes near endocortical surfaces, where increased apoptosis mainly occurs in response to bone remodeling stimuli, further suggest that regional differences in oxidative function may in part determine osteocyte susceptibility to undergo apoptosis in response

  12. Long-term Bone Remodeling in HA-coated Stems: A Radiographic Review of 208 Total Hip Arthroplasties (THAs) with 15 to 20 Years Follow-up.

    PubMed

    Boldt, Jens G; Cartillier, Jean-Claude; Machenaud, Alain; Vidalain, Jean-Pierre

    2015-11-01

    We present a prospective study focused on radiographic long-term outcomes and bone remodeling at a mean of 17.0 years (range: 15 to 20) in 208 cementless fully HA-coated femoral stems (Corail, DePuy International Ltd, Leeds, UK). Total hip replacements in this study were performed by three members of the surgeon design group between 1986 and 1991. Radiographic evaluation focused on periprosthetic osteolysis, bone remodeling, osseous integration, subsidence, metaphyseal or diaphyseal load transfer, and femoral stress shielding. The radiographs were digitized and examined with contrast-enhancing software for analysis of the trabecular architecture. Radiographic signs of aseptic stem loosening were visible in two cases (1%). Three stems (1.4%) showed metaphyseal periprosthetic osteolysis in four of seven Gruen zones associated with eccentric polyethylene wear awaiting metaphyseal bone grafting and cup liner exchange. One stem (0.5%) was revised due to infection. No stem altered in varus or valgus alignment more than two degrees, and mean subsidence was 0.1 mm (range: 0 to 2 mm) after a mean of 17.0 years. A total of 5 stems (2.4%) required or are awaiting revision surgery. Trabecular orientation and micro-anatomy suggested main proximal load-transfer patterns in all except 3 cases (98.6%). Combined metaphyseal and diaphyseal osseointegration and bone remodeling were visible in 100 stems (48%). Diaphyseal stress shielding and cortical thickening were observed in 3 stems (1.4%). Other radiographic features are discussed in depth. This long-term study of 208 fully HA-coated Corail stems showed satisfactory osseointegration and fixation in 203 cases (97.6%) after a mean of 17.0 years follow-up. Stem failures were associated with extreme eccentric polyethylene wear. PMID:26680411

  13. Postural muscle atrophy prevention and recovery and bone remodelling through high frequency proprioception for astronauts

    NASA Astrophysics Data System (ADS)

    Riva, Dario; Rossitto, Franco; Battocchio, Luciano

    2009-09-01

    The difficulty in applying active exercises during space flights increases the importance of passive countermeasures, but coupling load and instability remains indispensable for generating high frequency (HF) proprioceptive flows and preventing muscle atrophy and osteoporosis. The present study, in microgravity conditions during a parabolic flight, verified whether an electronic system, composed of a rocking board, a postural reader and a bungee-cord loading apparatus creates HF postural instability comparable to that reachable on the Earth. Tracking the subject, in single stance, to real-time visual signals is necessary to obtain HF instability situations. The bungee-cord loading apparatus allowed the subject to manage the 81.5% body weight load (100% could easily be exceeded). A preliminary training programme schedule on the Earth and in space is suggested. Comparison with a pathological muscle atrophy is presented. The possibility of generating HF proprioceptive flows could complement current countermeasures for the prevention and recovery of muscle atrophy and osteoporosis in terrestrial and space environments. These exercises combine massive activation of spindles and joint receptors, applying simultaneously HF variations of pressure to different areas of the sole of the foot. This class of exercises could improve the effectiveness of current countermeasures, reducing working time and fatigue.

  14. Aortic Valve Cyclic Stretch Causes Increased Remodeling Activity and Enhanced Serotonin Receptor Responsiveness

    PubMed Central

    Balachandran, Kartik; Bakay, Marina A.; Connolly, Jeanne M.; Zhang, Xuemei; Yoganathan, Ajit P.; Levy, Robert J.

    2011-01-01

    Background Increased serotonin(5HT) receptor(5HTR) signaling has been associated with cardiac valvulopathy. Prior cell culture studies of 5HTR signaling in heart valve interstitial cells have provided mechanistic insights concerning only static conditions. We investigated the hypothesis that aortic valve biomechanics participate in the regulation of both 5HTR expression and inter-related extracellular matrix remodeling events. Methods The effects of cyclic-stretch on aortic valve 5HTR, expression, signaling and extracellular matrix remodeling were investigated using a tensile stretch bioreactor in studies which also compared the effects of adding 5HT and/or the 5HT-transporter inhibitor, Fluoxetine. Results Cyclic-stretch alone increased both proliferation and collagen in porcine aortic valve cusp samples. However, with cyclic-stretch, unlike static conditions, 5HT plus Fluoxetine caused the greatest increase in proliferation (p<0.0001), and also caused significant increases in collagen(p<0.0001) and glycosaminoglycans (p<0.0001). DNA microarray data demonstrated upregulation of 5HTR2A and 5HTR2B (>4.5 fold) for cyclic-stretch versus static (p<0.001), while expression of the 5HT transporter was not changed significantly. Extracellular matrix genes (eg. Collagen Types I,II,III, and proteoglycans) were also upregulated by cyclic-stretch. Conclusions Porcine aortic valve cusp samples subjected to cyclic stretch upregulate 5HTR2A and 2B, and also initiate remodeling activity characterized by increased proliferation and collagen production. Importantly, enhanced 5HTR responsiveness, due to increased 5HTR2A and 2B expression, results in a significantly greater response in remodeling endpoints (proliferation, collagen and GAG production) to 5HT in the presence of 5HT transporter blockade. PMID:21718840

  15. Active Bone Conduction Prosthesis: BonebridgeTM

    PubMed Central

    Zernotti, Mario E.; Sarasty, Andrea Bravo

    2015-01-01

    Introduction Bone conduction implants are indicated for patients with conductive and mixed hearing loss, as well as for patients with single-sided deafness (SSD). The transcutaneous technology avoids several complications of the percutaneous bone conduction implants including skin reaction, skin growth over the abutment, and wound infection. The Bonebridge (MED-EL, Austria) prosthesis is a semi-implantable hearing system: the BCI (Bone Conduction Implant) is the implantable part that contains the Bone Conduction-Floating Mass Transducer (BC-FMT), which applies the vibrations directly to the bone; the external component is the audio processor Amadé BB (MED-EL, Austria), which digitally processes the sound and sends the information through the coil to the internal part. Bonebridge may be implanted through three different approaches: the transmastoid, the retrosigmoid, or the middle fossa approach. Objective This systematic review aims to describe the world́s first active bone conduction implant system, Bonebridge, as well as describe the surgical techniques in the three possible approaches, showing results from implant centers in the world in terms of functional gain, speech reception thresholds and word recognition scores. Data Synthesis The authors searched the MEDLINE database using the key term Bonebridge. They selected only five publications to include in this systematic review. The review analyzes 20 patients that received Bonebridge implants with different approaches and pathologies. Conclusion Bonebridge is a solution for patients with conductive/mixed hearing loss and SSD with different surgical approaches, depending on their anatomy. The system imparts fewer complications than percutaneous bone conduction implants and shows proven benefits in speech discrimination and functional gain. PMID:26491482

  16. Active Bone Conduction Prosthesis: Bonebridge(TM).

    PubMed

    Zernotti, Mario E; Sarasty, Andrea Bravo

    2015-10-01

    Introduction Bone conduction implants are indicated for patients with conductive and mixed hearing loss, as well as for patients with single-sided deafness (SSD). The transcutaneous technology avoids several complications of the percutaneous bone conduction implants including skin reaction, skin growth over the abutment, and wound infection. The Bonebridge (MED-EL, Austria) prosthesis is a semi-implantable hearing system: the BCI (Bone Conduction Implant) is the implantable part that contains the Bone Conduction-Floating Mass Transducer (BC-FMT), which applies the vibrations directly to the bone; the external component is the audio processor Amadé BB (MED-EL, Austria), which digitally processes the sound and sends the information through the coil to the internal part. Bonebridge may be implanted through three different approaches: the transmastoid, the retrosigmoid, or the middle fossa approach. Objective This systematic review aims to describe the world́s first active bone conduction implant system, Bonebridge, as well as describe the surgical techniques in the three possible approaches, showing results from implant centers in the world in terms of functional gain, speech reception thresholds and word recognition scores. Data Synthesis The authors searched the MEDLINE database using the key term Bonebridge. They selected only five publications to include in this systematic review. The review analyzes 20 patients that received Bonebridge implants with different approaches and pathologies. Conclusion Bonebridge is a solution for patients with conductive/mixed hearing loss and SSD with different surgical approaches, depending on their anatomy. The system imparts fewer complications than percutaneous bone conduction implants and shows proven benefits in speech discrimination and functional gain. PMID:26491482

  17. A Plasminogen Activator Inhibitor-1 Inhibitor Reduces Airway Remodeling in a Murine Model of Chronic Asthma

    PubMed Central

    Lee, Sun H.; Eren, Mesut; Vaughan, Douglas E.; Schleimer, Robert P.

    2012-01-01

    We previously reported that plasminogen activator inhibitor (PAI)-1 deficiency prevents collagen deposition in the airways of ovalbumin (OVA)-challenged mice. In this study, we explored the therapeutic utility of blocking PAI-1 in preventing airway remodeling, using a specific PAI-1 inhibitor, tiplaxtinin. C57BL/6J mice were immunized with intraperitoneal injections of OVA on Days 0, 3, and 6. Starting on Day 11, mice were challenged with phosphate-buffered saline or OVA by nebulization three times per week for 4 weeks. Tiplaxtinin was mixed with chow and administered orally from 1 day before the phosphate-buffered saline or OVA challenge. Lung tissues were harvested after challenge and characterized histologically for infiltrating inflammatory cells, mucus-secreting goblet cells, and collagen deposition. Airway hyperresponsiveness was measured using whole-body plethysmography. Tiplaxtinin treatment significantly decreased levels of PAI-1 activity in bronchoalveolar lavage fluids, which indicates successful blockage of PAI-1 activity in the airways. The number of infiltrated inflammatory cells was reduced by tiplaxtinin treatment in the lungs of the OVA-challenged mice. Furthermore, oral administration of tiplaxtinin significantly attenuated the degree of goblet cell hyperplasia and collagen deposition in the airways of the OVA-challenged mice, and methacholine-induced airway hyperresponsiveness was effectively reduced by tiplaxtinin in these animals. This study supports our previous findings that PAI-1 promotes airway remodeling in a murine model of chronic asthma, and suggests that PAI-1 may be a novel target of treatment of airway remodeling in asthma. PMID:22323366

  18. A plasminogen activator inhibitor-1 inhibitor reduces airway remodeling in a murine model of chronic asthma.

    PubMed

    Lee, Sun H; Eren, Mesut; Vaughan, Douglas E; Schleimer, Robert P; Cho, Seong H

    2012-06-01

    We previously reported that plasminogen activator inhibitor (PAI)-1 deficiency prevents collagen deposition in the airways of ovalbumin (OVA)-challenged mice. In this study, we explored the therapeutic utility of blocking PAI-1 in preventing airway remodeling, using a specific PAI-1 inhibitor, tiplaxtinin. C57BL/6J mice were immunized with intraperitoneal injections of OVA on Days 0, 3, and 6. Starting on Day 11, mice were challenged with phosphate-buffered saline or OVA by nebulization three times per week for 4 weeks. Tiplaxtinin was mixed with chow and administered orally from 1 day before the phosphate-buffered saline or OVA challenge. Lung tissues were harvested after challenge and characterized histologically for infiltrating inflammatory cells, mucus-secreting goblet cells, and collagen deposition. Airway hyperresponsiveness was measured using whole-body plethysmography. Tiplaxtinin treatment significantly decreased levels of PAI-1 activity in bronchoalveolar lavage fluids, which indicates successful blockage of PAI-1 activity in the airways. The number of infiltrated inflammatory cells was reduced by tiplaxtinin treatment in the lungs of the OVA-challenged mice. Furthermore, oral administration of tiplaxtinin significantly attenuated the degree of goblet cell hyperplasia and collagen deposition in the airways of the OVA-challenged mice, and methacholine-induced airway hyperresponsiveness was effectively reduced by tiplaxtinin in these animals. This study supports our previous findings that PAI-1 promotes airway remodeling in a murine model of chronic asthma, and suggests that PAI-1 may be a novel target of treatment of airway remodeling in asthma. PMID:22323366

  19. The chromatin remodelling factor Brg-1 interacts with β-catenin to promote target gene activation

    PubMed Central

    Barker, Nick; Hurlstone, Adam; Musisi, Hannah; Miles, Antony; Bienz, Mariann; Clevers, Hans

    2001-01-01

    Wnt-induced formation of nuclear Tcf–β-catenin complexes promotes transcriptional activation of target genes involved in cell fate decisions. Inappropriate expression of Tcf target genes resulting from mutational activation of this pathway is also implicated in tumorigenesis. The C-terminus of β-catenin is indispensable for the transactivation function, which probably reflects the presence of binding sites for essential transcriptional coactivators such as p300/CBP. However, the precise mechanism of transactivation remains unclear. Here we demonstrate an interaction between β-catenin and Brg-1, a component of mammalian SWI/SNF and Rsc chromatin-remodelling complexes. A functional consequence of reintroduction of Brg-1 into Brg-1-deficient cells is enhanced activity of a Tcf-responsive reporter gene. Consistent with this, stable expression of inactive forms of Brg-1 in colon carcinoma cell lines specifically inhibits expression of endogenous Tcf target genes. In addition, we observe genetic interactions between the Brg-1 and β-catenin homologues in flies. We conclude that β-catenin recruits Brg-1 to Tcf target gene promoters, facilitating chromatin remodelling as a prerequisite for transcriptional activation. PMID:11532957

  20. The Chromatin Remodeler CHD8 Is Required for Activation of Progesterone Receptor-Dependent Enhancers

    PubMed Central

    Giannopoulou, Eugenia G.; Soronellas, Daniel; Vázquez-Chávez, Elena; Vicent, Guillermo P.; Elemento, Olivier; Beato, Miguel; Reyes, José C.

    2015-01-01

    While the importance of gene enhancers in transcriptional regulation is well established, the mechanisms and the protein factors that determine enhancers activity have only recently begun to be unravelled. Recent studies have shown that progesterone receptor (PR) binds regions that display typical features of gene enhancers. Here, we show by ChIP-seq experiments that the chromatin remodeler CHD8 mostly binds promoters under proliferation conditions. However, upon progestin stimulation, CHD8 re-localizes to PR enhancers also enriched in p300 and H3K4me1. Consistently, CHD8 depletion severely impairs progestin-dependent gene regulation. CHD8 binding is PR-dependent but independent of the pioneering factor FOXA1. The SWI/SNF chromatin-remodelling complex is required for PR-dependent gene activation. Interestingly, we show that CHD8 interacts with the SWI/SNF complex and that depletion of BRG1 and BRM, the ATPases of SWI/SNF complex, impairs CHD8 recruitment. We also show that CHD8 is not required for H3K27 acetylation, but contributes to increase accessibility of the enhancer to DNaseI. Furthermore, CHD8 was required for RNAPII recruiting to the enhancers and for transcription of enhancer-derived RNAs (eRNAs). Taken together our data demonstrate that CHD8 is involved in late stages of PR enhancers activation. PMID:25894978

  1. Aldehyde dehydrogenase 2 activation in heart failure restores mitochondrial function and improves ventricular function and remodelling

    PubMed Central

    Gomes, Katia M.S.; Campos, Juliane C.; Bechara, Luiz R.G.; Queliconi, Bruno; Lima, Vanessa M.; Disatnik, Marie-Helene; Magno, Paulo; Chen, Che-Hong; Brum, Patricia C.; Kowaltowski, Alicia J.; Mochly-Rosen, Daria; Ferreira, Julio C.B.

    2014-01-01

    Aims We previously demonstrated that pharmacological activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) protects the heart against acute ischaemia/reperfusion injury. Here, we determined the benefits of chronic activation of ALDH2 on the progression of heart failure (HF) using a post-myocardial infarction model. Methods and results We showed that a 6-week treatment of myocardial infarction-induced HF rats with a selective ALDH2 activator (Alda-1), starting 4 weeks after myocardial infarction at a time when ventricular remodelling and cardiac dysfunction were present, improved cardiomyocyte shortening, cardiac function, left ventricular compliance and diastolic function under basal conditions, and after isoproterenol stimulation. Importantly, sustained Alda-1 treatment showed no toxicity and promoted a cardiac anti-remodelling effect by suppressing myocardial hypertrophy and fibrosis. Moreover, accumulation of 4-hydroxynonenal (4-HNE)-protein adducts and protein carbonyls seen in HF was not observed in Alda-1-treated rats, suggesting that increasing the activity of ALDH2 contributes to the reduction of aldehydic load in failing hearts. ALDH2 activation was associated with improved mitochondrial function, including elevated mitochondrial respiratory control ratios and reduced H2O2 release. Importantly, selective ALDH2 activation decreased mitochondrial Ca2+-induced permeability transition and cytochrome c release in failing hearts. Further supporting a mitochondrial mechanism for ALDH2, Alda-1 treatment preserved mitochondrial function upon in vitro aldehydic load. Conclusions Selective activation of mitochondrial ALDH2 is sufficient to improve the HF outcome by reducing the toxic effects of aldehydic overload on mitochondrial bioenergetics and reactive oxygen species generation, suggesting that ALDH2 activators, such as Alda-1, have a potential therapeutic value for treating HF patients. PMID:24817685

  2. Macrophage plasticity and polarization in tissue repair and remodelling.

    PubMed

    Mantovani, Alberto; Biswas, Subhra K; Galdiero, Maria Rosaria; Sica, Antonio; Locati, Massimo

    2013-01-01

    Mononuclear phagocyte plasticity includes the expression of functions related to the resolution of inflammation, tissue repair and remodelling, particularly when these cells are set in an M2 or an M2-like activation mode. Macrophages are credited with an essential role in remodelling during ontogenesis. In extraembryonic life, under homeostatic conditions, the macrophage trophic and remodelling functions are recapitulated in tissues such as bone, mammary gland, decidua and placenta. In pathology, macrophages are key components of tissue repair and remodelling that occur during wound healing, allergy, parasite infection and cancer. Interaction with cells bearing stem or progenitor cell properties is likely an important component of the role of macrophages in repair and remodelling. These properties of cells of the monocyte-macrophage lineage may represent a tool and a target for therapeutic exploitation. PMID:23096265

  3. Expression and activation of TGF‐β isoforms in acute allergen‐induced remodelling in asthma

    PubMed Central

    Torrego, Alfons; Hew, Mark; Oates, Tim; Sukkar, Maria; Chung, Kian Fan

    2007-01-01

    Background Airway wall remodelling and inflammation are features of chronic asthma. Transforming growth factor β (TGF‐β) has been implicated in these processes. Aim To determine the effect of allergen challenge on airway inflammation and remodelling and whether TGF‐β isoforms and the Smad signalling pathways are involved. Methods Thirteen patients with atopic asthma underwent inhalational challenge with 0.9% saline, followed by allergen 3–4 weeks later. After both challenges, fibreoptic bronchoscopy was undertaken to obtain bronchial biopsies and tissue samples were processed for immunohistochemistry and examined by microscopy. Results Forced expiratory volume in 1 s (FEV1) fell after allergen challenge (mean (SE) −28.1 (0.9)% at 30 min with a late response at 7 hours (−23.0 (1.2)%). Allergen challenge caused an increase in neutrophils and eosinophils in the bronchial mucosa compared with saline. Sub‐basement membrane (SBM) thickness did not change after allergen, but tenascin deposition in SBM was increased. Intranuclear (activated) Smad 2/3 and Smad 4 detected by immunohistochemistry were increased after allergen challenge in epithelial and subepithelial cells of bronchial biopsies. No inhibitory Smad (Smad 7) protein was detected. TGF‐β isoforms 1, 2 and 3 were expressed predominantly in bronchial epithelium after saline and allergen challenges, but only TGF‐β2 expression was increased after allergen. Double immunostaining showed an increase in TGF‐β2 positive eosinophils and neutrophils but not in TGF‐β1 positive eosinophils and neutrophils after allergen challenge. Conclusions TGF‐β2 may contribute to the remodelling changes in allergic asthma following single allergen exposure. PMID:17251317

  4. Implant of polymer containing pentacyclic triterpenes from Eugenia punicifolia inhibits inflammation and activates skeletal muscle remodeling.

    PubMed

    Leite, Paulo Emílio C; Lima-Araújo, Katia G; França, Guilherme R; Lagrota-Candido, Jussara; Santos, Wilson C; Quirico-Santos, Thereza

    2014-12-01

    Sustained chronic inflammation induces activation of genes involved in cellular proliferation and apoptosis, thereby causing skeletal muscle degeneration. To investigate in vitro effects of isolated pentacyclic triterpenes from Eugenia punicifolia (Ep-CM) upon signaling pathways involved in the regulation of skeletal muscle cell line proliferation, and in vivo muscular tissue remodeling. C2C12 cells were seeded on eight-well plates and [(3)H]-thymidine incorporation, TUNEL assays, mitochondria viability, zymography for matrix metalloproteases (MMPs), Western blot analysis for MAPKinase signaling pathway, NFκB activation and HMGB1 production subsequently determined under basal conditions and after Ep-CM treatment. A polymer containing Ep-CM was implanted on the volar surface of gastrocnemius muscles subjected to acute injury induced by bupivacaine for local slow and gradual release of bioactive compounds, and mice killed 4 days after surgery. Ep-CM inhibited proliferation of C2C12 myoblast cell line in a dose-dependent manner, confirmed by reduction of [(3)H]-thymidine uptake without affecting cell viability or inducing apoptosis. The cytostatic effect of Ep-CM occurred mainly via inhibition of phosphorylated extracellular signal-regulated kinase (pERK) activation and DNA synthesis, possibly inhibiting the G1 phase of the cell cycle, since Ep-CM increased pAkt and p27(kip1) but reduced Cyclin D1. Ep-CM in vitro treatment increased MMP-9 and MMP-2 activities of C2C12 myoblast cells, but reduced in vivo MMP-9 activity and acute muscular inflammation. Besides cytostatic and anti-inflammatory effects, Ep-CM pentacyclic triterpenes also contributed to degradation of basement membrane components by activating mechanisms of skeletal muscle remodeling in response to local injury. PMID:24830560

  5. Role of Osteocyte-derived Insulin-Like Growth Factor I in Developmental Growth, Modeling, Remodeling, and Regeneration of the Bone

    PubMed Central

    Sheng, Matilda H. C.; Lau, K. H. William

    2014-01-01

    The osteocyte has long been considered to be the primary mechanosensory cell in the bone. Recent evidence has emerged that the osteocyte is also a key regulator of various bone and mineral metabolism and that its regulatory effects are in part mediated through locally produced osteocyte-derived factors, such as sclerostin, receptor activator of nuclear factor-kappa B ligand (RANKL), and fibroblast growth factor (FGF)-23. Osteocytes secrete large amounts of insulin-like growth factor (IGF)-I in bone. Although IGF-I produced locally by other bone cells, such as osteoblasts and chondrocytes, has been shown to play important regulatory roles in bone turnover and developmental bone growth, the functional role of osteocyte-derived IGF-I in the bone and mineral metabolism has not been investigated and remains unclear. However, results of recent studies in osteocyte Igf1 conditional knockout transgenic mice have suggested potential regulatory roles of osteocyte-derived IGF-I in various aspects of bone and mineral metabolism. In this review, evidence supporting a regulatory role for osteocyte-derived IGF-I in the osteogenic response to mechanical loading, the developmental bone growth, the bone response to dietary calcium depletion and repletion, and in fracture repair is discussed. A potential coordinated regulatory relationship between the effect of osteocyte-derived IGF-I on bone size and the internal organ size is also proposed. PMID:24707466

  6. AMP-activated protein kinase (AMPK) activation regulates in vitro bone formation and bone mass.

    PubMed

    Shah, M; Kola, B; Bataveljic, A; Arnett, T R; Viollet, B; Saxon, L; Korbonits, M; Chenu, C

    2010-08-01

    Adenosine 5'-monophosphate-activated protein kinase (AMPK), a regulator of energy homeostasis, has a central role in mediating the appetite-modulating and metabolic effects of many hormones and antidiabetic drugs metformin and glitazones. The objective of this study was to determine if AMPK can be activated in osteoblasts by known AMPK modulators and if AMPK activity is involved in osteoblast function in vitro and regulation of bone mass in vivo. ROS 17/2.8 rat osteoblast-like cells were cultured in the presence of AMPK activators (AICAR and metformin), AMPK inhibitor (compound C), the gastric peptide hormone ghrelin and the beta-adrenergic blocker propranolol. AMPK activity was measured in cell lysates by a functional kinase assay and AMPK protein phosphorylation was studied by Western Blotting using an antibody recognizing AMPK Thr-172 residue. We demonstrated that treatment of ROS 17/2.8 cells with AICAR and metformin stimulates Thr-172 phosphorylation of AMPK and dose-dependently increases its activity. In contrast, treatment of ROS 17/2.8 cells with compound C inhibited AMPK phosphorylation. Ghrelin and propranolol dose-dependently increased AMPK phosphorylation and activity. Cell proliferation and alkaline phosphatase activity were not affected by metformin treatment while AICAR significantly inhibited ROS 17/2.8 cell proliferation and alkaline phosphatase activity at high concentrations. To study the effect of AMPK activation on bone formation in vitro, primary osteoblasts obtained from rat calvaria were cultured for 14-17days in the presence of AICAR, metformin and compound C. Formation of 'trabecular-shaped' bone nodules was evaluated following alizarin red staining. We demonstrated that both AICAR and metformin dose-dependently increase trabecular bone nodule formation, while compound C inhibits bone formation. When primary osteoblasts were co-treated with AICAR and compound C, compound C suppressed the stimulatory effect of AICAR on bone nodule formation

  7. cBid, Bax and Bcl-xL exhibit opposite membrane remodeling activities

    PubMed Central

    Bleicken, S; Hofhaus, G; Ugarte-Uribe, B; Schröder, R; García-Sáez, A J

    2016-01-01

    The proteins of the Bcl-2 family have a crucial role in mitochondrial outer membrane permeabilization during apoptosis and in the regulation of mitochondrial dynamics. Current models consider that Bax forms toroidal pores at mitochondria that are responsible for the release of cytochrome c, whereas Bcl-xL inhibits pore formation. However, how Bcl-2 proteins regulate mitochondrial fission and fusion remains poorly understood. By using a systematic analysis at the single vesicle level, we found that cBid, Bax and Bcl-xL are able to remodel membranes in different ways. cBid and Bax induced a reduction in vesicle size likely related to membrane tethering, budding and fission, besides membrane permeabilization. Moreover, they are preferentially located at highly curved membranes. In contrast, Bcl-xL not only counterbalanced pore formation but also membrane budding and fission. Our findings support a mechanism of action by which cBid and Bax induce or stabilize highly curved membranes including non-lamellar structures. This molecular activity reduces the energy for membrane remodeling, which is a necessary step in toroidal pore formation, as well as membrane fission and fusion, and provides a common mechanism that links the two main functions of Bcl-2 proteins. PMID:26913610

  8. cBid, Bax and Bcl-xL exhibit opposite membrane remodeling activities.

    PubMed

    Bleicken, S; Hofhaus, G; Ugarte-Uribe, B; Schröder, R; García-Sáez, A J

    2016-01-01

    The proteins of the Bcl-2 family have a crucial role in mitochondrial outer membrane permeabilization during apoptosis and in the regulation of mitochondrial dynamics. Current models consider that Bax forms toroidal pores at mitochondria that are responsible for the release of cytochrome c, whereas Bcl-xL inhibits pore formation. However, how Bcl-2 proteins regulate mitochondrial fission and fusion remains poorly understood. By using a systematic analysis at the single vesicle level, we found that cBid, Bax and Bcl-xL are able to remodel membranes in different ways. cBid and Bax induced a reduction in vesicle size likely related to membrane tethering, budding and fission, besides membrane permeabilization. Moreover, they are preferentially located at highly curved membranes. In contrast, Bcl-xL not only counterbalanced pore formation but also membrane budding and fission. Our findings support a mechanism of action by which cBid and Bax induce or stabilize highly curved membranes including non-lamellar structures. This molecular activity reduces the energy for membrane remodeling, which is a necessary step in toroidal pore formation, as well as membrane fission and fusion, and provides a common mechanism that links the two main functions of Bcl-2 proteins. PMID:26913610

  9. PPAR-pan activation induces hepatic oxidative stress and lipidomic remodelling.

    PubMed

    Ament, Zsuzsanna; West, James A; Stanley, Elizabeth; Ashmore, Tom; Roberts, Lee D; Wright, Jayne; Nicholls, Andrew W; Griffin, Julian L

    2016-06-01

    The peroxisome proliferator-activated receptors (PPARs) are ligand activated nuclear receptors that regulate cellular homoeostasis and metabolism. PPARs control the expression of genes involved in fatty-acid and lipid metabolism. Despite evidence showing beneficial effects of their activation in the treatment of metabolic diseases, particularly dyslipidaemias and type 2 diabetes, PPAR agonists have also been associated with a variety of side effects and adverse pathological changes. Agonists have been developed that simultaneously activate the three PPAR receptors (PPARα, γ and δ) in the hope that the beneficial effects can be harnessed while avoiding some of the negative side effects. In this study, the hepatic effects of a discontinued PPAR-pan agonist (a triple agonist of PPAR-α, -γ, and -δ), was investigated after dietary treatment of male Sprague-Dawley (SD) rats. The agonist induced liver enlargement in conjunction with metabolomic and lipidomic remodelling. Increased concentrations of several metabolites related to processes of oxidation, such as oxo-methionine, methyl-cytosine and adenosyl-methionine indicated increased stress and immune status. These changes are reflected in lipidomic changes, and increased energy demands as determined by free fatty acid (decreased 18:3 n-3, 20:5 n-3 and increased ratios of n-6/n-3 fatty acids) triacylglycerol, phospholipid (decreased and increased bulk changes respectively) and eicosanoid content (increases in PGB2 and 15-deoxy PGJ2). We conclude that the investigated PPAR agonist, GW625019, induces liver enlargement, accompanied by lipidomic remodelling, oxidative stress and increases in several pro-inflammatory eicosanoids. This suggests that such pathways should be monitored in the drug development process and also outline how PPAR agonists induce liver proliferation. PMID:26654758

  10. Assessing bone banking activities at University of Malaya medical centre.

    PubMed

    Mohd, Suhaili; Samsuddin, Sharifah Mazni; Ramalingam, Saravana; Min, Ng Wuey; Yusof, Norimah; Zaman, T Kamarul; Mansor, Azura

    2015-12-01

    The main advantage of establishing in-house bone banks is its ability to readily provide allograft bones for local surgeries. Bone procurement activities of our university bone bank during the 10 years of operation were reviewed. Socio-demographic data of donors, types of bone procured, cases of rejected bones and types of allograft bones transplanted are presented. From 179 potential donors, 73 % were accepted with 213 procured bones. Femoral head was the common bone transplanted (45 %), as it was also the most common procured (82 %). Bones were rejected mainly due to non-technical reasons (83 %) rather than positive results of microbiological (13 %) and serological (4 %) tests. Comprehensive data could not be obtained for further analysis due to difficulties in retrieving information. Therefore, quality assurance system was improved to establish more systematic documentations, as the basis of good banking practice with process control hence allowing traceability. PMID:25656787

  11. Halofuginone attenuates osteoarthritis by inhibition of TGF-β activity and H-type vessel formation in subchondral bone

    PubMed Central

    Cui, Zhuang; Crane, Janet; Xie, Hui; Jin, Xin; Zhen, Gehua; Li, Changjun; Xie, Liang; Wang, Long; Bian, Qin; Qiu, Tao; Wan, Mei; Xie, Min; Ding, Sheng; Yu, Bin; Cao, Xu

    2016-01-01

    Objectives Examine whether osteoarthritis (OA) progression can be delayed by halofuginone in anterior cruciate ligament transection (ACLT) rodent models. Methods 3-month-old male C57BL/6J (wild type; WT) mice and Lewis rats were randomised to sham-operated, ACLT-operated, treated with vehicle, or ACLT-operated, treated with halofuginone. Articular cartilage degeneration was graded using the Osteoarthritis Research Society International (OARSI)-modified Mankin criteria. Immunostaining, flow cytometry, RT-PCR and western blot analyses were conducted to detect relative protein and RNA expression. Bone micro CT (μCT) and CT-based microangiography were quantitated to detect alterations of microarchitecture and vasculature in tibial subchondral bone. Results Halofuginone attenuated articular cartilage degeneration and subchondral bone deterioration, resulting in substantially lower OARSI scores. Specifically, we found that proteoglycan loss and calcification of articular cartilage were significantly decreased in halofuginone-treated ACLT rodents compared with vehicle-treated ACLT controls. Halofuginone reduced collagen X (Col X), matrix metalloproteinase-13 and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS 5) and increased lubricin, collagen II and aggrecan. In parallel, halofuginone-attenuated uncoupled subchondral bone remodelling as defined by reduced subchondral bone tissue volume, lower trabecular pattern factor (Tb.pf) and increased thickness of subchondral bone plate compared with vehicle-treated ACLT controls. We found that halofuginone exerted protective effects in part by suppressing Th17-induced osteoclastic bone resorption, inhibiting Smad2/3-dependent TGF-β signalling to restore coupled bone remodelling and attenuating excessive angiogenesis in subchondral bone. Conclusions Halofuginone attenuates OA progression by inhibition of subchondral bone TGF-β activity and aberrant angiogenesis as a potential preventive therapy for OA

  12. [Bone Conduction and Active Middle Ear Implants].

    PubMed

    Volkenstein, S; Thomas, J P; Dazert, S

    2016-05-01

    The majority of patients with moderate to severe hearing loss can be supplied with conventional hearing aids depending on severity and cause for hearing loss in a satisfying way. However, some patients either do not benefit enough from conventional hearing aids or cannot wear them due to inflammatory reactions and chronic infections of the external auditory canal or due to anatomical reasons. For these patients there are fully- and semi-implantable middle ear and bone conduction implants available. These devices either directly stimulate the skull (bone conduction devices), middle ear structures (active middle ear implants) or the cochlea itself (direct acoustic stimulation). Patients who failed surgical hearing rehabilitation or do not benefit from conventional hearing aids may achieve a significant better speech understanding and tremendous improvement in quality of life by implantable hearing devices with careful attention to the audiological and anatomical indication criteria. PMID:27135430

  13. Changes of blood parameters associated with bone remodeling following experimentally induced fatty liver disorder in laying hens.

    PubMed

    Jiang, S; Cheng, H W; Cui, L Y; Zhou, Z L; Hou, J F

    2013-06-01

    Studies have demonstrated that obesity and osteoporosis are linked disorders in humans. This study examined the hypothesis that excessive lipid consumption affects bone metabolism in laying hens. A total of one hundred 63-wk-old laying hens were randomly divided into 2 treatments and fed either a regular layer diet (control) or a high energy and low protein diet (HE-LP; experimental treatment) for 80 d. Egg production, feed intake, and BW were recorded at various days during the treatment. At d 80, ten randomly chosen birds per treatment group were killed. Abdominal fat weight, liver weight, and liver fat content were determined. Serum levels of total calcium, inorganic phosphate, and alkaline phosphatase were measured using a biochemical analyzer. Serum concentrations of osteocalcin, leptin-like protein, and estrogen were measured by enzyme-linked immunosorbent assay. Tibia length and width were measured using a vernier caliper; density of the right tibias was determined using an x-ray scanner; and mechanical properties of the left tibias were analyzed using a material testing machine. The expression of osteocalcin and osteoprotegerin mRNA in the keel bone was analyzed by real-time PCR. The concentration of osteocalcin protein in the keels was measured using western blot. Compared with control hens, hens fed the HE-LP diet had lower egg production, lower feed intake, greater liver fat content, and greater abdominal fat pad mass (P < 0.05). Feeding the HE-LP diet increased serum alkaline phosphatase activity, osteocalcin, leptin-like protein, and estrogen concentrations (P < 0.05), and decreased the keel osteocalcin concentrations (P < 0.05). There were significant positive correlations between the serum concentrations of leptin-like protein, estrogen, and osteocalcin regardless of treatment (P < 0.05). The results indicated that HE-LP diet induced a fatty liver disorder in laying hens with an upregulation in bone turnover and exacerbated skeletal damage. The data

  14. Stromal miR-200s contribute to breast cancer cell invasion through CAF activation and ECM remodeling.

    PubMed

    Tang, X; Hou, Y; Yang, G; Wang, X; Tang, S; Du, Y-E; Yang, L; Yu, T; Zhang, H; Zhou, M; Wen, S; Xu, L; Liu, M

    2016-01-01

    The activation of cancer-associated fibroblasts (CAFs) is a key event in tumor progression, and alternative extracellular matrix (ECM) proteins derived from CAFs induce ECM remodeling and cancer cell invasion. Here we found that miR-200 s, which are generally downregulated in activated CAFs in breast cancer tissues and in normal fibroblasts (NFs) activated by breast cancer cells, are direct mediators of NF reprogramming into CAFs and of ECM remodeling. NFs with downregulated miR-200 s displayed the traits of activated CAFs, including accelerated migration and invasion. Ectopic expression of miR-200 s in CAFs at least partially restored the phenotypes of NFs. CAF activation may be governed by the targets of miR-200 s, Fli-1 and TCF12, which are responsible for cell development and differentiation; Fli-1 and TCF12 were obviously elevated in CAFs. Furthermore, miR-200 s and their targets influenced collagen contraction by CAFs. The upregulation of fibronectin and lysyl oxidase directly by miR-200 or indirectly through Fli-1 or TCF12 contributed to ECM remodeling, triggering the invasion and metastasis of breast cancer cells both in vitro and vivo. Thus, these data provide important and novel insights into breast CAF activation and ECM remodeling, which trigger tumor cell invasion. PMID:26068592

  15. Stromal miR-200s contribute to breast cancer cell invasion through CAF activation and ECM remodeling

    PubMed Central

    Tang, X; Hou, Y; Yang, G; Wang, X; Tang, S; Du, Y-E; Yang, L; Yu, T; Zhang, H; Zhou, M; Wen, S; Xu, L; Liu, M

    2016-01-01

    The activation of cancer-associated fibroblasts (CAFs) is a key event in tumor progression, and alternative extracellular matrix (ECM) proteins derived from CAFs induce ECM remodeling and cancer cell invasion. Here we found that miR-200 s, which are generally downregulated in activated CAFs in breast cancer tissues and in normal fibroblasts (NFs) activated by breast cancer cells, are direct mediators of NF reprogramming into CAFs and of ECM remodeling. NFs with downregulated miR-200 s displayed the traits of activated CAFs, including accelerated migration and invasion. Ectopic expression of miR-200 s in CAFs at least partially restored the phenotypes of NFs. CAF activation may be governed by the targets of miR-200 s, Fli-1 and TCF12, which are responsible for cell development and differentiation; Fli-1 and TCF12 were obviously elevated in CAFs. Furthermore, miR-200 s and their targets influenced collagen contraction by CAFs. The upregulation of fibronectin and lysyl oxidase directly by miR-200 or indirectly through Fli-1 or TCF12 contributed to ECM remodeling, triggering the invasion and metastasis of breast cancer cells both in vitro and vivo. Thus, these data provide important and novel insights into breast CAF activation and ECM remodeling, which trigger tumor cell invasion. PMID:26068592

  16. Bisphosphonates and bone quality

    PubMed Central

    Pazianas, Michael; van der Geest, Stefan; Miller, Paul

    2014-01-01

    Bisphosphonates (BPs) are bone-avid compounds used as first-line medications for the prevention and treatment of osteoporosis. They are also used in other skeletal pathologies such as Paget's and metastatic bone disease. They effectively reduce osteoclast viability and also activity in the resorptive phase of bone remodelling and help preserve bone micro-architecture, both major determinants of bone strength and ultimately of the susceptibility to fractures. The chemically distinctive structure of each BP used in the clinic determines their unique affinity, distribution/penetration throughout the bone and their individual effects on bone geometry, micro-architecture and composition or what we call ‘bone quality'. BPs have no clinically significant anabolic effects. This review will touch upon some of the components of bone quality that could be affected by the administration of BPs. PMID:24876930

  17. [Bone histomorphometry;A role of evaluation for bone quality and mechanical strength].

    PubMed

    Yamamoto, Noriaki; Takahashi, Hideaki; Shimakura, Taketoshi

    2016-01-01

    Bone histomorphometry is defined as a quantitative evaluation of bone remodeling and bone turnover. Bone remodeling is the important mechanism for calcium metabolism and mechanical usage. The changes of bone remodeling in special condition with metabolic bone disease or osteoporosis agents have the effectiveness on bone mechanical strength. PMID:26728526

  18. Cabozantinib inhibits growth of androgen-sensitive and castration-resistant prostate cancer and affects bone remodeling.

    PubMed

    Nguyen, Holly M; Ruppender, Nazanin; Zhang, Xiaotun; Brown, Lisha G; Gross, Ted S; Morrissey, Colm; Gulati, Roman; Vessella, Robert L; Schimmoller, Frauke; Aftab, Dana T; Corey, Eva

    2013-01-01

    Cabozantinib is an inhibitor of multiple receptor tyrosine kinases, including MET and VEGFR2. In a phase II clinical trial in advanced prostate cancer (PCa), cabozantinib treatment improved bone scans in 68% of evaluable patients. Our studies aimed to determine the expression of cabozantinib targets during PCa progression and to evaluate its efficacy in hormone-sensitive and castration-resistant PCa in preclinical models while delineating its effects on tumor and bone. Using immunohistochemistry and tissue microarrays containing normal prostate, primary PCa, and soft tissue and bone metastases, our data show that levels of MET, P-MET, and VEGFR2 are increasing during PCa progression. Our data also show that the expression of cabozantinib targets are particularly pronounced in bone metastases. To evaluate cabozantinib efficacy on PCa growth in the bone environment and in soft tissues we used androgen-sensitive LuCaP 23.1 and castration-resistant C4-2B PCa tumors. In vivo, cabozantinib inhibited the growth of PCa in bone as well as growth of subcutaneous tumors. Furthermore, cabozantinib treatment attenuated the bone response to the tumor and resulted in increased normal bone volume. In summary, the expression pattern of cabozantinib targets in primary and castration-resistant metastatic PCa, and its efficacy in two different models of PCa suggest that this agent has a strong potential for the effective treatment of PCa at different stages of the disease. PMID:24205338

  19. Role of Plasminogen Activator in Spinal Cord Remodeling after Spinal Cord Injury

    PubMed Central

    Seeds, Nicholas W.; Akison, Lisa; Minor, Kenneth

    2009-01-01

    Plasminogen activators play an active role in synaptic plasticity associated with the crossed phrenic phenomenon (CPP) and recovery of respiratory function following spinal cord injury. A genetic approach has been used to identify molecular mechanisms underlying this synaptic plasticity. Knockout mice lacking different genes in the plasminogen activator/plasmin system demonstrate that expression of urokinase plasminogen activator (uPA) is required during the critical 1-2h delay period following C2-hemisection for acquisition of a good CPP response. uPA knockout mice fail to show the structural remodeling of phrenic motor neuron synapses that underlie the CPP response. Potential mechanisms by which uPA may promote phrenic motor neuron synaptic plasticity have been explored. Expression of uPA receptors, uPAR and LRP-1, are both up-regulated in the ipsilateral phrenic motor nucleus (PMN) following C2-hemisection. A comparison of microarray data and real-time PCR analysis of mRNAs induced in the PMN after hemisection indicate potential cell signaling pathways downstream of uPA’s interaction with these cell surface receptors in the PMN. Knowledge of these uPA-mediated signaling pathways may identify potential means for pharmacological activation of the synaptic plasticity required for recovery of phrenic motor neuron activity. PMID:19651246

  20. Role of plasminogen activator in spinal cord remodeling after spinal cord injury.

    PubMed

    Seeds, Nicholas W; Akison, Lisa; Minor, Kenneth

    2009-11-30

    Plasminogen activators play an active role in synaptic plasticity associated with the crossed phrenic phenomenon (CPP) and recovery of respiratory function following spinal cord injury. A genetic approach has been used to identify molecular mechanisms underlying this synaptic plasticity. Knockout mice lacking different genes in the plasminogen activator/plasmin system demonstrate that expression of urokinase plasminogen activator (uPA) is required during the critical 1-2h delay period following C2-hemisection for the acquisition of a good CPP response. uPA knockout mice fail to show the structural remodeling of phrenic motorneuron synapses that underlie the CPP response. Potential mechanisms by which uPA may promote phrenic motorneuron synaptic plasticity have been explored. Expression of uPA receptors, uPAR and LRP-1, are both up-regulated in the ipsilateral phrenic motor nucleus (PMN) following C2-hemisection. A comparison of microarray data and real-time PCR analysis of mRNAs induced in the PMN after hemisection indicate potential cell signaling pathways downstream of uPA's interaction with these cell surface receptors in the PMN. Knowledge of these uPA-mediated signaling pathways may identify potential means for the pharmacological activation of the synaptic plasticity required for recovery of phrenic motorneuron activity. PMID:19651246

  1. GPER activation ameliorates aortic remodeling induced by salt-sensitive hypertension.

    PubMed

    Liu, Liu; Kashyap, Shreya; Murphy, Brennah; Hutson, Dillion D; Budish, Rebecca A; Trimmer, Emma H; Zimmerman, Margaret A; Trask, Aaron J; Miller, Kristin S; Chappell, Mark C; Lindsey, Sarah H

    2016-04-15

    The mRen2 female rat is an estrogen- and salt-sensitive model of hypertension that reflects the higher pressure and salt sensitivity associated with menopause. We previously showed that the G protein-coupled estrogen receptor (GPER) mediates estrogenic effects in this model. The current study hypothesized that GPER protects against vascular injury during salt loading. Intact mRen2 female rats were fed a normal (NS; 0.5% Na(+)) or high-salt diet (HS; 4% Na(+)) for 10 wk, which significantly increased systolic blood pressure (149 ± 5 vs. 224 ± 8 mmHg;P< 0.001). Treatment with the selective GPER agonist G-1 for 2 wk did not alter salt-sensitive hypertension (216 ± 4 mmHg;P> 0.05) or ex vivo vascular responses to angiotensin II or phenylephrine (P> 0.05). However, G-1 significantly attenuated salt-induced aortic remodeling assessed by media-to-lumen ratio (NS: 0.43; HS+veh: 0.89; HS+G-1: 0.61;P< 0.05). Aortic thickening was not accompanied by changes in collagen, elastin, or medial proliferation. However, HS induced increases in medial layer glycosaminoglycans (0.07 vs. 0.42 mm(2);P< 0.001) and lipid peroxidation (0.11 vs. 0.51 mm(2);P< 0.01), both of which were reduced by G-1 (0.20 mm(2)and 0.23 mm(2); both P< 0.05). We conclude that GPER's beneficial actions in the aorta of salt-loaded mRen2 females occur independently of changes in blood pressure and vasoreactivity. GPER-induced attenuation of aortic remodeling was associated with a reduction in oxidative stress and decreased accumulation of glycosaminoglycans. Endogenous activation of GPER may protect females from salt- and pressure-induced vascular damage. PMID:26873963

  2. Cardiac Tissue Injury and Remodeling Is Dependent Upon MR Regulation of Activation Pathways in Cardiac Tissue Macrophages.

    PubMed

    Shen, Jimmy Z; Morgan, James; Tesch, Greg H; Rickard, Amanda J; Chrissobolis, Sophocles; Drummond, Grant R; Fuller, Peter J; Young, Morag J

    2016-08-01

    Macrophage mineralocorticoid receptor (MR) signaling is an important mediator of cardiac tissue inflammation and fibrosis. The goal of the present study was to determine the cellular mechanisms of MR signaling in macrophages that promote cardiac tissue injury and remodeling. We sought to identify specific markers of MR signaling in isolated tissue macrophages (cardiac, aortic) vs splenic mononuclear cells from wild-type and myeloid MR-null mice given vehicle/salt or deoxycorticosterone (DOC)/salt for 8 weeks. Cardiac tissue fibrosis in response to 8 weeks of DOC/salt treatment was found in the hearts from wild-type but not myeloid MR-null mice. This was associated with an increased expression of the profibrotic markers TGF-β1 and matrix metalloproteinase-12 and type 1 inflammatory markers TNFα and chemokine (C-X-C motif) ligand-9 in cardiac macrophages. Differential expression of immunomodulatory M2-like markers (eg, arginase-1, macrophage scavenger receptor 1) was dependent on the tissue location of wild-type and MR-null macrophages. Finally, intact MR signaling is required for the phosphorylation of c-Jun NH2-terminal kinase in response to a proinflammatory stimulus in bone marrow monocytes/macrophages in culture. These data suggest that the activation of the c-Jun NH2-terminal kinase pathway in macrophages after a tissue injury and inflammatory stimuli in the DOC/salt model is MR dependent and regulates the transcription of downstream profibrotic factors, which may represent potential therapeutic targets in heart failure patients. PMID:27253999

  3. Similar healthy osteoclast and osteoblast activity on nanocrystalline hydroxyapatite and nanoparticles of tri-calcium phosphate compared to natural bone

    PubMed Central

    MacMillan, Adam K; Lamberti, Francis V; Moulton, Julia N; Geilich, Benjamin M; Webster, Thomas J

    2014-01-01

    While there have been numerous studies to determine osteoblast (bone forming cell) functions on nanocrystalline compared to micron crystalline ceramics, there have been few studies which have examined osteoclast activity (including tartrate-resistant acid phosphatase, formation of resorption pits, size of resorption pits, and receptor activator of nuclear factor κB [RANK]). This is despite the fact that osteoclasts are an important part of maintaining healthy bone since they resorb bone during the bone remodeling process. Moreover, while it is now well documented that bone formation is enhanced on nanoceramics compared to micron ceramics, some have pondered whether osteoblast functions (such as osteoprotegerin and RANK ligand [RANKL]) are normal (ie, non-diseased) on such materials compared to natural bone. For these reasons, the objective of the present in vitro study was to determine various functions of osteoclasts and osteoblasts on nanocrystalline and micron crystalline hydroxyapatite as well as tri-calcium phosphate materials and compare such results to cortical and cancellous bone. Results showed for the first time similar osteoclast activity (including tartrate-resistant acid phosphatase, formation of resorption pits, size of resorption pits, and RANK) and osteoblast activity (osteoprotegerin and RANKL) on nanocrystalline hydroxyapatite compared to natural bone, whereas osteoclast and osteoblast functions on micron crystalline versions of these ceramics were much different than natural bone. In this manner, this study provides additional evidence that nanocrystalline calcium phosphates can serve as suitable synthetic analogs to natural bone to improve numerous orthopedic applications. It also provides the first data of healthy osteoclast and osteoblast functions on nanocrystalline calcium phosphates compared to natural bone. PMID:25506216

  4. Transcriptional activation by the thyroid hormone receptor through ligand-dependent receptor recruitment and chromatin remodelling.

    PubMed

    Grøntved, Lars; Waterfall, Joshua J; Kim, Dong Wook; Baek, Songjoon; Sung, Myong-Hee; Zhao, Li; Park, Jeong Won; Nielsen, Ronni; Walker, Robert L; Zhu, Yuelin J; Meltzer, Paul S; Hager, Gordon L; Cheng, Sheue-yann

    2015-01-01

    A bimodal switch model is widely used to describe transcriptional regulation by the thyroid hormone receptor (TR). In this model, the unliganded TR forms stable, chromatin-bound complexes with transcriptional co-repressors to repress transcription. Binding of hormone dissociates co-repressors and facilitates recruitment of co-activators to activate transcription. Here we show that in addition to hormone-independent TR occupancy, ChIP-seq against endogenous TR in mouse liver tissue demonstrates considerable hormone-induced TR recruitment to chromatin associated with chromatin remodelling and activated gene transcription. Genome-wide footprinting analysis using DNase-seq provides little evidence for TR footprints both in the absence and presence of hormone, suggesting that unliganded TR engagement with repressive complexes on chromatin is, similar to activating receptor complexes, a highly dynamic process. This dynamic and ligand-dependent interaction with chromatin is likely shared by all steroid hormone receptors regardless of their capacity to repress transcription in the absence of ligand. PMID:25916672

  5. Bone Markers

    MedlinePlus

    ... Alkaline Phosphatase; Osteocalcin; P1NP; Procollagen Type 1 N-Terminal Propeptide Formal name: Biochemical Markers of Bone Remodeling ... tests for evaluating bone turnover: C-telopeptide (C-terminal telopeptide of type 1 collagen (CTx)) – a marker ...

  6. Moderate Physical Activity in Healthy Adults Is Associated With Cardiac Remodeling

    PubMed Central

    Dawes, Timothy J.W.; Corden, Ben; Cotter, Sorcha; de Marvao, Antonio; Walsh, Roddy; Ware, James S.; Cook, Stuart A.

    2016-01-01

    Background— Cardiac mass and volumes are often elevated in athletes, but it is not known whether moderate physical activity is also associated with cardiac dilatation and hypertrophy in a healthy adult population. Methods and Results— In total, 1096 adults (54% female, median age 39 years) without cardiovascular disease or cardiomyopathy-associated genetic variants underwent cardiac magnetic resonance imaging to determine biventricular volumes and function. Physical activity was assessed using a validated activity questionnaire. The relationship between cardiac parameters and activity was assessed using multiple linear regression adjusting for age, sex, race, and systolic blood pressure. Logistic regression was performed to determine the effect of activity on the likelihood of subjects having cardiac dilatation or hypertrophy according to standard cardiac magnetic resonance normal ranges. Increasing physical activity was associated with greater left ventricular (LV) mass (β=0.23; P<0.0001) and elevated LV and right ventricular volumes (LV: β=0.26, P<0.0001; right ventricular: β=0.26, P<0.0001). Physical activity had a larger effect on cardiac parameters than systolic blood pressure (0.06≤β≤0.21) and a similar effect to age (−0.20≤β≤−0.31). Increasing physical activity was a risk factor for meeting imaging criteria for LV hypertrophy (adjusted odds ratio 2.1; P<0.0001), LV dilatation (adjusted odds ratio 2.2; P<0.0001), and right ventricular dilatation (adjusted odds ratio 2.2; P<0.0001). Conclusions— Exercise-related cardiac remodeling is not confined to athletes, and there is a risk of overdiagnosing cardiac dilatation or hypertrophy in a proportion of active, healthy adults. PMID:27502059

  7. Mechanisms and Management of Stress Fractures in Physically Active Persons

    PubMed Central

    Romani, William A.; Gieck, Joe H.; Perrin, David H.; Saliba, Ethan N.; Kahler, David M.

    2002-01-01

    Objective: To describe the anatomy of bone and the physiology of bone remodeling as a basis for the proper management of stress fractures in physically active people. Data Sources: We searched PubMed for the years 1965 through 2000 using the key words stress fracture, bone remodeling, epidemiology, and rehabilitation. Data Synthesis: Bone undergoes a normal remodeling process in physically active persons. Increased stress leads to an acceleration of this remodeling process, a subsequent weakening of bone, and a higher susceptibility to stress fracture. When a stress fracture is suspected, appropriate management of the injury should begin immediately. Effective management includes a cyclic process of activity and rest that is based on the remodeling process of bone. Conclusions/Recommendations: Bone continuously remodels itself to withstand the stresses involved with physical activity. Stress fractures occur as the result of increased remodeling and a subsequent weakening of the outer surface ofthe bone. Once a stress fracture is suspected, a cyclic management program that incorporates the physiology of bone remodeling should be initiated. The cyclic program should allow the physically active person to remove the source of the stress to the bone, maintain fitness, promote a safe return to activity, and permit the bone to heal properly. PMID:16558676

  8. HOS1-mediated activation of FLC via chromatin remodeling under cold stress.

    PubMed

    Jung, Jae-Hoon; Park, Chung-Mo

    2013-01-01

    The Arabidopsis E3 ubiquitin ligase HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENE 1 (HOS1) has been shown to act as a negative regulator of cold responses by degrading the INDUCER OF CBF EXPRESSION 1 (ICE1) transcription factor through the ubiquitin/proteasome pathway. Notably, loss-of-function hos1 mutants exhibit early flowering, and the transcript level of the floral repressor FLOWERING LOCUS C (FLC) is downregulated in the mutants. However, it is largely unknown how HOS1 regulates FLC transcription. We found that HOS1 activates FLC transcription by inhibiting the activity of histone deacetylase 6 (HDA6) under cold stress. Cold temperatures induce the binding of HOS1 to FLC chromatin in an FVE-dependent manner. Cold-activated HOS1 promotes the dissociation of HDA6 from FLC chromatin, and the cold effects disappear in both hos1 and fve mutants. It is therefore clear that HOS1 regulates FLC transcription via chromatin remodeling, providing new insights into the signaling crosstalks between cold response and flowering time control. PMID:24390058

  9. Bone Marrow-Derived Multipotent Stromal Cells Promote Myocardial Fibrosis and Reverse Remodeling of the Left Ventricle

    PubMed Central

    Fatkhudinov, Timur; Bolshakova, Galina; Arutyunyan, Irina; Elchaninov, Andrey; Makarov, Andrey; Kananykhina, Evgeniya; Khokhlova, Oksana; Murashev, Arkady; Glinkina, Valeria; Goldshtein, Dmitry; Sukhikh, Gennady

    2015-01-01

    Cell therapy is increasingly recognized as a beneficial practice in various cardiac conditions, but its fundamentals remain largely unclear. The fates of transplanted multipotent stromal cells in postinfarction cardiac microenvironments are particularly understudied. To address this issue, labeled multipotent stromal cells were infused into rat myocardium at day 30 after myocardial infarction, against the background of postinfarction cardiosclerosis. Therapeutic effects of the transplantation were assessed by an exercise tolerance test. Histological examination at 14 or 30 days after the transplantation was conducted by means of immunostaining and quantitative image analysis. An improvement in the functional status of the cardiovascular system was observed after both the autologous and the allogeneic transplantations. Location of the label-positive cells within the heart was restricted to the affected part of myocardium. The transplanted cells could give rise to fibroblasts or myofibroblasts but not to cardiac myocytes or blood vessel cells. Both types of transplantation positively influenced scarring processes, and no expansion of fibrosis to border myocardium was observed. Left ventricular wall thickening associated with reduced dilatation index was promoted by transplantation of the autologous cells. According to the results, multipotent stromal cell transplantation prevents adverse remodeling and stimulates left ventricular reverse remodeling. PMID:25685158

  10. An evaluation of the effect of age and the peri-parturient period on bone metabolism in dairy cows as measured by serum bone-specific alkaline phosphatase activity and urinary deoxypyridinoline concentration.

    PubMed

    Sato, Reiichiro; Onda, Ken; Kato, Hajime; Ochiai, Hideharu; Kawai, Kazuhiro; Iriki, Tsunenori; Kaneko, Kazuyuki; Yamazaki, Yukio; Wada, Yasunori

    2013-08-01

    Various biochemical markers help to evaluate the state of bone turnover in humans and could be used during the peri-parturient period in dairy cows when calcium (Ca) metabolism changes dramatically. To investigate this, the peri-partum characteristics of serum bone-specific alkaline phosphatase (BAP) and urinary deoxypyridinoline (DPD) were investigated. Both serum BAP activity and urinary DPD concentrations were increased and demonstrated wide variability in younger animals, and these findings were consistent with other bone turnover markers. Around the time of parturition, serum Ca concentration and serum BAP activity in multiparous cows were significantly lower than in primiparous cows, but urinary DPD concentration was unchanged. The use of BAP as a bone formation marker appears to be valuable for evaluating bone remodelling status in cows, but the specificity of the test needs to be confirmed. The DPD/BAP ratio around parturition demonstrated a clear difference in bone turnover status between the two parity groups with multiparous cows demonstrating increased signs of bone resorption compared with primiparous cows, corresponding to the Ca requirement for milk production. In future studies, the applicability of the ratio of bone resorption marker to bone formation marker should be evaluated for bone turnover assessment. PMID:23422881

  11. Prostaglandin E2 Prevents Bone Loss and Adds Extra Bone to Immobilized Distal Femoral Metaphysis in Female Rats

    NASA Technical Reports Server (NTRS)

    Akamine, T.; Jee, W. S. S.; Ke, H. Z.; Li, X. J.; Lin, B. Y.

    1992-01-01

    The object of this study was to determine whether prostaglandin E2 (PGE2) can prevent disuse (underloading)-induced cancellous bone loss. Thirteen-month-old retired female Sprague-Dawley breeders served as controls or were subjected to right hindlimb immobilization by bandaging and simultaneously treated subcutaneously daily with 0, 1, 3, or 6 mg PGE2/kg/d for two and six weeks. Histomorphometric analyses were performed on the cancellous bone using double-fluorescent labeled, 20 micron thick, undecalcified distal femoral metaphysis sections. We found that PGE2 administration not only prevented disuse-induced bone loss, but also added extra bone to disuse cancellous bone in a dose-response manner. PGE2 prevented the disuse-induced osteopenia by stimulating more bone formation than and shortening the period of bone remodeling. It activated woven bone formation, stimulated lamellar bone formation, and increased the eroded bone surface above that caused by disuse alone. While underloading increased the remodeling period (sigma), PGE2 treatment of underloaded bone shortened the time for osteoclastic bone resorption and bone remodeling, and thus reduced the remodeling space. The study shows that PGE2 is a powerful anabolic agent that prevents disuse-induced osteopenia and adds extra bone to these same bones.

  12. The membrane remodeling protein Pex11p activates the GTPase Dnm1p during peroxisomal fission

    PubMed Central

    Opalinski, Lukasz; Landgraf, Christiane; Costello, Joseph; Schrader, Michael; Krikken, Arjen M.; Knoops, Kèvin; Kram, Anita M.; Volkmer, Rudolf; van der Klei, Ida J.

    2015-01-01

    The initial phase of peroxisomal fission requires the peroxisomal membrane protein Peroxin 11 (Pex11p), which remodels the membrane, resulting in organelle elongation. Here, we identify an additional function for Pex11p, demonstrating that Pex11p also plays a crucial role in the final step of peroxisomal fission: dynamin-like protein (DLP)-mediated membrane scission. First, we demonstrate that yeast Pex11p is necessary for the function of the GTPase Dynamin-related 1 (Dnm1p) in vivo. In addition, our data indicate that Pex11p physically interacts with Dnm1p and that inhibiting this interaction compromises peroxisomal fission. Finally, we demonstrate that Pex11p functions as a GTPase activating protein (GAP) for Dnm1p in vitro. Similar observations were made for mammalian Pex11β and the corresponding DLP Drp1, indicating that DLP activation by Pex11p is conserved. Our work identifies a previously unknown requirement for a GAP in DLP function. PMID:25941407

  13. The Costimulatory Receptor OX40 Inhibits Interleukin-17 Expression through Activation of Repressive Chromatin Remodeling Pathways.

    PubMed

    Xiao, Xiang; Shi, Xiaomin; Fan, Yihui; Wu, Chenglin; Zhang, Xiaolong; Minze, Laurie; Liu, Wentao; Ghobrial, Rafik M; Lan, Peixiang; Li, Xian Chang

    2016-06-21

    T helper 17 (Th17) cells are prominently featured in multiple autoimmune diseases, but the regulatory mechanisms that control Th17 cell responses are poorly defined. Here we found that stimulation of OX40 triggered a robust chromatin remodeling response and produced a "closed" chromatin structure at interleukin-17 (IL-17) locus to inhibit Th17 cell function. OX40 activated the NF-κB family member RelB, and RelB recruited the histone methyltransferases G9a and SETDB1 to the Il17 locus to deposit "repressive" chromatin marks at H3K9 sites, and consequently repressing IL-17 expression. Unlike its transcriptional activities, RelB acted independently of both p52 and p50 in the suppression of IL-17. In an experimental autoimmune encephalomyelitis (EAE) disease model, we found that OX40 stimulation inhibited IL-17 and reduced EAE. Conversely, RelB-deficient CD4(+) T cells showed enhanced IL-17 induction and exacerbated the disease. Our data uncover a mechanism in the control of Th17 cells that might have important clinic implications. PMID:27317259

  14. RNA Remodeling Activity of DEAD Box Proteins Tuned by Protein Concentration, RNA Length, and ATP.

    PubMed

    Kim, Younghoon; Myong, Sua

    2016-09-01

    DEAD box RNA helicases play central roles in RNP biogenesis. We reported earlier that LAF-1, a DEAD box RNA helicase in C. elegans, dynamically interacts with RNA and that the interaction likely contributes to the fluidity of RNP droplets. Here we investigate the molecular basis of the interaction of RNA with LAF-1 and its human homolog, DDX3X. We show that both LAF-1 and DDX3X, at low concentrations, are monomers that induce tight compaction of single-stranded RNA. At high concentrations, the proteins are multimeric and dynamically interact with RNA in an RNA length-dependent manner. The dynamic LAF-1-RNA interaction stimulates RNA annealing activity. ATP adversely affects the RNA remodeling ability of LAF-1 by suppressing the affinity, dynamics, and annealing activity of LAF-1, suggesting that ATP may promote disassembly of the RNP complex. Based on our results, we postulate a plausible molecular mechanism underlying the dynamic equilibrium of the LAF-1 RNP complex. PMID:27546789

  15. Chromatin remodelling and autocrine TNFα are required for optimal interleukin-6 expression in activated human neutrophils.

    PubMed

    Zimmermann, Maili; Aguilera, Francisco Bianchetto; Castellucci, Monica; Rossato, Marzia; Costa, Sara; Lunardi, Claudio; Ostuni, Renato; Girolomoni, Giampiero; Natoli, Gioacchino; Bazzoni, Flavia; Tamassia, Nicola; Cassatella, Marco A

    2015-01-01

    Controversy currently exists about the ability of human neutrophils to produce IL-6. Here, we show that the chromatin organization of the IL-6 genomic locus in human neutrophils is constitutively kept in an inactive configuration. However, we also show that upon exposure to stimuli that trigger chromatin remodelling at the IL-6 locus, such as ligands for TLR8 or, less efficiently, TLR4, highly purified neutrophils express and secrete IL-6. In TLR8-activated neutrophils, but not monocytes, IL-6 expression is preceded by the induction of a latent enhancer located 14 kb upstream of the IL-6 transcriptional start site. In addition, IL-6 induction is potentiated by endogenous TNFα, which prolongs the synthesis of the IκBζ co-activator and sustains C/EBPβ recruitment and histone acetylation at IL-6 regulatory regions. Altogether, these data clarify controversial literature on the ability of human neutrophils to generate IL-6 and uncover chromatin-dependent layers of regulation of IL-6 in these cells. PMID:25616107

  16. Age‐related remodeling of small arteries is accompanied by increased sphingomyelinase activity and accumulation of long‐chain ceramides

    PubMed Central

    Ohanian, Jacqueline; Liao, Aiyin; Forman, Simon P.; Ohanian, Vasken

    2014-01-01

    Abstract The structure and function of large arteries alters with age leading to increased risk of cardiovascular disease. Age‐related large artery remodeling and arteriosclerosis is associated with increased collagen deposition, inflammation, and endothelial dysfunction. Bioactive sphingolipids are known to regulate these processes, and are also involved in aging and cellular senescence. However, less is known about age‐associated alterations in small artery morphology and function or whether changes in arterial sphingolipids occur in aging. We show that mesenteric small arteries from old sheep have increased lumen diameter and media thickness without a change in media to lumen ratio, indicative of outward hypertrophic remodeling. This remodeling occurred without overt changes in blood pressure or pulse pressure indicating it was a consequence of aging per se. There was no age‐associated change in mechanical properties of the arteries despite an increase in total collagen content and deposition of collagen in a thickened intima layer in arteries from old animals. Analysis of the sphingolipid profile showed an increase in long‐chain ceramide (C14–C20), but no change in the levels of sphingosine or sphingosine‐1‐phosphate in arteries from old compared to young animals. This was accompanied by a parallel increase in acid and neutral sphingomyelinase activity in old arteries compared to young. This study demonstrates remodeling of small arteries during aging that is accompanied by accumulation of long‐chain ceramides. This suggests that sphingolipids may be important mediators of vascular aging. PMID:24872355

  17. [Bone and Calcium Metabolisms Associated with Dental and Oral-Maxillofacial Diseases. Orthodontic treatment and the role of osteocytes].

    PubMed

    Kamioka, Hiroshi

    2015-10-01

    Tooth movement accompanies the active morphological changes of the alveolar bone that was applied mechanical force via teeth. Coordination of initial changes of periodontal membrane and subsequent bone remodeling produce dramatic tooth alignment. It is well known small bone cells support this dynamic change of tooth movement. Especially, osteocytes are thought to be mechanosensor cells in bone remodeling. This review focuses on the bone remodeling during tooth movement as well as molecular events of osteocytes in RANKL/RANK/OPG pathway. In addition, dynamics of DMP-1, MEPE and Sclerostin during orthodontic tooth movement are discussed with published literature. PMID:26412736

  18. Changes of blood parameters associated with bone remodeling following experimentally induced fatty liver disorder in laying hens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Studies have demonstrated that obesity and osteoporosis are two linked disorders in humans. This study examined if excessive lipid consumption affects bone metabolism in laying hens. One hundred 63-week-old laying hens were randomly divided into two treatments, i.e., fed with a regular diet (control...

  19. Active-site remodelling in the bifunctional fructose-1,6-bisphosphate aldolase/phosphatase.

    PubMed

    Du, Juan; Say, Rafael F; Lü, Wei; Fuchs, Georg; Einsle, Oliver

    2011-10-27

    Fructose-1,6-bisphosphate (FBP) aldolase/phosphatase is a bifunctional, thermostable enzyme that catalyses two subsequent steps in gluconeogenesis in most archaea and in deeply branching bacterial lineages. It mediates the aldol condensation of heat-labile dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (GAP) to FBP, as well as the subsequent, irreversible hydrolysis of the product to yield the stable fructose-6-phosphate (F6P) and inorganic phosphate; no reaction intermediates are released. Here we present a series of structural snapshots of the reaction that reveal a substantial remodelling of the active site through the movement of loop regions that create different catalytic functionalities at the same location. We have solved the three-dimensional structures of FBP aldolase/phosphatase from thermophilic Thermoproteus neutrophilus in a ligand-free state as well as in complex with the substrates DHAP and FBP and the product F6P to resolutions up to 1.3 Å. In conjunction with mutagenesis data, this pinpoints the residues required for the two reaction steps and shows that the sequential binding of additional Mg(2+) cations reversibly facilitates the reaction. FBP aldolase/phosphatase is an ancestral gluconeogenic enzyme optimized for high ambient temperatures, and our work resolves how consecutive structural rearrangements reorganize the catalytic centre of the protein to carry out two canonical reactions in a very non-canonical type of bifunctionality. PMID:21983965

  20. Epidermal β-catenin activation remodels the dermis via paracrine signalling to distinct fibroblast lineages

    PubMed Central

    Lichtenberger, Beate M.; Mastrogiannaki, Maria; Watt, Fiona M.

    2016-01-01

    Sustained epidermal Wnt/β-catenin signalling expands the stem cell compartment and induces ectopic hair follicles (EFs). This is accompanied by extensive fibroblast proliferation and extracellular matrix (ECM) remodelling in the underlying dermis. Here we show that epidermal Hedgehog (Hh) and Transforming growth factor-beta (TGF-β) signalling mediate the dermal changes. Pharmacological inhibition or genetic deletion of these pathways prevents β-catenin-induced dermal reprogramming and EF formation. Epidermal Shh stimulates proliferation of the papillary fibroblast lineage, whereas TGF-β2 controls proliferation, differentiation and ECM production by reticular fibroblasts. Hh inhibitors do not affect TGF-β target gene expression in reticular fibroblasts, and TGF-β inhibition does not prevent Hh target gene induction in papillary fibroblasts. However, when Hh signalling is inhibited the reticular dermis does not respond to epidermal β-catenin activation. We conclude that the dermal response to epidermal Wnt/β-catenin signalling depends on distinct fibroblast lineages responding to different paracrine signals. PMID:26837596

  1. Epidermal β-catenin activation remodels the dermis via paracrine signalling to distinct fibroblast lineages.

    PubMed

    Lichtenberger, Beate M; Mastrogiannaki, Maria; Watt, Fiona M

    2016-01-01

    Sustained epidermal Wnt/β-catenin signalling expands the stem cell compartment and induces ectopic hair follicles (EFs). This is accompanied by extensive fibroblast proliferation and extracellular matrix (ECM) remodelling in the underlying dermis. Here we show that epidermal Hedgehog (Hh) and Transforming growth factor-beta (TGF-β) signalling mediate the dermal changes. Pharmacological inhibition or genetic deletion of these pathways prevents β-catenin-induced dermal reprogramming and EF formation. Epidermal Shh stimulates proliferation of the papillary fibroblast lineage, whereas TGF-β2 controls proliferation, differentiation and ECM production by reticular fibroblasts. Hh inhibitors do not affect TGF-β target gene expression in reticular fibroblasts, and TGF-β inhibition does not prevent Hh target gene induction in papillary fibroblasts. However, when Hh signalling is inhibited the reticular dermis does not respond to epidermal β-catenin activation. We conclude that the dermal response to epidermal Wnt/β-catenin signalling depends on distinct fibroblast lineages responding to different paracrine signals. PMID:26837596

  2. The Nucleosome Remodeling and Deacetylase Complex NuRD Is Built from Preformed Catalytically Active Sub-modules.

    PubMed

    Zhang, W; Aubert, A; Gomez de Segura, J M; Karuppasamy, M; Basu, S; Murthy, A S; Diamante, A; Drury, T A; Balmer, J; Cramard, J; Watson, A A; Lando, D; Lee, S F; Palayret, M; Kloet, S L; Smits, A H; Deery, M J; Vermeulen, M; Hendrich, B; Klenerman, D; Schaffitzel, C; Berger, I; Laue, E D

    2016-07-17

    The nucleosome remodeling deacetylase (NuRD) complex is a highly conserved regulator of chromatin structure and transcription. Structural studies have shed light on this and other chromatin modifying machines, but much less is known about how they assemble and whether stable and functional sub-modules exist that retain enzymatic activity. Purification of the endogenous Drosophila NuRD complex shows that it consists of a stable core of subunits, while others, in particular the chromatin remodeler CHD4, associate transiently. To dissect the assembly and activity of NuRD, we systematically produced all possible combinations of different components using the MultiBac system, and determined their activity and biophysical properties. We carried out single-molecule imaging of CHD4 in live mouse embryonic stem cells, in the presence and absence of one of core components (MBD3), to show how the core deacetylase and chromatin-remodeling sub-modules associate in vivo. Our experiments suggest a pathway for the assembly of NuRD via preformed and active sub-modules. These retain enzymatic activity and are present in both the nucleus and the cytosol, an outcome with important implications for understanding NuRD function. PMID:27117189

  3. The DEG/ENaC cation channel protein UNC-8 drives activity-dependent synapse removal in remodeling GABAergic neurons.

    PubMed

    Miller-Fleming, Tyne W; Petersen, Sarah C; Manning, Laura; Matthewman, Cristina; Gornet, Megan; Beers, Allison; Hori, Sayaka; Mitani, Shohei; Bianchi, Laura; Richmond, Janet; Miller, David M

    2016-01-01

    Genetic programming and neural activity drive synaptic remodeling in developing neural circuits, but the molecular components that link these pathways are poorly understood. Here we show that the C. elegans Degenerin/Epithelial Sodium Channel (DEG/ENaC) protein, UNC-8, is transcriptionally controlled to function as a trigger in an activity-dependent mechanism that removes synapses in remodeling GABAergic neurons. UNC-8 cation channel activity promotes disassembly of presynaptic domains in DD type GABA neurons, but not in VD class GABA neurons where unc-8 expression is blocked by the COUP/TF transcription factor, UNC-55. We propose that the depolarizing effect of UNC-8-dependent sodium import elevates intracellular calcium in a positive feedback loop involving the voltage-gated calcium channel UNC-2 and the calcium-activated phosphatase TAX-6/calcineurin to initiate a caspase-dependent mechanism that disassembles the presynaptic apparatus. Thus, UNC-8 serves as a link between genetic and activity-dependent pathways that function together to promote the elimination of GABA synapses in remodeling neurons. PMID:27403890

  4. The DEG/ENaC cation channel protein UNC-8 drives activity-dependent synapse removal in remodeling GABAergic neurons

    PubMed Central

    Miller-Fleming, Tyne W; Petersen, Sarah C; Manning, Laura; Matthewman, Cristina; Gornet, Megan; Beers, Allison; Hori, Sayaka; Mitani, Shohei; Bianchi, Laura; Richmond, Janet; Miller, David M

    2016-01-01

    Genetic programming and neural activity drive synaptic remodeling in developing neural circuits, but the molecular components that link these pathways are poorly understood. Here we show that the C. elegans Degenerin/Epithelial Sodium Channel (DEG/ENaC) protein, UNC-8, is transcriptionally controlled to function as a trigger in an activity-dependent mechanism that removes synapses in remodeling GABAergic neurons. UNC-8 cation channel activity promotes disassembly of presynaptic domains in DD type GABA neurons, but not in VD class GABA neurons where unc-8 expression is blocked by the COUP/TF transcription factor, UNC-55. We propose that the depolarizing effect of UNC-8-dependent sodium import elevates intracellular calcium in a positive feedback loop involving the voltage-gated calcium channel UNC-2 and the calcium-activated phosphatase TAX-6/calcineurin to initiate a caspase-dependent mechanism that disassembles the presynaptic apparatus. Thus, UNC-8 serves as a link between genetic and activity-dependent pathways that function together to promote the elimination of GABA synapses in remodeling neurons. DOI: http://dx.doi.org/10.7554/eLife.14599.001 PMID:27403890

  5. Dimethyloxaloylglycine Improves Angiogenic Activity of Bone Marrow Stromal Cells in the Tissue-Engineered Bone

    PubMed Central

    Ding, Hao; Chen, Song; Song, Wen-Qi; Gao, You-Shui; Guan, Jun-Jie; Wang, Yang; Sun, Yuan; Zhang, Chang-Qing

    2014-01-01

    One of the big challenges in tissue engineering for treating large bone defects is to promote the angiogenesis of the tissue-engineered bone. Hypoxia inducible factor-1α (HIF-1α) plays an important role in angiogenesis-osteogenesis coupling during bone regeneration, and can activate a broad array of angiogenic factors. Dimethyloxaloylglycine (DMOG) can activate HIF-1α expression in cells at normal oxygen tension. In this study, we explored the effect of DMOG on the angiogenic activity of bone mesenchymal stem cells (BMSCs) in the tissue-engineered bone. The effect of different concentrations of DMOG on HIF-1a expression in BMSCs was detected with western blotting, and the mRNA expression and secretion of related angiogenic factors in DMOG-treated BMSCs were respectively analyzed using qRT-PCR and enzyme linked immunosorbent assay. The tissue-engineered bone constructed with β-tricalcium phosphate (β-TCP) and DMOG-treated BMSCs were implanted into the critical-sized calvarial defects to test the effectiveness of DMOG in improving the angiogenic activity of BMSCs in the tissue-engineered bone. The results showed DMOG significantly enhanced the mRNA expression and secretion of related angiogenic factors in BMSCs by activating the expression of HIF-1α. More newly formed blood vessels were observed in the group treated with β-TCP and DMOG-treated BMSCs than in other groups. And there were also more bone regeneration in the group treated with β-TCP and DMOG-treated BMSCs. Therefore, we believed DMOG could enhance the angiogenic activity of BMSCs by activating the expression of HIF-1α, thereby improve the angiogenesis of the tissue-engineered bone and its bone healing capacity. PMID:25013382

  6. Shear-induced Endothelial NOS Activation and Remodeling via Heparan Sulfate, Glypican-1, and Syndecan-1

    PubMed Central

    Ebong, Eno E; Lopez-Quintero, Sandra V; Rizzo, Victor; Spray, David C; Tarbell, John M

    2014-01-01

    Mammalian epithelial cells are coated with a multifunctional surface glycocalyx (GCX). On vascular endothelial cells (EC), intact GCX is atheroprotective. It is degraded in many vascular diseases. GCX heparan sulfate (HS) is essential for healthy flow-induced EC nitric oxide (NO) release, elongation, and alignment. The HS core protein mechanisms involved in these processes are unknown. We hypothesized that the glypican-1 (GPC1) HS core protein mediates flow-induced EC NO synthase (eNOS) activation because GPC1 is anchored to caveolae where eNOS resides. We also hyphothesized that the HS core protein syndecan-1 (SDC1) mediates flow-induced EC elongation and alignment because SDC1 is linked to the cytoskeleton which impacts cell shape. We tested our hypotheses by exposing EC monolayers treated with HS degrading heparinase III (HepIII), and monolayers with RNA-silenced GPC1, or SDC1, to 3 to 24 hours of physiological shear stress. Shear-conditioned EC with intact GCX exhibited characteristic eNOS activation in short-term flow conditions. After long-term exposure, EC with intact GCX were elongated and aligned in the direction of flow. HS removal and GPC1 inhibition, not SDC1 reduction, blocked shear-induced eNOS activation. EC remodeling in response to flow was attenuated by HS degradation and in the absence of SDC1, but preserved with GPC1 knockdown. These findings clearly demonstrate that HS is involved in both centralized and decentralized GCX-mediated mechanotransduction mechanisms, with GPC1 acting as a centralized mechanotransmission agent and SDC1 functioning in decentralized mechanotransmission. This foundational work demonstrates how EC can transform fluid shear forces into diverse biomolecular and biomechanical responses. PMID:24480876

  7. Calcium-regulating hormones, bone mineral content, breaking load and trabecular remodeling are altered in growing pigs fed calcium-deficient diets.

    PubMed

    Eklou-Kalonji, E; Zerath, E; Colin, C; Lacroix, C; Holy, X; Denis, I; Pointillart, A

    1999-01-01

    Studies on calcium nutrition in appropriate large animal models can be directly relevant to humans. We have examined the effect of dietary Ca deficiency on various bone and bone-related variables, including plasma markers, histomorphometry, mineral content and breaking strength in pigs. Three groups of eight 38-d-old female pigs were fed adequate (0.9%; control), low (0.4%; LCa) or very low (0.1%; VLCa) Ca diets for 32 d. Plasma Ca significantly decreased over time only in the VLCa-deficient pigs. The concentrations of the parathyroid hormones (PTH) and calcitriol increased as Ca deficiency developed, and the plasma PTH and calcitriol levels varied inversely with dietary Ca. The total bone ash contents, bending moments, trabecular bone volume and the mineral apposition rate all decreased as the calcium intake decreased. The osteoclast surface areas were greater than those of controls in both Ca-deficient groups, whereas the osteoblast surface areas were greater only in the VLCa group. The plasma osteoblast-related markers (alkaline phosphatase, carboxy-terminal propeptide of type I procollagen and osteocalcin) were either greater or unaffected in the Ca-deficient pigs. The results indicate that deficient bone mineralization combined with an increased bone resorption led to bone loss and fragility. The differences in the changes in bone cells (number and activity) between LCa and VLCa groups might be due to differences (time and extent) of circulating PTH and calcitriol. The defective mineralization in both Ca-depleted groups resulted mainly from the lack of Ca because their osteoblast activity was either maintained or stimulated. The results also underline the progressive sensitivity of pigs to Ca supply and the usefulness of this model. PMID:9915898

  8. Glycosynthase Mutants of Endoglycosidase S2 Show Potent Transglycosylation Activity and Remarkably Relaxed Substrate Specificity for Antibody Glycosylation Remodeling.

    PubMed

    Li, Tiezheng; Tong, Xin; Yang, Qiang; Giddens, John P; Wang, Lai-Xi

    2016-08-01

    Glycosylation can exert a profound impact on the structures and biological functions of antibodies. Glycosylation remodeling using the endoglycosidase-catalyzed deglycosylation and transglycosylation approach is emerging as a promising platform to produce homogeneous glycoforms of antibodies, but the broad application of this method will require the availability of highly efficient glycosynthase mutants. We describe in this paper a systematic site-directed mutagenesis of an endoglycosidase from Streptococcus pyogenes of serotype M49 (Endo-S2) and the evaluation of the resulting mutants for their hydrolysis and transglycosylation activities. We found that mutations at the Asp-184 residue gave mutants that demonstrated significantly different properties, some possessed potent transglycosylation activity with diminished hydrolysis activity but others did not, which would be otherwise difficult to predict without the comparative study. In contrast to the previously reported Endo-S mutants that are limited to action on complex type N-glycans, the Endo-S2 glycosynthases described here, including D184M and D184Q, were found to have remarkably relaxed substrate specificity and were capable of transferring three major types (complex, high-mannose, and hybrid type) of N-glycans for antibody glycosylation remodeling. In addition, the Endo-S2 glycosynthase mutants were found to be much more active in general than the Endo-S mutants for transglycosylation. The usefulness of these Endo-S2 glycosynthase mutants was exemplified by an efficient glycosylation remodeling of two therapeutic monoclonal antibodies, rituximab and trastuzumab (Herceptin). PMID:27288408

  9. Cone Beam Computed Tomography Evaluation of Bone Remodeling Following the Osteotome Sinus Floor Elevation Technique for Future Site Development.

    PubMed

    Nakajima, Kazutoshi; Kusama, Yukio

    2016-01-01

    The effectiveness of the osteotome technique for sinus augmentation was evaluated using cone beam computed tomography (CBCT) analysis. Clinical results of two-stage sinus floor elevation using the osteotome technique performed on 15 patients at the Nakajima Dental Clinic between 2006 and 2013 were evaluated retrospectively. CBCT imaging revealed that the maxillary sinus floor was elevated by an average of 7.28 mm (SD 1.62) immediately following surgery, with a mean bone height of 9.55 mm (SD 1.43). In all cases, the osteotome technique provided sufficient bone height for implant placement. No pre- or postoperative complications (eg, mucosal perforation) were reported. The minimal surgical stress and morbidity further underscore the practicality of this approach for two-stage maxillary sinus floor augmentation. PMID:27333007

  10. Dynamic Cross Talk between S1P and CXCL12 Regulates Hematopoietic Stem Cells Migration, Development and Bone Remodeling

    PubMed Central

    Golan, Karin; Kollet, Orit; Lapidot, Tsvee

    2013-01-01

    Hematopoietic stem cells (HSCs) are mostly retained in a quiescent non-motile mode in their bone marrow (BM) niches, shifting to a migratory cycling and differentiating state to replenish the blood with mature leukocytes on demand. The balance between the major chemo-attractants CXCL12, predominantly in the BM, and S1P, mainly in the blood, dynamically regulates HSC recruitment to the circulation versus their retention in the BM. During alarm situations, stress-signals induce a decrease in CXCL12 levels in the BM, while S1P levels are rapidly and transiently increased in the circulation, thus favoring mobilization of stem cells as part of host defense and repair mechanisms. Myeloid cytokines, including G-CSF, up-regulate S1P signaling in the BM via the PI3K pathway. Induced CXCL12 secretion from stromal cells via reactive oxygen species (ROS) generation and increased S1P1 expression and ROS signaling in HSCs, all facilitate mobilization. Bone turnover is also modulated by both CXCL12 and S1P, regulating the dynamic BM stromal microenvironment, osteoclasts and stem cell niches which all functionally express CXCL12 and S1P receptors. Overall, CXCL12 and S1P levels in the BM and circulation are synchronized to mutually control HSC motility, leukocyte production and osteoclast/osteoblast bone turnover during homeostasis and stress situations. PMID:24276423

  11. The effects of pullet body weight, dietary nonpyhtate phosphorus intake, and breeder feeding regimen on production performance, chick quality, and bone remodeling in broiler breeders.

    PubMed

    Ekmay, R D; Salas, C; England, J; Cerrate, S; Coon, C N

    2012-04-01

    A 3 × 2 × 2 factorial experiment, consisting of 52 hens per treatment, was conducted to determine the effects of pullet BW, dietary nonphytate phosphorus (NPP), and feeding regimen on performance, progeny quality, and bone remodeling. Cobb 500 broiler breeder pullets were reared to 3 different growth curves: 20% under, Cobb standard, and 20% over. Body weights were recorded weekly and feed adjustments made accordingly. At 21 wk, 624 hens were fed one of 2 breeder diets differing only in the amount of dietary NPP: 0.15 or 0.40%. A normal feeding regimen was appropriate for the particular growth curve; an alternative regimen considered the 3 growth curves together as a flock. At 24, 26, and 29 wk, blood was collected from 5 hens per treatment every 4 h over a 24-h period. Plasma samples were analyzed for total alkaline phosphatase, tartrate-resistant acid phosphatase, parathyroid hormone-related peptide, Ca, and inorganic P. Eggs per hen housed were diminished in hens fed the low dietary NPP and by low pullet target weight. Hens fed low dietary NPP also had lower egg weights but better eggshell quality. Mortality was significantly higher in hens fed low dietary NPP. Breeder tibia relative strength and ash were also significantly lower in hens fed low dietary NPP, regardless of the quantitative amount. Progeny tibia ash was not affected by any treatment. Total alkaline phosphatase responded to pullet BW, however by wk 29, total alkaline phosphatase also became sensitive to dietary NPP. The NPP by pullet BW interaction for tartrate-resistant acid phosphatase levels became significant by 29 wk, and pullet BW was significant at wk 24. The NPP by pullet growth curve interaction was also critical for plasma inorganic P levels throughout the sampling period. In summary, both 0.15% dietary NPP and reared pullets 20% under standard BW negatively affect egg production but do not impair progeny productivity. Body composition appears to be a main contributor in bone remodeling

  12. [Effect of calcitonin on regional blood flow in bones, serum levels of IGF-I and osteocalcin, density and weight of bone ash in oophorectomized rats].

    PubMed

    Zák, J; Kapitola, J; Wallischová, J

    2003-01-01

    It is known that in cases of increased bone remodelation rate, i.e. after castration, local bone blood flow is also increased. But in case of adequate hormonal substitution, bone blood flow, similarly as the remodelation rate, return to normal ranges. Until now, there is no knowledge, if other drug can influence enhanced bone blood flow in oophorectomized animals. In this study authors treated oophorectomized female rats with calcitonin and followed bone blood flow, together with biochemical parameters of bone remodelation activity (osteocalcine), IGF-I levels, weight of bone ash and bone density. The female rats were divided in four groups: controls, oophorectomized, with calcitonin and oophorectomized with calcitonin. The bone blood flow was determined by method of body dispersion of radioactive strontium labelled microspheres. The results of this study show, that, in comparison with controls, the bone remodelation rate (documented with increased osteocalcine levels) and radioactive strontium labelled microspheres capture in bone in increased after oophorectomy (p < 0.05). Ash weight and bone density were decreased (p < 0.05). Simultaneously, the blood IGF-I levels were increased (p < 0.05). After oophorectomized animals were treated with calcitonin, all parameters mentioned above headed towards normal ranges in comparison with group of oophorectomized female rats without calcitonin (p < 0.05). Changes of serum IGF-I levels follow changes of microspheres capture in each group of animals. Authors support the hypothesis, that blood levels of IGF-I could influence local bone blood flow. Calcitonin treatment of oophorectomized animals diminishes also decrement of ash weight and bone density. Results of this work show, that similarly as hormonal substitution therapy after oophorectomy, calcitonin also diminishes increased bone blood flow and bone remodelation parameters. The degree of bone blood flow is probably connected with activity of bone remodelling. PMID

  13. DIVERGENT TNF RECEPTOR-RELATED REMODELING RESPONSES IN HEART FAILURE: Role of NF-κB and Inflammatory Activation

    PubMed Central

    Hamid, Tariq; Gu, Yan; Ortines, Roger V.; Bhattacharya, Chhandashri; Wang, Guangwu; Xuan, Yu-Ting; Prabhu, Sumanth D.

    2009-01-01

    Background Although pre-clinical data suggested that tumor necrosis factor-α (TNF) neutralization in heart failure (HF) would be beneficial, clinical trials of TNF antagonists were paradoxically negative. We hypothesized that TNF induces opposing inflammatory and remodeling responses in HF that are TNF-receptor (TNFR) specific. Methods and Results HF was induced in wild-type (WT), TNFR1−/−, and TNFR2−/− mice via coronary ligation. Compared to WT HF, 4-week post-infarction survival was significantly improved in both TNFR1−/− and TNFR2−/− HF. Compared to sham, WT HF hearts exhibited significant remodeling with robust activation of nuclear factor(NF)-κB, p38 MAPK, and JNK2, and upregulation of TNF, interleukin(IL)-1β, IL-6, and IL-10. Compared to WT HF, TNFR1−/− HF exhibited: 1) improved remodeling, hypertrophy, and contractile function; 2) less apoptosis; and 3) diminished NF-κB, p38 MAPK, and JNK2 activation and cytokine expression. In contrast, TNFR2−/− HF had exaggerated remodeling and hypertrophy, increased border zone fibrosis, augmented NF-κB and p38 MAPK activation, higher IL-1β and IL-6 gene expression, greater activated macrophages, and greater apoptosis. Oxidative stress and diastolic function were improved in both TNFR1−/− and TNFR2−/− HF. In H9c2 cardiomyocytes, sustained NF-κB activation was pro-apoptotic, an effect dependent on TNFR1 signaling, whereas TNFR2 overexpression attenuated TNF-induced NF-κB activation. Conclusions TNFR1 and TNFR2 have disparate and opposing effects on remodeling, hypertrophy, NF-κB and inflammation, and apoptosis in HF: TNFR1 exacerbates, whereas TNFR2 ameliorates, these events. However, signaling through both receptors is required to induce diastolic dysfunction and oxidative stress. TNF receptor-specific effects in HF should be considered when developing therapeutic anti-TNF strategies. PMID:19255345

  14. Interleukin-1{beta} regulates cell proliferation and activity of extracellular matrix remodelling enzymes in cultured primary pig heart cells

    SciTech Connect

    Zitta, Karina; Brandt, Berenice; Wuensch, Annegret; Meybohm, Patrick; Bein, Berthold; Steinfath, Markus; Scholz, Jens; Albrecht, Martin

    2010-09-03

    Research highlights: {yields} Levels of IL-1{beta} are increased in the pig myocardium after infarction. {yields} Cultured pig heart cells possess IL-1 receptors. {yields} IL-1{beta} increases cell proliferation of pig heart cells in-vitro. {yields} IL-1{beta} increases MMP-2 and MMP-9 activity in pig heart cells in-vitro. {yields} IL-1{beta} may be important for tissue remodelling events after myocardial infarction. -- Abstract: After myocardial infarction, elevated levels of interleukins (ILs) are found within the myocardial tissue and IL-1{beta} is considered to play a major role in tissue remodelling events throughout the body. In the study presented, we have established a cell culture model of primary pig heart cells to evaluate the effects of different concentrations of IL-1{beta} on cell proliferation as well as expression and activity of enzymes typically involved in tissue remodelling. Primary pig heart cell cultures were derived from three different animals and stimulated with recombinant pig IL-1{beta}. RNA expression was detected by RT-PCR, protein levels were evaluated by Western blotting, activity of matrix metalloproteinases (MMPs) was quantified by gelatine zymography and cell proliferation was measured using colorimetric MTS assays. Pig heart cells express receptors for IL-1 and application of IL-1{beta} resulted in a dose-dependent increase of cell proliferation (P < 0.05 vs. control; 100 ng/ml; 24 h). Gene expression of caspase-3 was increased by IL-1{beta} (P < 0.05 vs. control; 100 ng/ml; 3 h), and pro-caspase-3 but not active caspase was detected in lysates of pig heart cells by Western blotting. MMP-2 gene expression as well as enzymatic activities of MMP-2 and MMP-9 were increased by IL-1{beta} (P < 0.05 vs. control; 100 ng/ml; 3 h for gene expression, 48 and 72 h for enzymatic activities of MMP-2 and MMP-9, respectively). Our in vitro data suggest that IL-1{beta} plays a major role in the events of tissue remodelling in the heart. Combined

  15. Antioxidant Impregnated Ultra-High Molecular Weight Polyethylene Wear Debris Particles Display Increased Bone Remodeling and a Superior Osteogenic:Osteolytic Profile vs. Conventional UHMWPE Particles in a Murine Calvaria Model

    PubMed Central

    Chen, Yu; Hallab, Nadim J.; Liao, Yen-Shuo; Narayan, Venkat; Schwarz, Edward M.; Xie, Chao

    2015-01-01

    Periprosthetic osteolysis remains a major limitation of long-term successful total hip replacements with ultra-high molecular weight polyethylene (UHMWPE) bearings. As intra and extracellular reactive oxygen species are know to contribute to wear debris-induced osteoclastic bone resorption and decreased osteoblastic bone formation, antioxidant doped UHMWPE has emerged as an approach to reduce the osteolytic potential of wear debris and maintain coupled bone remodeling. To test this hypothesis in vivo, we evaluated the effects of crosslinked UHMWPE wear debris particles (AltrX™), versus similar wear particles made from COVERNOX™ containing UHMWPE (AOX™), in an established murine calvaria model. Eight-week-old female C57B/6 mice (n=10/Group) received a pre-op micro-CT scan prior to surgical implantation of the UHMWPE particles (2mg), or surgery without particles (sham). Dynamic labeling was performed by intraperitoneal injection of calcein on day 7 and alizarin on day 9, and the calvaria were harvested for micro-CT and histology on day 10. Surprisingly, we found that AOX particles induced significantly more bone resorption (1.72-fold) and osteoclast numbers (1.99-fold) vs. AltrX (p<0.001). However, AOX also significantly induced 1.64-fold more new bone formation vs. AltrX (p<0.01). Moreover, while the osteolytic:osteogenic ratio of both particles was very close to 1.0, which is indicative of coupled remodeling, AOX was more osteogenic (Slope=1.13±0.10 vs. 0.97±0.10). Histomorphometry of the metabolically labeled undecalcified calvaria revealed a consistent trend of greater MAR in AOX vs. AltrX. Collectively, these results demonstrate that anti-oxidant impregnated UHMWPE particles have decreased osteolytic potential due to their increased osteogenic properties that support coupled bone remodeling. PMID:26495749

  16. Reoxygenation‐Derived Toxic Reactive Oxygen/Nitrogen Species Modulate the Contribution of Bone Marrow Progenitor Cells to Remodeling After Myocardial Infarction

    PubMed Central

    Moldovan, Nicanor I.; Anghelina, Mirela; Varadharaj, Saradhadevi; Butt, Omer I.; Wang, Tiangshen; Yang, Fuchun; Moldovan, Leni; Zweier, Jay L.

    2014-01-01

    Background The core region of a myocardial infarction is notoriously unsupportive of cardiomyocyte survival. However, there has been less investigation of the potentially beneficial spontaneous recruitment of endogenous bone marrow progenitor cells (BMPCs) within infarcted areas. In the current study we examined the role of tissue oxygenation and derived toxic species in the control of BMPC engraftment during postinfarction heart remodeling. Methods and Results For assessment of cellular origin, local oxygenation, redox status, and fate of cells in the infarcted region, myocardial infarction in mice with or without LacZ+ bone marrow transplantation was induced by coronary ligation. Sham‐operated mice served as controls. After 1 week, LacZ+ BMPC‐derived cells were found inhomogeneously distributed into the infarct zone, with a lower density at its core. Electron paramagnetic resonance (EPR) oximetry showed that pO2 in the infarct recovered starting on day 2 post–myocardial infarction, concomitant with wall thinning and erythrocytes percolating through muscle microruptures. Paralleling this reoxygenation, increased generation of reactive oxygen/nitrogen species was detected at the infarct core. This process delineated a zone of diminished BMPC engraftment, and at 1 week infiltrating cells displayed immunoreactive 3‐nitrotyrosine and apoptosis. In vivo treatment with a superoxide dismutase mimetic significantly reduced reactive oxygen species formation and amplified BMPC accumulation. This treatment also salvaged wall thickness by 43% and left ventricular ejection fraction by 27%, with significantly increased animal survival. Conclusions BMPC engraftment in the infarct inversely mirrored the distribution of reactive oxygen/nitrogen species. Antioxidant treatment resulted in increased numbers of engrafted BMPCs, provided functional protection to the heart, and decreased the incidence of myocardial rupture and death. PMID:24419735

  17. The Chromatin Remodeling Protein Bptf Promotes Posterior Neuroectodermal Fate by Enhancing Smad2-Activated wnt8a Expression.

    PubMed

    Ma, Yuanqing; Liu, Xiuli; Liu, Zhaoting; Wei, Shi; Shang, Hanqiao; Xue, Yu; Cao, Yu; Meng, Anming; Wang, Qiang

    2015-06-01

    During vertebrate embryogenesis, the neuroectoderm is induced from dorsal ectoderm and then partitioned into anterior and posterior neuroectodermal domains by posteriorizing signals, such as Wnt and fibroblast growth factor. However, little is known about epigenetic regulation of posteriorizing gene expression. Here, we report a requirement of the chromatin remodeling protein Bptf for neuroectodermal posteriorization in zebrafish embryos. Knockdown of bptf leads to an expansion of the anterior neuroectoderm at the expense of the posterior ectoderm. Bptf functionally and physically interacts with p-Smad2, which is activated by non-Nodal TGF-β signaling, to promote the expression of wnt8a, a critical gene for neural posteriorization. Bptf and Smad2 directly bind to and activate the wnt8a promoter through recruiting NURF remodeling complex. When bptf function or TGF-β signal transduction is inhibited, the nucleosome density on the wnt8a promoter is increased. We propose that Bptf and TGF-β/Smad2 mediate nucleosome remodeling to regulate wnt8a expression and hence neural posteriorization. PMID:26041917

  18. [Bone marrow stromal damage mediated by immune response activity].

    PubMed

    Vojinović, J; Kamenov, B; Najman, S; Branković, Lj; Dimitrijević, H

    1994-01-01

    The aim of this work was to estimate influence of activated immune response on hematopoiesis in vitro, using the experimental model of BCG immunized BALB/c mice and in patients with chronic immunoactivation: long-lasting infections, autoimmunity or malignancy. We correlated changes in long term bone marrow cultures (Dexter) and NBT reduction with appearance of anemia in patients and experimental model of immunization by BCG. Increased spontaneous NBT reduction pointed out role of macrophage activation in bone marrow stroma damage. Long-term bone marrow cultures showed reduced number of hematopoietic cells, with predomination of fibroblasts and loss of fat cells. This results correlated with anemia and leucocytosis with stimulated myelopoiesis in peripheral blood. Activation of immune response, or acting of any agent that directly changes extracellular matrix and cellularity of bone marrow, may result in microenviroment bone marrow damage that modify hematopoiesis. PMID:18173180

  19. IMD-4690, a novel specific inhibitor for plasminogen activator inhibitor-1, reduces allergic airway remodeling in a mouse model of chronic asthma via regulating angiogenesis and remodeling-related mediators.

    PubMed

    Tezuka, Toshifumi; Ogawa, Hirohisa; Azuma, Masahiko; Goto, Hisatsugu; Uehara, Hisanori; Aono, Yoshinori; Hanibuchi, Masaki; Yamaguchi, Yoichi; Fujikawa, Tomoyuki; Itai, Akiko; Nishioka, Yasuhiko

    2015-01-01

    Plasminogen activator inhibitor (PAI)-1 is the principal inhibitor of plasminogen activators, and is responsible for the degradation of fibrin and extracellular matrix. IMD-4690 is a newly synthesized inhibitor for PAI-1, whereas the effect on allergic airway inflammation and remodeling is still unclear. We examined the in vivo effects by using a chronic allergen exposure model of bronchial asthma in mice. The model was generated by an immune challenge for 8 weeks with house dust mite antigen, Dermatophagoides pteronyssinus (Dp). IMD-4690 was intraperitoneally administered during the challenge. Lung histopathology, hyperresponsiveness and the concentrations of mediators in lung homogenates were analyzed. The amount of active PAI-1 in the lungs was increased in mice treated with Dp. Administration with IMD-4690 reduced an active/total PAI-1 ratio. IMD-4690 also reduced the number of bronchial eosinophils in accordance with the decreased expressions of Th2 cytokines in the lung homogenates. Airway remodeling was inhibited by reducing subepithelial collagen deposition, smooth muscle hypertrophy, and angiogenesis. The effects of IMD-4690 were partly mediated by the regulation of TGF-β, HGF and matrix metalloproteinase. These results suggest that PAI-1 plays crucial roles in airway inflammation and remodeling, and IMD-4690, a specific PAI-1 inhibitor, may have therapeutic potential for patients with refractory asthma due to airway remodeling. PMID:25785861

  20. Deficiency of MAPK-activated protein kinase 2 (MK2) prevents adverse remodelling and promotes endothelial healing after arterial injury.

    PubMed

    Kapopara, P R; von Felden, J; Soehnlein, O; Wang, Y; Napp, L C; Sonnenschein, K; Wollert, K C; Schieffer, B; Gaestel, M; Bauersachs, J; Bavendiek, U

    2014-12-01

    Maladaptive remodelling of the arterial wall after mechanical injury (e. g. angioplasty) is characterised by inflammation, neointima formation and media hypertrophy, resulting in narrowing of the affected artery. Moreover, mechanical injury of the arterial wall causes loss of the vessel protecting endothelial cell monolayer. Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2), a major downstream target of p38 MAPK, regulates inflammation, cell migration and proliferation, essential processes for vascular remodelling and re-endothelialisation. Therefore, we investigated the role of MK2 in remodelling and re-endothelialisation after arterial injury in genetically modified mice in vivo. Hypercholesterolaemic low-density-lipoprotein-receptor-deficient mice (ldlr-/-) were subjected to wire injury of the common carotid artery. MK2-deficiency (ldlr-/-/mk2-/-) nearly completely prevented neointima formation, media hypertrophy, and lumen loss after injury. This was accompanied by reduced proliferation and migration of MK2-deficient smooth muscle cells. In addition, MK2-deficiency severely reduced monocyte adhesion to the arterial wall (day 3 after injury, intravital microscopy), which may be attributed to reduced expression of the chemokine ligands CCL2 and CCL5. In line, MK2-deficiency significantly reduced the content of monocytes, neutrophiles and lymphocytes of the arterial wall (day 7 after injury, flow cytometry). In conclusion, in a model of endothelial injury (electric injury), MK2-deficiency strongly increased proliferation of endothelial cells and improved re-endothelialisation of the arterial wall after injury. Deficiency of MK2 prevents adverse remodelling and promotes endothelial healing of the arterial wall after injury, suggesting that MK2-inhibition is a very attractive intervention to prevent restenosis after percutaneous therapeutic angioplasty. PMID:25120198

  1. Evaluation of cleaning methods applied in home environments after renovation and remodeling activities.

    PubMed

    Yiin, Lih-Ming; Lu, Shou-En; Sannoh, Sulaiman; Lim, Benjamin S; Rhoads, George G

    2004-10-01

    We conducted a cleaning trial in 40 northern New Jersey homes where home renovation and remodeling (R&R) activities were undertaken. Two cleaning protocols were used in the study: a specific method recommended by the US Department of Housing and Urban Development (HUD), in the 1995 "Guidelines for the Evaluation and Control of Lead-Based Paint Hazards in Housing," using a high-efficiency particulate air (HEPA)-filtered vacuum cleaner and a tri-sodium phosphate solution (TSP); and an alternative method using a household vacuum cleaner and a household detergent. Eligible homes were built before the 1970s with potential lead-based paint and had recent R&R activities without thorough cleaning. The two cleaning protocols were randomly assigned to the participants' homes and followed the HUD-recommended three-step procedure: vacuuming, wet washing, and repeat vacuuming. Wipe sampling was conducted on floor surfaces or windowsills before and after cleaning to evaluate the efficacy. All floor and windowsill data indicated that both methods (TSP/HEPA and non-TSP/non-HEPA) were effective in reducing lead loading on the surfaces (P < 0.001). When cleaning was applied to surfaces with initial lead loading above the clearance standards, the reductions were even greater, above 95% for either cleaning method. The mixed-effect model analysis showed no significant difference between the two methods. Baseline lead loading was found to be associated with lead loading reduction significantly on floors (P < 0.001) and marginally on windowsills (P = 0.077). Such relations were different between the two cleaning methods significantly on floors (P < 0.001) and marginally on windowsills (P = 0.066), with the TSP/HEPA method being favored for higher baseline levels and the non-TSP/non-HEPA method for lower baseline levels. For the 10 homes with lead abatement, almost all post-cleaning lead loadings were below the standards using either cleaning method. Based on our results, we recommend

  2. A direct measurement of strontium-89 activity in bone metastases.

    PubMed

    Ben-Josef, E; Maughan, R L; Vasan, S; Porter, A T

    1995-06-01

    The total absorbed dose after systemic administration of 89Sr has been determined by measuring directly its activity in bone metastases. Autoradiography was performed on sections of bones obtained from patients treated with 89Sr to study the pattern of deposition. Discs of 5 and 8 mm diameter were cut from metastatic sites and normal bone. The beta-ray activity was determined with a scintillation counter, which was calibrated using similar bovine cancellous bone discs, onto which a known activity of 89Sr was transferred by pipette. From the activity measured, the initial activity (at the time of 89Sr administration) was calculated. The absorbed dose was estimated using the methodology described in NCRP Report No. 58. The estimated initial activity of 89Sr in the bone metastases varied from 2.3 to 240 MBq kg-1, with a mean value of 31 +/- 27 MBq kg-1. The total absorbed dose ranged from 1.3 to 64 Gy, with a mean of 18 +/- 16 Gy. The average total dose to normal bone sites was 1.1 +/- 0.4 Gy. The metastases to normal bone dose ratio in individual samples varied from 8 +/- 4 to 40 +/- 25. These estimates are in agreement with those obtained previously by indirect methods. PMID:7675358

  3. Changes in functional activity of bone tissue cells under space flight conditions.

    NASA Astrophysics Data System (ADS)

    Rodionova, Natalia; Nesterenko, Olga; Kabitskaya, Olga

    The space flight conditions affect considerably the state of bone tissue, leading to the development of osteoporosis and osteopenia. Many aspects of reactions of bone tissue cells still remain unclear until now. With the use of electron microscopy we studied the samples gathered from the femoral bonеs metaphyses of rats flown on board the space laboratory (Spacelab - 2) during 2 weeks and samples from tibial bones of mice C57 Black ( Bion М-1). It was established, that under microgravity conditions there occur remodelling processes in a spongy bone related with a deficit of support load. In this work the main attention is focused on studying the ultrastructure of osteogenetic cells and osteoclasts. The degree of differentiation and functional state are evaluated according to the degree of development of organelles for specific biosynthesis: rough endoplasmic reticulum (RER), Golgy complex (GC), as well as the state of mitochondria and cell nucleus. As compared with a synchronous control, the population of osteogenetic cells from zones of bone reconstruction shows a decrease in the number of functionally active forms. We can judge of this from the reduction of a specific volume of RER, GC, mitochondria in osteoblasts. RER loses architectonics typical for osteoblasts and, as against the control, is represented by short narrow canaliculi distributed throughout the cytoplasm; some canals disintegrate. GC is slightly pronounced, mitochondria become smaller in size and acquire an optically dark matrix. These phenomena are supposed to be associated with the desorganization of microtubules and microfilaments in the cells under microgravity conditions. The population of osteogenetic cells shows a decrease in the number of differentiating osteoblasts and an increase in the number of little-differentiated stromal cells. In the population of osteoblasts, degrading and apoptotic cells are sometimes encountered. Such zones show a numerical increase of monocytic cells and

  4. HIV and Cocaine Impact Glial Metabolism: Energy Sensor AMP-activated protein kinase Role in Mitochondrial Biogenesis and Epigenetic Remodeling.

    PubMed

    Samikkannu, Thangavel; Atluri, Venkata S R; Nair, Madhavan P N

    2016-01-01

    HIV infection and cocaine use have been identified as risk factors for triggering neuronal dysfunction. In the central nervous system (CNS), energy resource and metabolic function are regulated by astroglia. Glia is the major reservoir of HIV infection and disease progression in CNS. However, the role of cocaine in accelerating HIV associated energy deficit and its impact on neuronal dysfunction has not been elucidated yet. The aim of this study is to elucidate the molecular mechanism of HIV associated neuropathogenesis in cocaine abuse and how it accelerates the energy sensor AMPKs and its subsequent effect on mitochondrial oxidative phosphorylation (OXPHOS), BRSKs, CDC25B/C, MAP/Tau, Wee1 and epigenetics remodeling complex SWI/SNF. Results showed that cocaine exposure during HIV infection significantly increased the level of p24, reactive oxygen species (ROS), ATP-utilization and upregulated energy sensor AMPKs, CDC25B/C, MAP/Tau and Wee1 protein expression. Increased ROS production subsequently inhibits OCR/ECAR ratio and OXPHOS, and eventually upregulate epigenetics remodeling complex SWI/SNF in CHME-5 cells. These results suggest that HIV infection induced energy deficit and metabolic dysfunction is accelerated by cocaine inducing energy sensor AMPKs, mitochondrial biogenesis and chromatin remodeling complex SWI/SNF activation, which may lead to neuroAIDS disease progression. PMID:27535703

  5. HIV and Cocaine Impact Glial Metabolism: Energy Sensor AMP-activated protein kinase Role in Mitochondrial Biogenesis and Epigenetic Remodeling

    PubMed Central

    Samikkannu, Thangavel; Atluri, Venkata S. R.; Nair, Madhavan P. N.

    2016-01-01

    HIV infection and cocaine use have been identified as risk factors for triggering neuronal dysfunction. In the central nervous system (CNS), energy resource and metabolic function are regulated by astroglia. Glia is the major reservoir of HIV infection and disease progression in CNS. However, the role of cocaine in accelerating HIV associated energy deficit and its impact on neuronal dysfunction has not been elucidated yet. The aim of this study is to elucidate the molecular mechanism of HIV associated neuropathogenesis in cocaine abuse and how it accelerates the energy sensor AMPKs and its subsequent effect on mitochondrial oxidative phosphorylation (OXPHOS), BRSKs, CDC25B/C, MAP/Tau, Wee1 and epigenetics remodeling complex SWI/SNF. Results showed that cocaine exposure during HIV infection significantly increased the level of p24, reactive oxygen species (ROS), ATP-utilization and upregulated energy sensor AMPKs, CDC25B/C, MAP/Tau and Wee1 protein expression. Increased ROS production subsequently inhibits OCR/ECAR ratio and OXPHOS, and eventually upregulate epigenetics remodeling complex SWI/SNF in CHME-5 cells. These results suggest that HIV infection induced energy deficit and metabolic dysfunction is accelerated by cocaine inducing energy sensor AMPKs, mitochondrial biogenesis and chromatin remodeling complex SWI/SNF activation, which may lead to neuroAIDS disease progression. PMID:27535703

  6. Improving upon Nature: Active site remodeling produces highly efficient aldolase activity towards hydrophobic electrophilic substrates

    PubMed Central

    Cheriyan, Manoj; Toone, Eric J.; Fierke, Carol A.

    2012-01-01

    Substrate specificity of enzymes is frequently narrow and constrained by multiple interactions, limiting the use of natural enzymes in biocatalytic applications. Aldolases have important synthetic applications, but the usefulness of these enzymes is hampered by their narrow reactivity profile with unnatural substrates. To explore the determinants of substrate selectivity and alter the specificity of E. coli 2-keto-3-deoxy-6-phosphogluconate (KDPG) aldolase, we employed structure-based mutagenesis coupled with library screening of mutant enzymes localized to the bacterial periplasm. We identified two active site mutations (T161S/S184L) that work additively to enhance the substrate specificity of this aldolase to include catalysis of retro-aldol cleavage of (4S)-2-keto-4-hydroxy-4-(2′-pyridyl)butyrate (S-KHPB). These mutations improve the value of kcat/KMS-KHPB by >450-fold, resulting in a catalytic efficiency that is comparable to that of the wild-type enzyme with the natural substrate while retaining high stereoselectivity. Moreover, the value of kcatS-KHPB for this mutant enzyme, a parameter critical for biocatalytic applications, is 3-fold higher than the maximum value achieved by the natural aldolase with any substrate. This mutant also possesses high catalytic efficiency for the retro-aldol cleavage of the natural substrate, KDPG, and a >50-fold improved activity for cleavage of 2-keto-4-hydroxy-octonoate (KHO), a non-functionalized hydrophobic analog. These data suggest a substrate binding mode that illuminates the origin of facial selectivity in aldol addition reactions catalyzed by KDPG and 2-keto-3-deoxy-6-phosphogalactonate (KDPGal) aldolases. Furthermore, targeting mutations to the active site provides marked improvement in substrate selectivity, demonstrating that structure-guided active site mutagenesis combined with selection techniques can efficiently identify proteins with characteristics that compare favorably to naturally occurring enzymes. PMID

  7. Bone biosensors: knowing the present and predicting the future

    NASA Astrophysics Data System (ADS)

    Khashayar, Patricia; Amoabediny, Ghassem; Larijani, Bagher; Vanfleteren, Jan

    2016-02-01

    Bone is an active organ with the capacity of continuous remodeling throughout adult life. In view of the fact that the current gold standard to assess bone remodeling, bone mineral density, suffers from certain limitations, newer techniques are being developed. Currently enzyme-linked immunosorbent assay is commonly used to assess bone turnover markers; the technique, however, is expensive, time consuming and needs trained personnel. Thus, there is a growing demand to fabricate different types of biosensors to provide low cost miniaturized platforms to assess the bone remodeling process more accurately. This review focuses on the latest advancements in the field of bone biosensing technologies. Its results might help provide possible solutions for translation of this technology for point-of-care diagnostic applications.

  8. Human Upf1 is a highly processive RNA helicase and translocase with RNP remodelling activities

    PubMed Central

    Fiorini, Francesca; Bagchi, Debjani; Le Hir, Hervé; Croquette, Vincent

    2015-01-01

    RNA helicases are implicated in most cellular RNA-dependent events. In eukaryotes however, only few have been functionally characterized. Upf1 is a RNA helicase essential for nonsense-mediated mRNA decay (NMD). Here, using magnetic tweezers and bulk assays, we observe that human Upf1 is able to translocate slowly over long single-stranded nucleic acids with a processivity >10 kb. Upf1 efficiently translocates through double-stranded structures and protein-bound sequences, demonstrating that Upf1 is an efficient ribonucleoprotein complex remodeler. Our observation of processive unwinding by an eukaryotic RNA helicase reveals that Upf1, once recruited onto NMD mRNA targets, can scan the entire transcript to irreversibly remodel the mRNP, facilitating its degradation by the NMD machinery. PMID:26138914

  9. Human Upf1 is a highly processive RNA helicase and translocase with RNP remodelling activities

    NASA Astrophysics Data System (ADS)

    Fiorini, Francesca; Bagchi, Debjani; Le Hir, Hervé; Croquette, Vincent

    2015-07-01

    RNA helicases are implicated in most cellular RNA-dependent events. In eukaryotes however, only few have been functionally characterized. Upf1 is a RNA helicase essential for nonsense-mediated mRNA decay (NMD). Here, using magnetic tweezers and bulk assays, we observe that human Upf1 is able to translocate slowly over long single-stranded nucleic acids with a processivity >10 kb. Upf1 efficiently translocates through double-stranded structures and protein-bound sequences, demonstrating that Upf1 is an efficient ribonucleoprotein complex remodeler. Our observation of processive unwinding by an eukaryotic RNA helicase reveals that Upf1, once recruited onto NMD mRNA targets, can scan the entire transcript to irreversibly remodel the mRNP, facilitating its degradation by the NMD machinery.

  10. Flax Fiber Hydrophobic Extract Inhibits Human Skin Cells Inflammation and Causes Remodeling of Extracellular Matrix and Wound Closure Activation

    PubMed Central

    Styrczewska, Monika; Kostyn, Anna; Kulma, Anna; Majkowska-Skrobek, Grazyna; Augustyniak, Daria; Prescha, Anna; Czuj, Tadeusz; Szopa, Jan

    2015-01-01

    Inflammation is the basis of many diseases, with chronic wounds amongst them, limiting cell proliferation and tissue regeneration. Our previous preclinical study of flax fiber applied as a wound dressing and analysis of its components impact on the fibroblast transcriptome suggested flax fiber hydrophobic extract use as an anti-inflammatory and wound healing preparation. The extract contains cannabidiol (CBD), phytosterols, and unsaturated fatty acids, showing great promise in wound healing. In in vitro proliferation and wound closure tests the extract activated cell migration and proliferation. The activity of matrix metalloproteinases in skin cells was increased, suggesting activation of extracellular components remodeling. The expression of cytokines was diminished by the extract in a cannabidiol-dependent manner, but β-sitosterol can act synergistically with CBD in inflammation inhibition. Extracellular matrix related genes were also analyzed, considering their importance in further stages of wound healing. The extract activated skin cell matrix remodeling, but the changes were only partially cannabidiol- and β-sitosterol-dependent. The possible role of fatty acids also present in the extract is suggested. The study shows the hydrophobic flax fiber components as wound healing activators, with anti-inflammatory cannabidiol acting in synergy with sterols, and migration and proliferation promoting agents, some of which still require experimental identification. PMID:26347154

  11. Flax Fiber Hydrophobic Extract Inhibits Human Skin Cells Inflammation and Causes Remodeling of Extracellular Matrix and Wound Closure Activation.

    PubMed

    Styrczewska, Monika; Kostyn, Anna; Kulma, Anna; Majkowska-Skrobek, Grazyna; Augustyniak, Daria; Prescha, Anna; Czuj, Tadeusz; Szopa, Jan

    2015-01-01

    Inflammation is the basis of many diseases, with chronic wounds amongst them, limiting cell proliferation and tissue regeneration. Our previous preclinical study of flax fiber applied as a wound dressing and analysis of its components impact on the fibroblast transcriptome suggested flax fiber hydrophobic extract use as an anti-inflammatory and wound healing preparation. The extract contains cannabidiol (CBD), phytosterols, and unsaturated fatty acids, showing great promise in wound healing. In in vitro proliferation and wound closure tests the extract activated cell migration and proliferation. The activity of matrix metalloproteinases in skin cells was increased, suggesting activation of extracellular components remodeling. The expression of cytokines was diminished by the extract in a cannabidiol-dependent manner, but β-sitosterol can act synergistically with CBD in inflammation inhibition. Extracellular matrix related genes were also analyzed, considering their importance in further stages of wound healing. The extract activated skin cell matrix remodeling, but the changes were only partially cannabidiol- and β-sitosterol-dependent. The possible role of fatty acids also present in the extract is suggested. The study shows the hydrophobic flax fiber components as wound healing activators, with anti-inflammatory cannabidiol acting in synergy with sterols, and migration and proliferation promoting agents, some of which still require experimental identification. PMID:26347154

  12. [Inhibitory effect of 8-prenylnaringenin on osteoclastogensis of bone marrow cells and bone resorption activity].

    PubMed

    Lü, Xiang; Zhou, Ying; Chen, Ke-Ming; Zhao, Zhi; Zhou, Jian; Ma, Xiao-Ni

    2013-03-01

    This study is to investigate the effect of 8-prenylnaringenin (8-PNG) on osteoclastogensis of bone marrow cells and bone resorption activity of osteoclasts. Osteoclasts were separated from long bone marrow of newborn rabbits and cultured in alpha-MEM containing 10% FBS. 8-PNG was added into culture media at 1 x 10(-7), 1 x 10(-6), 1 x 10(-5) mol xL(-1), separately. 17beta-Estradiol (E2, 1 x 10(-7) mol x L(-7)) was used as positive control. T RAP staining and TRAP activity measurement were performed after 5 days, and the bone resorption pits were analyzed after 7 days. Annexin V staining for the detection of apoptotic osteoclasts was performed after 2, 4, 8, 12, 24, 36 and 48 h separately. The mRNA expression level of TRAP and cathepsin K (CTSK) was measured by real-time RT-PCR. 8-PNG significantly reduced the number of osteoclasts which was TRAP staining positive and with more than three nucleus, the area and number of bone resorption pits decreased obviously in 8-PNG-supplemented groups. The apoptosis rate peaked earlier in the 8-PNG-supplemented groups and the mRNA expression level of TRAP and CTSK decreased significantly. All these inhibitory effects were in a dose dependent manner, the highest effect was obtained by 1 x 10(-5) mol x L(-1) 8-PNG. 8-PNG inhibits bone resorption activity of osteoclasts by inducing osteoclast apoptosis and inhibiting the gene expression and enzyme activity including TRAP and CTSK, and restrains bone marrow cells to osteoclast differentiation. PMID:23724646

  13. Transcriptional activation of muscle atrophy promotes cardiac muscle remodeling during mammalian hibernation

    PubMed Central

    Zhang, Yichi; Aguilar, Oscar A.

    2016-01-01

    during late torpor by 2.4-fold. Protein levels of MAFbx and MuRF1 increased in late torpor as well as during early arousal by as much as 2.8-fold, and MAFbx levels remained elevated during interbout arousal, whereas MuRF1 levels returned to control levels. Discussion. The present results indicate that upregulation and activation of Foxo1 and 3a, in addition to the increase in MyoG levels at late torpor, may be upregulating the expression of MAFbx and MuRF1. These findings suggest that there is activation of the ubiquitin proteasome system (UPS) as ground squirrels arouse from torpor. Therefore, the signalling pathway involving MyoG, and the E3 ligases MAFbx and MuRF1, plays a significant role in cardiac muscle remodelling during hibernation. These findings provide insights into the regulation of protein degradation and turnover in the cardiac muscle of a hibernator model. PMID:27602284

  14. Transcriptional activation of muscle atrophy promotes cardiac muscle remodeling during mammalian hibernation.

    PubMed

    Zhang, Yichi; Aguilar, Oscar A; Storey, Kenneth B

    2016-01-01

    upregulated only during late torpor by 2.4-fold. Protein levels of MAFbx and MuRF1 increased in late torpor as well as during early arousal by as much as 2.8-fold, and MAFbx levels remained elevated during interbout arousal, whereas MuRF1 levels returned to control levels. Discussion. The present results indicate that upregulation and activation of Foxo1 and 3a, in addition to the increase in MyoG levels at late torpor, may be upregulating the expression of MAFbx and MuRF1. These findings suggest that there is activation of the ubiquitin proteasome system (UPS) as ground squirrels arouse from torpor. Therefore, the signalling pathway involving MyoG, and the E3 ligases MAFbx and MuRF1, plays a significant role in cardiac muscle remodelling during hibernation. These findings provide insights into the regulation of protein degradation and turnover in the cardiac muscle of a hibernator model. PMID:27602284

  15. Deoxypodophyllotoxin suppresses tumor vasculature in HUVECs by promoting cytoskeleton remodeling through LKB1-AMPK dependent Rho A activation

    PubMed Central

    Wang, Yurong; Wang, Bin; Guerram, Mounia; Sun, Li; Shi, Wei; Tian, Chongchong; Zhu, Xiong; Jiang, Zhenzhou; Zhang, Luyong

    2015-01-01

    Angiogenesis plays a critical role in the growth and metastasis of tumors, which makes it an attractive target for anti-tumor drug development. Deoxypodophyllotoxin (DPT), a natural product isolated from Anthriscus sylvestris, inhibits cell proliferation and migration in various cancer cell types. Our previous studies indicate that DPT possesses both anti-angiogenic and vascular-disrupting activities. Although the RhoA/ RhoA kinase (ROCK) signaling pathway is implicated in DPT-stimulated cytoskeleton remodeling and tumor vasculature suppressing, the detailed mechanisms by which DPT mediates these effects are poorly understood. In the current study, we found that DPT promotes cytoskeleton remodeling in human umbilical vein endothelial cells (HUVECs) via stimulation of AMP-activated protein kinase (AMPK) and that this effect is abolished by either treatment with a selective AMPK inhibitor or knockdown. Moreover, the cellular levels of LKB1, a kinase upstream of AMPK, were enhanced following DPT exposure. DPT-induced activation of AMPK in tumor vasculature effect was also verified by transgenic zebrafish (VEGFR2:GFP), Matrigel plug assay, and xenograft model in nude mice. The present findings may lay the groundwork for a novel therapeutic approach in treating cancer. PMID:26470595

  16. Endothelial Bmx tyrosine kinase activity is essential for myocardial hypertrophy and remodeling.

    PubMed

    Holopainen, Tanja; Räsänen, Markus; Anisimov, Andrey; Tuomainen, Tomi; Zheng, Wei; Tvorogov, Denis; Hulmi, Juha J; Andersson, Leif C; Cenni, Bruno; Tavi, Pasi; Mervaala, Eero; Kivelä, Riikka; Alitalo, Kari

    2015-10-20

    Cardiac hypertrophy accompanies many forms of heart disease, including ischemic disease, hypertension, heart failure, and valvular disease, and it is a strong predictor of increased cardiovascular morbidity and mortality. Deletion of bone marrow kinase in chromosome X (Bmx), an arterial nonreceptor tyrosine kinase, has been shown to inhibit cardiac hypertrophy in mice. This finding raised the possibility of therapeutic use of Bmx tyrosine kinase inhibitors, which we have addressed here by analyzing cardiac hypertrophy in gene-targeted mice deficient in Bmx tyrosine kinase activity. We found that angiotensin II (Ang II)-induced cardiac hypertrophy is significantly reduced in mice deficient in Bmx and in mice with inactivated Bmx tyrosine kinase compared with WT mice. Genome-wide transcriptomic profiling showed that Bmx inactivation suppresses myocardial expression of genes related to Ang II-induced inflammatory and extracellular matrix responses whereas expression of RNAs encoding mitochondrial proteins after Ang II administration was maintained in Bmx-inactivated hearts. Very little or no Bmx mRNA was expressed in human cardiomyocytes whereas human cardiac endothelial cells expressed abundant amounts. Ang II stimulation of endothelial cells increased Bmx phosphorylation, and Bmx gene silencing inhibited downstream STAT3 signaling, which has been implicated in cardiac hypertrophy. Furthermore, activation of the mechanistic target of rapamycin complex 1 pathway by Ang II treatment was decreased in the Bmx-deficient hearts. Our results demonstrate that inhibition of the cross-talk between endothelial cells and cardiomyocytes by Bmx inactivation suppresses Ang II-induced signals for cardiac hypertrophy. These results suggest that the endothelial Bmx tyrosine kinase could provide a target to attenuate the development of cardiac hypertrophy. PMID:26430242

  17. Endothelial Bmx tyrosine kinase activity is essential for myocardial hypertrophy and remodeling

    PubMed Central

    Holopainen, Tanja; Räsänen, Markus; Anisimov, Andrey; Tuomainen, Tomi; Zheng, Wei; Tvorogov, Denis; Hulmi, Juha J.; Andersson, Leif C.; Cenni, Bruno; Tavi, Pasi; Mervaala, Eero; Kivelä, Riikka; Alitalo, Kari

    2015-01-01

    Cardiac hypertrophy accompanies many forms of heart disease, including ischemic disease, hypertension, heart failure, and valvular disease, and it is a strong predictor of increased cardiovascular morbidity and mortality. Deletion of bone marrow kinase in chromosome X (Bmx), an arterial nonreceptor tyrosine kinase, has been shown to inhibit cardiac hypertrophy in mice. This finding raised the possibility of therapeutic use of Bmx tyrosine kinase inhibitors, which we have addressed here by analyzing cardiac hypertrophy in gene-targeted mice deficient in Bmx tyrosine kinase activity. We found that angiotensin II (Ang II)-induced cardiac hypertrophy is significantly reduced in mice deficient in Bmx and in mice with inactivated Bmx tyrosine kinase compared with WT mice. Genome-wide transcriptomic profiling showed that Bmx inactivation suppresses myocardial expression of genes related to Ang II-induced inflammatory and extracellular matrix responses whereas expression of RNAs encoding mitochondrial proteins after Ang II administration was maintained in Bmx-inactivated hearts. Very little or no Bmx mRNA was expressed in human cardiomyocytes whereas human cardiac endothelial cells expressed abundant amounts. Ang II stimulation of endothelial cells increased Bmx phosphorylation, and Bmx gene silencing inhibited downstream STAT3 signaling, which has been implicated in cardiac hypertrophy. Furthermore, activation of the mechanistic target of rapamycin complex 1 pathway by Ang II treatment was decreased in the Bmx-deficient hearts. Our results demonstrate that inhibition of the cross-talk between endothelial cells and cardiomyocytes by Bmx inactivation suppresses Ang II-induced signals for cardiac hypertrophy. These results suggest that the endothelial Bmx tyrosine kinase could provide a target to attenuate the development of cardiac hypertrophy. PMID:26430242

  18. Human umbilical cord tissue-derived mesenchymal stromal cells attenuate remodeling after myocardial infarction by proangiogenic, antiapoptotic, and endogenous cell-activation mechanisms

    PubMed Central

    2014-01-01

    Introduction Among the plethora of cells under investigation to restore a functional myocardium, mesenchymal stromal cells (MSCs) have been granted considerable interest. However, whereas the beneficial effects of bone marrow MSCs (BM-MSCs) in the context of the diseased heart are widely reported, data are still scarce on MSCs from the umbilical cord matrix (UCM-MSCs). Herein we report on the effect of UCM-MSC transplantation to the infarcted murine heart, seconded by the dissection of the molecular mechanisms at play. Methods Human umbilical cord tissue-derived MSCs (UCX®), obtained by using a proprietary technology developed by ECBio, were delivered via intramyocardial injection to C57BL/6 females subjected to permanent ligation of the left descending coronary artery. Moreover, medium produced by cultured UCX® preconditioned under normoxia (CM) or hypoxia (CMH) was collected for subsequent in vitro assays. Results Evaluation of the effects upon intramyocardial transplantation shows that UCX® preserved cardiac function and attenuated cardiac remodeling subsequent to myocardial infarction (MI). UCX® further led to increased capillary density and decreased apoptosis in the injured tissue. In vitro, UCX®-conditioned medium displayed (a) proangiogenic activity by promoting the formation of capillary-like structures by human umbilical vein endothelial cells (HUVECs), and (b) antiapoptotic activity in HL-1 cardiomyocytes subjected to hypoxia. Moreover, in adult murine cardiac Sca-1+ progenitor cells (CPCs), conditioned medium enhanced mitogenic activity while activating a gene program characteristic of cardiomyogenic differentiation. Conclusions UCX® preserve cardiac function after intramyocardial transplantation in a MI murine model. The cardioprotective effects of UCX® were attributed to paracrine mechanisms that appear to enhance angiogenesis, limit the extent of the apoptosis, augment proliferation, and activate a pool of resident CPCs. Overall, these results

  19. Nucleosome positioning and kinetics near transcription-start-site barriers are controlled by interplay between active remodeling and DNA sequence

    PubMed Central

    Parmar, Jyotsana J.; Marko, John F.; Padinhateeri, Ranjith

    2014-01-01

    We investigate how DNA sequence, ATP-dependent chromatin remodeling and nucleosome-depleted ‘barriers’ co-operate to determine the kinetics of nucleosome organization, in a stochastic model of nucleosome positioning and dynamics. We find that ‘statistical’ positioning of nucleosomes against ‘barriers’, hypothesized to control chromatin structure near transcription start sites, requires active remodeling and therefore cannot be described using equilibrium statistical mechanics. We show that, unlike steady-state occupancy, DNA site exposure kinetics near a barrier is dominated by DNA sequence rather than by proximity to the barrier itself. The timescale for formation of positioning patterns near barriers is proportional to the timescale for active nucleosome eviction. We also show that there are strong gene-to-gene variations in nucleosome positioning near barriers, which are eliminated by averaging over many genes. Our results suggest that measurement of nucleosome kinetics can reveal information about sequence-dependent regulation that is not apparent in steady-state nucleosome occupancy. PMID:24068556

  20. Robustness of nucleosome patterns in the presence of DNA sequence-specific free energy landscapes and active remodeling

    NASA Astrophysics Data System (ADS)

    Nuebler, Johannes; Obermayer, Benedikt; Möbius, Wolfram; Wolff, Michael; Gerland, Ulrich

    Proper positioning of nucleosomes in eukaryotic cells is important for transcription regulation. When averaged over many genes, nucleosome positions in coding regions follow a simple oscillatory pattern, which is described to a surprising degree of accuracy by a simple one-dimensional gas model for particles interacting via a soft-core repulsion. The quantitative agreement is surprising given that nucleosome positions are known to be determined by a complex interplay of mechanisms including DNA sequence-specific nucleosome stability and active repositioning of nucleosomes by remodeling enzymes. We rationalize the observed robustness of the simple oscillatory pattern by showing that the main effect of several known nucleosome positioning mechanisms is a renormalization of the particle interaction. For example, ``disorder'' from sequence-specific affinities leads to an apparent softening, while active remodeling can result in apparent softening for directional sliding or apparent stiffening for clamping mechanisms. We suggest that such parameter renormalization can explain the apparent difference of nucleosome properties in two yeast species, S. cerevisiae and S. pombe.

  1. Structure and membrane remodeling activity of ESCRT-III helical polymers

    DOE PAGESBeta

    McCullough, John; Clippinger, Amy K.; Talledge, Nathaniel; Skowyra, Michael L.; Saunders, Marissa G.; Naismith, Teresa V.; Colf, Leremy A.; Afonine, Pavel; Arthur, Christopher; Sundquist, Wesley I.; et al

    2015-12-18

    The endosomal sorting complexes required for transport (ESCRT) proteins mediate fundamental membrane remodeling events that require stabilizing negative membrane curvature. These include endosomal intralumenal vesicle formation, HIV budding, nuclear envelope closure, and cytokinetic abscission. ESCRT-III subunits perform key roles in these processes by changing conformation and polymerizing into membrane-remodeling filaments. Here, we report the 4 angstrom resolution cryogenic electron microscopy reconstruction of a one-start, double-stranded helical copolymer composed of two different human ESCRT-III subunits, charged multivesicular body protein 1B (CHMP1B) and increased sodium tolerance 1 (IST1). The inner strand comprises “open” CHMP1B subunits that interlock in an elaborate domain-swapped architecturemore » and is encircled by an outer strand of “closed” IST1 subunits. Unlike other ESCRT-III proteins, CHMP1B and IST1 polymers form external coats on positively curved membranes in vitro and in vivo. In conclusion, our analysis suggests how common ESCRT-III filament architectures could stabilize different degrees and directions of membrane curvature.« less

  2. Structure and membrane remodeling activity of ESCRT-III helical polymers

    SciTech Connect

    McCullough, John; Clippinger, Amy K.; Talledge, Nathaniel; Skowyra, Michael L.; Saunders, Marissa G.; Naismith, Teresa V.; Colf, Leremy A.; Afonine, Pavel; Arthur, Christopher; Sundquist, Wesley I.; Hanson, Phyllis I.; Frost, Adam

    2015-12-18

    The endosomal sorting complexes required for transport (ESCRT) proteins mediate fundamental membrane remodeling events that require stabilizing negative membrane curvature. These include endosomal intralumenal vesicle formation, HIV budding, nuclear envelope closure, and cytokinetic abscission. ESCRT-III subunits perform key roles in these processes by changing conformation and polymerizing into membrane-remodeling filaments. Here, we report the 4 angstrom resolution cryogenic electron microscopy reconstruction of a one-start, double-stranded helical copolymer composed of two different human ESCRT-III subunits, charged multivesicular body protein 1B (CHMP1B) and increased sodium tolerance 1 (IST1). The inner strand comprises “open” CHMP1B subunits that interlock in an elaborate domain-swapped architecture and is encircled by an outer strand of “closed” IST1 subunits. Unlike other ESCRT-III proteins, CHMP1B and IST1 polymers form external coats on positively curved membranes in vitro and in vivo. In conclusion, our analysis suggests how common ESCRT-III filament architectures could stabilize different degrees and directions of membrane curvature.

  3. Structure and membrane remodeling activity of ESCRT-III helical polymers

    PubMed Central

    McCullough, John; Clippinger, Amy K.; Talledge, Nathaniel; Skowyra, Michael L.; Saunders, Marissa G.; Naismith, Teresa V.; Colf, Leremy A.; Afonine, Pavel; Arthur, Christopher; Sundquist, Wesley I.; Hanson, Phyllis I.; Frost, Adam

    2015-01-01

    The Endosomal Sorting Complexes Required for Transport (ESCRT) proteins mediate fundamental membrane remodeling events that require stabilizing negative membrane curvature. These include endosomal intralumenal vesicle formation, HIV budding, nuclear envelope closure and cytokinetic abscission. ESCRT-III subunits perform key roles in these processes by changing conformation and polymerizing into membrane-remodeling filaments. Here, we report the 4 Å resolution cryo-EM reconstruction of a one-start, double-stranded helical copolymer composed of two different human ESCRT-III subunits, CHMP1B and IST1. The inner strand comprises “open” CHMP1B subunits that interlock in an elaborate domain-swapped architecture, and is encircled by an outer strand of “closed” IST1 subunits. Unlike other ESCRT-III proteins, CHMP1B and IST1 polymers form external coats on positively-curved membranes in vitro and in vivo. Our analysis suggests how common ESCRT-III filament architectures could stabilize different degrees and directions of membrane curvature. PMID:26634441

  4. Antimicrobial activity of bone cements embedded with organic nanoparticles

    PubMed Central

    Perni, Stefano; Thenault, Victorien; Abdo, Pauline; Margulis, Katrin; Magdassi, Shlomo; Prokopovich, Polina

    2015-01-01

    Infections after orthopedic surgery are a very unwelcome outcome; despite the widespread use of antibiotics, their incidence can be as high as 10%. This risk is likely to increase as antibiotics are gradually losing efficacy as a result of bacterial resistance; therefore, novel antimicrobial approaches are required. Parabens are a class of compounds whose antimicrobial activity is employed in many cosmetic and pharmaceutical products. We developed propylparaben nanoparticles that are hydrophilic, thus expanding the applicability of parabens to aqueous systems. In this paper we assess the possibility of employing paraben nanoparticles as antimicrobial compound in bone cements. The nanoparticles were embedded in various types of bone cement (poly(methyl methacrylate) [PMMA], hydroxyapatite, and brushite) and the antimicrobial activity was determined against common causes of postorthopedic surgery infections such as: Staphylococcus aureus, methicillin-resistant S. aureus, Staphylococcus epidermidis, and Acinetobacter baumannii. Nanoparticles at concentrations as low as 1% w/w in brushite bone cement were capable of preventing pathogens growth, 5% w/w was needed for hydroxyapatite bone cement, while 7% w/w was required for PMMA bone cement. No detrimental effect was determined by the addition of paraben nanoparticles on bone cement compression strength and cytocompatibility. Our results demonstrate that paraben nanoparticles can be encapsulated in bone cement, providing concentration-dependent antimicrobial activity; furthermore, lower concentrations are needed in calcium phosphate (brushite and hydroxyapatite) than in acrylic (PMMA) bone cements. These nanoparticles are effective against a wide spectrum of bacteria, including those already resistant to the antibiotics routinely employed in orthopedic applications, such as gentamicin. PMID:26487803

  5. Osteogenic Scaffolds for Bone Reconstruction

    PubMed Central

    Li, Ling-jiang; Liu, Ning; Liu, Qing; Jia, Lian-shun; Yuan, Wen

    2012-01-01

    Abstract A highly osteogenic hybrid bioabsorbable scaffold was developed for bone reconstruction/augmentation. Through the use of a solid free-form fabrication technology, a bioabsorbable polycaprolactone (PCL) cage scaffold with a desired size and shape was produced and then filled with osteogenic bone graft particles, that is, morselized autologous bone chips. A rabbit total lamina defect model was chosen to demonstrate its efficacy in regenerating bone with a complicated anatomic shape. Both iliac bone and morselized iliac bone grafts were used in this study for comparison purposes. Serum osteocalcin and collagen type I cross-linked C-terminal telopeptide (CTx) determination showed that active bone remodeling occurred after bone grafts were implanted. X-ray images showed that the bony defects were completely filled with bone mass in all the groups with bone grafts. However, biomechanical tests showed that only the iliac bone and hybrid scaffold groups could restore the mechanical properties to the normal level after 10 weeks of implantation. A histology study showed that both iliac and hybrid scaffold groups had extensive new bone formation, and no adhesion and fibrosis were found. These results indicated that this osteogenic hybrid scaffold can be a good alternative to autologous iliac bone, because it does not need a second iliac bone-harvesting surgery, and thus the morbidity and the possible infections that are often associated with the bone harvesting surgery can be avoided. PMID:23515416

  6. [Interaction between bone and artery].

    PubMed

    Kurabayashi, Masahiko

    2016-08-01

    Both osteoporosis and vascular calcification are highly prevalent in aged subjects and patients with diabetes and chronic kidney disease(CKD). Although it has long been thought that vascular calcification is a consequence of degeneration of vessel walls, recent studies unveiled the molecular mechanism of vascular calcification and identified the vascular calcification as a process similar to bone formation. With the advent of the understanding of the basis for bone remodeling, several hypotheses have been proposed for the underlying mechanism of the interaction between osteoporosis and vascular calcification. Briefly,(1)impaired bone remodeling may perturb serum calcium/phosphate, thus contributing to increased vascular calcification,(2)vascular calcification may precede osteoporosis, and(3)molecules responsible for bone remodeling, including estrogen, parathyroid hormone and vitamin D, RANK(receptor activator of nuclear factor kB), RANK ligand(RANKL), and osteoprotegerin(OPG), Wnt signaling, and loss of calcification inhibitors(matrix Gla protein)may promote vascular calcification. This review discusses the emerging role of bone remodeling factors in vascular calcification. PMID:27461494

  7. Deletion of FGFR3 in Osteoclast Lineage Cells Results in Increased Bone Mass in Mice by Inhibiting Osteoclastic Bone Resorption.

    PubMed

    Su, Nan; Li, Xiaogang; Tang, Yubin; Yang, Jing; Wen, Xuan; Guo, Jingyuan; Tang, Junzhou; Du, Xiaolan; Chen, Lin

    2016-09-01

    Fibroblast growth factor receptor 3 (FGFR3) participates in bone remodeling. Both Fgfr3 global knockout and activated mice showed decreased bone mass with increased osteoclast formation or bone resorption activity. To clarify the direct effect of FGFR3 on osteoclasts, we specifically deleted Fgfr3 in osteoclast lineage cells. Adult mice with Fgfr3 deficiency in osteoclast lineage cells (mutant [MUT]) showed increased bone mass. In a drilled-hole defect model, the bone remodeling of the holed area in cortical bone was also impaired with delayed resorption of residual woven bone in MUT mice. In vitro assay demonstrated that there was no significant difference between the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts derived from wild-type and Fgfr3-deficient bone marrow monocytes, suggesting that FGFR3 had no remarkable effect on osteoclast formation. The bone resorption activity of Fgfr3-deficient osteoclasts was markedly decreased accompanying with downregulated expressions of Trap, Ctsk, and Mmp 9. The upregulated activity of osteoclastic bone resorption by FGF2 in vitro was also impaired in Fgfr3-deficient osteoclasts, indicating that FGFR3 may participate in the regulation of bone resorption activity of osteoclasts by FGF2. Reduced adhesion but not migration in osteoclasts with Fgfr3 deficiency may be responsible for the impaired bone resorption activity. Our study for the first time genetically shows the direct positive regulation of FGFR3 on osteoclastic bone resorption. © 2016 American Society for Bone and Mineral Research. PMID:26990430

  8. ITE and TCDD differentially regulate the vascular remodeling of rat placenta via the activation of AhR.

    PubMed

    Wu, Yanming; Chen, Xiao; Zhou, Qian; He, Qizhi; Kang, Jiuhong; Zheng, Jing; Wang, Kai; Duan, Tao

    2014-01-01

    Vascular remodeling in the placenta is essential for normal fetal development. The previous studies have demonstrated that in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, an environmental toxicant) induces the intrauterine fetal death in many species via the activation of aryl hydrocarbon receptor (AhR). In the current study, we compared the effects of 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) and TCDD on the vascular remodeling of rat placentas. Pregnant rats on gestational day (GD) 15 were randomly assigned into 5 groups, and were exposed to a single dose of 1.6 and 8.0 mg/kg body weight (bw) ITE, 1.6 and 8.0 µg/kg bw TCDD, or an equivalent volume of the vehicle, respectively. The dams were sacrificed on GD20 and the placental tissues were gathered. The intrauterine fetal death was observed only in 8.0 µg/kg bw TCDD-exposed group and no significant difference was seen in either the placental weight or the fetal weight among all these groups. The immunohistochemical and histological analyses revealed that as compared with the vehicle-control, TCDD, but not ITE, suppressed the placental vascular remodeling, including reduced the ratio of the placental labyrinth zone to the basal zone thickness (at least 0.71 fold of control), inhibited the maternal sinusoids dilation and thickened the trophoblastic septa. However, no marked difference was observed in the density of fetal capillaries in the labyrinth zone among these groups, although significant differences were detected in the expression of angiogenic growth factors between ITE and TCDD-exposed groups, especially Angiopoietin-2 (Ang-2), Endoglin, Interferon-γ (IFN-γ) and placenta growth factor (PIGF). These results suggest ITE and TCDD differentially regulate the vascular remodeling of rat placentas, as well as the expression of angiogenic factors and their receptors, which in turn may alter the blood flow in the late gestation and partially resulted in

  9. ITE and TCDD Differentially Regulate the Vascular Remodeling of Rat Placenta via the Activation of AhR

    PubMed Central

    Zhou, Qian; He, Qizhi; Kang, Jiuhong; Zheng, Jing; Wang, Kai; Duan, Tao

    2014-01-01

    Vascular remodeling in the placenta is essential for normal fetal development. The previous studies have demonstrated that in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, an environmental toxicant) induces the intrauterine fetal death in many species via the activation of aryl hydrocarbon receptor (AhR). In the current study, we compared the effects of 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) and TCDD on the vascular remodeling of rat placentas. Pregnant rats on gestational day (GD) 15 were randomly assigned into 5 groups, and were exposed to a single dose of 1.6 and 8.0 mg/kg body weight (bw) ITE, 1.6 and 8.0 µg/kg bw TCDD, or an equivalent volume of the vehicle, respectively. The dams were sacrificed on GD20 and the placental tissues were gathered. The intrauterine fetal death was observed only in 8.0 µg/kg bw TCDD-exposed group and no significant difference was seen in either the placental weight or the fetal weight among all these groups. The immunohistochemical and histological analyses revealed that as compared with the vehicle-control, TCDD, but not ITE, suppressed the placental vascular remodeling, including reduced the ratio of the placental labyrinth zone to the basal zone thickness (at least 0.71 fold of control), inhibited the maternal sinusoids dilation and thickened the trophoblastic septa. However, no marked difference was observed in the density of fetal capillaries in the labyrinth zone among these groups, although significant differences were detected in the expression of angiogenic growth factors between ITE and TCDD-exposed groups, especially Angiopoietin-2 (Ang-2), Endoglin, Interferon-γ (IFN-γ) and placenta growth factor (PIGF). These results suggest ITE and TCDD differentially regulate the vascular remodeling of rat placentas, as well as the expression of angiogenic factors and their receptors, which in turn may alter the blood flow in the late gestation and partially resulted in

  10. Activation of bone marrow phagocytes following benzene treatment of mice.

    PubMed Central

    Laskin, D L; MacEachern, L; Snyder, R

    1989-01-01

    Techniques in flow cytometry/cell sorting were used to characterize the effects of benzene and its metabolites on subpopulations of bone marrow cells. Treatment of male Balb/c mice with benzene (880 mg/kg) or a combination of its metabolites, hydroquinone and phenol (50 mg/kg), resulted in a 30 to 40% decrease in bone marrow cellularity. Flow cytometric analysis revealed two subpopulations of bone marrow cells that could be distinguished by their size and density or granularity. The larger, more dense subpopulation was found to consist predominantly of macrophages and granulocytes as determined by monoclonal antibody binding and by cell sorting. Benzene treatment had no selective cytotoxic effects on subpopulations of bone marrow cells. To determine if benzene treatment activated bone marrow phagocytes, we quantified production of hydrogen peroxide by these cells using the fluorescent indicator dye, 2',7'-dichlorofluorescein diacetate. We found that macrophages and granulocytes from bone marrow of treated mice produced 50% more hydrogen peroxide in response to the phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate than did cells from control animals. It is hypothesized that phagocyte activation and production of cytotoxic reactive oxygen intermediates may contribute to hematotoxicity induced by benzene. PMID:2676504

  11. Remodeling of Hyperpolarization-Activated Current, Ih, in Ah-Type Visceral Ganglion Neurons Following Ovariectomy in Adult Rats

    PubMed Central

    Xu, Wen-Xiao; Yan, Zhen-Yu; Liu, Yang; Zhou, Jia-Ying; Zhang, Hao-Cheng; Wang, Li-Juan; Pan, Xiao-Dong; Fu, Yili

    2013-01-01

    Hyperpolarization-activated currents (Ih) mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels modulate excitability of myelinated A− and Ah-type visceral ganglion neurons (VGN). Whether alterations in Ih underlie the previously reported reduction of excitability of myelinated Ah-type VGNs following ovariectomy (OVX) has remained unclear. Here we used the intact nodose ganglion preparation in conjunction with electrophysiological approaches to examine the role of Ih remodeling in altering Ah-type neuron excitability following ovariectomy in adult rats. Ah-type neurons were identified based on their afferent conduction velocity. Ah-type neurons in nodose ganglia from non-OVX rats exhibited a voltage ‘sag’ as well as ‘rebound’ action potentials immediately following hyperpolarizing current injections, which both were suppressed by the Ih blocker ZD7288. Repetitive spike activity induced afterhyperpolarizations lasting several hundreds of milliseconds (termed post-excitatory membrane hyperpolarizations, PEMHs), which were significantly reduced by ZD7288, suggesting that they resulted from transient deactivation of Ih during the preceding spike trains. Ovariectomy reduced whole-cell Ih density, caused a hyperpolarizing shift of the voltage-dependence of Ih activation, and slowed Ih activation. OVX-induced Ih remodeling was accompanied by a flattening of the stimulus frequency/response curve and loss of PEMHs. Also, HCN1 mRNA levels were reduced by ∼30% in nodose ganglia from OVX rats compared with their non-OVX counterparts. Acute exposure of nodose ganglia to 17beta-estradiol partly restored Ih density and accelerated Ih activation in Ah-type cells. In conclusion, Ih plays a significant role in modulating the excitability of myelinated Ah-type VGNs in adult female rats. PMID:23951107

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

    SciTech Connect

    Nurmio, Mirja; Joki, Henna; Kallio, Jenny; Maeaettae, Jorma A.; Vaeaenaenen, H. Kalervo; Toppari, Jorma; Jahnukainen, Kirsi; Laitala-Leinonen, Tiina

    2011-08-01

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

  13. Rhus javanica Gall Extract Inhibits the Differentiation of Bone Marrow-Derived Osteoclasts and Ovariectomy-Induced Bone Loss

    PubMed Central

    Kim, Tae-Ho; Park, Eui Kyun; Huh, Man-Il; Kim, Hong Kyun; Kim, Shin-Yoon; Lee, Sang-Han

    2016-01-01

    Inhibition of osteoclast differentiation and bone resorption is a therapeutic strategy for the management of postmenopausal bone loss. This study investigated the effects of Rhus javanica (R. javanica) extracts on bone marrow cultures to develop agents from natural sources that may prevent osteoclastogenesis. Extracts of R. javanica (eGr) cocoons spun by Rhus javanica (Bell.) Baker inhibited the osteoclast differentiation and bone resorption. The effects of aqueous extract (aeGr) or 100% ethanolic extract (eeGr) on ovariectomy- (OVX-) induced bone loss were investigated by various biochemical assays. Furthermore, microcomputed tomography (µCT) was performed to study bone remodeling. Oral administration of eGr (30 mg or 100 mg/kg/day for 6 weeks) augmented the inhibition of femoral bone mineral density (BMD), bone mineral content (BMC), and other factors involved in bone remodeling when compared to OVX controls. Additionally, eGr slightly decreased bone turnover markers that were increased by OVX. Therefore, it may be suggested that the protective effects of eGr could have originated from the suppression of OVX-induced increase in bone turnover. Collectively, the findings of this study indicate that eGr has potential to activate bone remodeling by inhibiting osteoclast differentiation and bone loss. PMID:27313644

  14. Antioxidant impregnated ultra-high molecular weight polyethylene wear debris particles display increased bone remodeling and a superior osteogenic:osteolytic profile vs. conventional UHMWPE particles in a murine calvaria model.

    PubMed

    Chen, Yu; Hallab, Nadim J; Liao, Yen-Shuo; Narayan, Venkat; Schwarz, Edward M; Xie, Chao

    2016-05-01

    Periprosthetic osteolysis remains a major limitation of long-term successful total hip replacements with ultra-high molecular weight polyethylene (UHMWPE) bearings. As intra and extracellular reactive oxygen species are know to contribute to wear debris-induced osteoclastic bone resorption and decreased osteoblastic bone formation, antioxidant doped UHMWPE has emerged as an approach to reduce the osteolytic potential of wear debris and maintain coupled bone remodeling. To test this hypothesis in vivo, we evaluated the effects of crosslinked UHMWPE wear debris particles (AltrX(™) ), versus similar wear particles made from COVERNOX(™) containing UHMWPE (AOX(™) ), in an established murine calvaria model. Eight-week-old female C57B/6 mice (n = 10/Group) received a pre-op micro-CT scan prior to surgical implantation of the UHMWPE particles (2mg), or surgery without particles (sham). Dynamic labeling was performed by intraperitoneal injection of calcein on day 7 and alizarin on day 9, and the calvaria were harvested for micro-CT and histology on day 10. Surprisingly, we found that AOX particles induced significantly more bone resorption (1.72-fold) and osteoclast numbers (1.99-fold) vs. AltrX (p < 0.001). However, AOX also significantly induced 1.64-fold more new bone formation vs. AltrX (p < 0.01). Moreover, while the osteolytic:osteogenic ratio of both particles was very close to 1.0, which is indicative of coupled remodeling, AOX was more osteogenic (Slope = 1.13 ± 0.10 vs. 0.97 ± 0.10). Histomorphometry of the metabolically labeled undecalcified calvaria revealed a consistent trend of greater MAR in AOX vs. AltrX. Collectively, these results demonstrate that anti-oxidant impregnated UHMWPE particles have decreased osteolytic potential due to their increased osteogenic properties that support coupled bone remodeling. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:845-851, 2016. PMID:26495749

  15. β2-Adrenoceptor is involved in connective tissue remodeling in regenerating muscles by decreasing the activity of MMP-9.

    PubMed

    Silva, Meiricris T; Nascimento, Tábata L; Pereira, Marcelo G; Siqueira, Adriane S; Brum, Patrícia C; Jaeger, Ruy G; Miyabara, Elen H

    2016-07-01

    We investigated the role of β2-adrenoceptors in the connective tissue remodeling of regenerating muscles from β2-adrenoceptor knockout (β2KO) mice. Tibialis anterior muscles from β2KO mice were cryolesioned and analyzed after 3, 10, and 21 days. Regenerating muscles from β2KO mice showed a significant increase in the area density of the connective tissue and in the amount of collagen at 10 days compared with wild-type (WT) mice. A greater increase occurred in the expression levels of collagen I, III, and IV in regenerating muscles from β2KO mice evaluated at 10 days compared with WT mice; this increase continued at 21 days, except for collagen III. Matrix metalloproteinase (MMP-2) activity increased to a similar extent in regenerating muscles from both β2KO and WT mice at 3 and 10 days. This was also the case for MMP-9 activity in regenerating muscles from both β2KO and WT mice at 3 days; however, at 10 days post-cryolesion, this activity returned to baseline levels only in WT mice. MMP-3 activity was unaltered in regenerating muscles at 10 days. mRNA levels of tumor necrosis factor-α increased in regenerating muscles from WT and β2KO mice at 3 days and, at 10 days post-cryolesion, returned to baseline only in WT mice. mRNA levels of interleukin-6 increased in muscles from WT mice at 3 days post-cryolesion and returned to baseline at 10 days post-cryolesion but were unchanged in β2KO mice. Our results suggest that the β2-adrenoceptor contributes to collagen remodeling during muscle regeneration by decreasing MMP-9 activity. PMID:26896238

  16. Spliceosomal DEAH-Box ATPases Remodel Pre-mRNA to Activate Alternative Splice Sites.

    PubMed

    Semlow, Daniel R; Blanco, Mario R; Walter, Nils G; Staley, Jonathan P

    2016-02-25

    During pre-mRNA splicing, a central step in the expression and regulation of eukaryotic genes, the spliceosome selects splice sites for intron excision and exon ligation. In doing so, the spliceosome must distinguish optimal from suboptimal splice sites. At the catalytic stage of splicing, suboptimal splice sites are repressed by the DEAH-box ATPases Prp16 and Prp22. Here, using budding yeast, we show that these ATPases function further by enabling the spliceosome to search for and utilize alternative branch sites and 3' splice sites. The ATPases facilitate this search by remodeling the splicing substrate to disengage candidate splice sites. Our data support a mechanism involving 3' to 5' translocation of the ATPases along substrate RNA and toward a candidate site, but, surprisingly, not across the site. Thus, our data implicate DEAH-box ATPases in acting at a distance by pulling substrate RNA from the catalytic core of the spliceosome. PMID:26919433

  17. Transplantation of expanded bone marrow-derived very small embryonic-like stem cells (VSEL-SCs) improves left ventricular function and remodelling after myocardial infarction

    PubMed Central

    Zuba-Surma, Ewa K; Guo, Yiru; Taher, Hisham; Sanganalmath, Santosh K; Hunt, Greg; Vincent, Robert J; Kucia, Magda; Abdel-Latif, Ahmed; Tang, Xian-Liang; Ratajczak, Mariusz Z; Dawn, Buddhadeb; Bolli, Roberto

    2011-01-01

    Abstract Adult bone marrow-derived very small embryonic-like stem cells (VSEL-SCs) exhibit a Sca-1+/Lin–/CD45– phenotype and can differentiate into various cell types, including cardiomyocytes and endothelial cells. We have previously reported that transplantation of a small number (1 × 106) of freshly isolated, non-expanded VSEL-SCs into infarcted mouse hearts resulted in improved left ventricular (LV) function and anatomy. Clinical translation, however, will require large numbers of cells. Because the frequency of VSEL-SCs in the marrow is very low, we examined whether VSEL-SCs can be expanded in culture without loss of therapeutic efficacy. Mice underwent a 30 min. coronary occlusion followed by reperfusion and, 48 hrs later, received an intramyocardial injection of vehicle (group I, n= 11), 1 × 105 enhanced green fluorescent protein (EGFP)-labelled expanded untreated VSEL-SCs (group II, n= 7), or 1 × 105 EGFP-labelled expanded VSEL-SCs pre-incubated in a cardiogenic medium (group III, n= 8). At 35 days after myocardial infarction (MI), mice treated with pre-incubated VSEL-SCs exhibited better global and regional LV systolic function and less LV hypertrophy compared with vehicle-treated controls. In contrast, transplantation of expanded but untreated VSEL-SCs did not produce appreciable reparative benefits. Scattered EGFP+ cells expressing α-sarcomeric actin, platelet endothelial cell adhesion molecule (PECAM)-1, or von Willebrand factor were present in VSEL-SC-treated mice, but their numbers were very small. No tumour formation was observed. We conclude that VSEL-SCs expanded in culture retain the ability to alleviate LV dysfunction and remodelling after a reperfused MI provided that they are exposed to a combination of cardiomyogenic growth factors and cytokines prior to transplantation. Counter intuitively, the mechanism whereby such pre-incubation confers therapeutic efficacy does not involve differentiation into new cardiac cells. These results

  18. Chromatin Remodeling Factors Isw2 and Ino80 Regulate Checkpoint Activity and Chromatin Structure in S Phase

    PubMed Central

    Lee, Laura; Rodriguez, Jairo; Tsukiyama, Toshio

    2015-01-01

    When cells undergo replication stress, proper checkpoint activation and deactivation are critical for genomic stability and cell survival and therefore must be highly regulated. Although mechanisms of checkpoint activation are well studied, mechanisms of checkpoint deactivation are far less understood. Previously, we reported that chromatin remodeling factors Isw2 and Ino80 attenuate the S-phase checkpoint activity in Saccharomyces cerevisiae, especially during recovery from hydroxyurea. In this study, we found that Isw2 and Ino80 have a more pronounced role in attenuating checkpoint activity during late S phase in the presence of methyl methanesulfonate (MMS). We therefore screened for checkpoint factors required for Isw2 and Ino80 checkpoint attenuation in the presence of MMS. Here we demonstrate that Isw2 and Ino80 antagonize checkpoint activators and attenuate checkpoint activity in S phase in MMS either through a currently unknown pathway or through RPA. Unexpectedly, we found that Isw2 and Ino80 increase chromatin accessibility around replicating regions in the presence of MMS through a novel mechanism. Furthermore, through growth assays, we provide additional evidence that Isw2 and Ino80 partially counteract checkpoint activators specifically in the presence of MMS. Based on these results, we propose that Isw2 and Ino80 attenuate S-phase checkpoint activity through a novel mechanism. PMID:25701287

  19. Noradrenergic activation of the basolateral amygdala enhances object recognition memory and induces chromatin remodeling in the insular cortex

    PubMed Central

    Beldjoud, Hassiba; Barsegyan, Areg; Roozendaal, Benno

    2015-01-01

    It is well established that arousal-induced memory enhancement requires noradrenergic activation of the basolateral complex of the amygdala (BLA) and modulatory influences on information storage processes in its many target regions. While this concept is well accepted, the molecular basis of such BLA effects on neural plasticity changes within other brain regions remains to be elucidated. The present study investigated whether noradrenergic activation of the BLA after object recognition training induces chromatin remodeling through histone post-translational modifications in the insular cortex (IC), a brain region that is importantly involved in object recognition memory. Male Sprague—Dawley rats were trained on an object recognition task, followed immediately by bilateral microinfusions of norepinephrine (1.0 μg) or saline administered into the BLA. Saline-treated control rats exhibited poor 24-h retention, whereas norepinephrine treatment induced robust 24-h object recognition memory. Most importantly, this memory-enhancing dose of norepinephrine induced a global reduction in the acetylation levels of histone H3 at lysine 14, H2B and H4 in the IC 1 h later, whereas it had no effect on the phosphorylation of histone H3 at serine 10 or tri-methylation of histone H3 at lysine 27. Norepinephrine administered into the BLA of non-trained control rats did not induce any changes in the histone marks investigated in this study. These findings indicate that noradrenergic activation of the BLA induces training-specific effects on chromatin remodeling mechanisms, and presumably gene transcription, in its target regions, which may contribute to the understanding of the molecular mechanisms of stress and emotional arousal effects on memory consolidation. PMID:25972794

  20. Early active mobilization following UCL repair With Mitek bone anchor.

    PubMed

    Crowley, Timothy P; Stevenson, Susan; Taghizadeh, Reika; Addison, Patrick; Milner, Richard H

    2013-09-01

    Ulnar collateral ligament (UCL) injuries of the thumb are common. Surgical repair is accepted as the treatment of choice for complete rupture of the ligament. Biomechanical studies have suggested that Mitek bone anchor repairs are potentially safe and strong enough to allow early controlled active mobilization. To date, there have been no studies to compare early active mobilization following Mitek bone anchor repair to standard postoperative rehabilitation involving thumb spica immobilization for the first 4 to 6 weeks. We performed a small pilot randomized control trial to assess the outcome of this new rehabilitation technique to that of standard immobilization following UCL repair with Mitek bone anchor. Our results show that on average early active mobilization leads to an earlier return to full hand function (6 vs. 8 wk) and an earlier return to work (7 vs. 11 wk). There is no difference in the final range of motion achieved. We suggest that Mitek bone anchor repairs for UCL ruptures are robust enough to allow early active mobilization and that a larger trial is warranted to assess whether early active mobilization is superior to standard rehabilitation. PMID:23970193

  1. Proresolving Nanomedicines Activate Bone Regeneration in Periodontitis

    PubMed Central

    Hasturk, H.; Kantarci, A.; Freire, M.O.; Nguyen, D.; Dalli, J.; Serhan, C.N.

    2015-01-01

    Therapies to reverse tissue damage from osteolytic inflammatory diseases are limited by the inability of current tissue-engineering procedures to restore lost hard and soft tissues. There is a critical need for new therapeutics in regeneration. In addition to scaffolds, cells, and soluble mediators necessary for tissue engineering, control of endogenous inflammation is an absolute requirement for success. Although significant progress has been made in understanding natural resolution of inflammation pathways to limit uncontrolled inflammation in disease, harnessing the biomimetic properties of proresolving lipid mediators has not been demonstrated. Here, we report the use of nano-proresolving medicines (NPRM) containing a novel lipoxin analog (benzo-lipoxin A4, bLXA4) to promote regeneration of hard and soft tissues irreversibly lost to periodontitis in the Hanford miniature pig. In this proof-of-principle experiment, NPRM-bLXA4 dramatically reduced inflammatory cell infiltrate into chronic periodontal disease sites treated surgically and dramatically increased new bone formation and regeneration of the periodontal organ. These findings indicate that NPRM-bLXA4 is a mimetic of endogenous resolving mechanisms with potent bioactions that offers a new therapeutic tissue-engineering approach for the treatment of chronic osteolytic inflammatory diseases. PMID:25389003

  2. MAPKAPK-2-mediated LIM-kinase activation is critical for VEGF-induced actin remodeling and cell migration

    PubMed Central

    Kobayashi, Miho; Nishita, Michiru; Mishima, Toshiaki; Ohashi, Kazumasa; Mizuno, Kensaku

    2006-01-01

    Vascular endothelial growth factor-A (VEGF-A) induces actin reorganization and migration of endothelial cells through a p38 mitogen-activated protein kinase (MAPK) pathway. LIM-kinase 1 (LIMK1) induces actin remodeling by phosphorylating and inactivating cofilin, an actin-depolymerizing factor. In this study, we demonstrate that activation of LIMK1 by MAPKAPK-2 (MK2; a downstream kinase of p38 MAPK) represents a novel signaling pathway in VEGF-A-induced cell migration. VEGF-A induced LIMK1 activation and cofilin phosphorylation, and this was inhibited by the p38 MAPK inhibitor SB203580. Although p38 phosphorylated LIMK1 at Ser-310, it failed to activate LIMK1 directly; however, MK2 activated LIMK1 by phosphorylation at Ser-323. Expression of a Ser-323-non-phosphorylatable mutant of LIMK1 suppressed VEGF-A-induced stress fiber formation and cell migration; however, expression of a Ser-323-phosphorylation-mimic mutant enhanced these processes. Knockdown of MK2 by siRNA suppressed VEGF-A-induced LIMK1 activation, stress fiber formation, and cell migration. Expression of kinase-dead LIMK1 suppressed VEGF-A-induced tubule formation. These findings suggest that MK2-mediated LIMK1 phosphorylation/activation plays an essential role in VEGF-A-induced actin reorganization, migration, and tubule formation of endothelial cells. PMID:16456544

  3. Changes in the Mechanical Properties and Composition of Bone during Microdamage Repair

    PubMed Central

    Yu, Zhifeng

    2014-01-01

    Under normal conditions, loading activities result in microdamage in the living skeleton, which is repaired by bone remodeling. However, microdamage accumulation can affect the mechanical properties of bone and increase the risk of fracture. This study aimed to determine the effect of microdamage on the mechanical properties and composition of bone. Fourteen male goats aged 28 months were used in the present study. Cortical bone screws were placed in the tibiae to induce microdamage around the implant. The goats were euthanized, and 3 bone segments with the screws in each goat were removed at 0 days, 21 days, 4 months, and 8 months after implantation. The bone segments were used for observing microdamage and bone remodeling, as well as nanoindentation and bone composition, separately. Two regions were measured: the first region (R1), located 1.5 mm from the interface between the screw hole and bone; and the second region (R2), located>1.5 mm from the bone-screw interface. Both diffuse and linear microdamage decreased significantly with increasing time after surgery, with the diffuse microdamage disappearing after 8 months. Thus, screw implantation results in increased bone remodeling either in the proximal or distal cortical bone, which repairs the microdamage. Moreover, bone hardness and elastic modulus decreased with microdamage repair, especially in the proximal bone tissue. Bone composition changed greatly during the production and repair of microdamage, especially for the C (Carbon) and Ca (Calcium) in the R1 region. In conclusion, the presence of mechanical microdamage accelerates bone remodeling either in the proximal or distal cortical bone. The bone hardness and elastic modulus decreased with microdamage repair, with the micromechanical properties being restored on complete repair of the microdamage. Changes in bone composition may contribute to changes in bone mechanical properties. PMID:25313565

  4. Data Mining Activities for Bone Discipline - Current Status

    NASA Technical Reports Server (NTRS)

    Sibonga, J. D.; Pietrzyk, R. A.; Johnston, S. L.; Arnaud, S. B.

    2008-01-01

    The disciplinary goals of the Human Research Program are broadly discussed. There is a critical need to identify gaps in the evidence that would substantiate a skeletal health risk during and after spaceflight missions. As a result, data mining activities will be engaged to gather reviews of medical data and flight analog data and to propose additional measures and specific analyses. Several studies are briefly reviewed which have topics that partially address these gaps in knowledge, including bone strength recovery with recovery of bone mass density, current renal stone formation knowledge, herniated discs, and a review of bed rest studies conducted at Ames Human Research Facility.

  5. Targeted SPECT/CT Imaging of Matrix Metalloproteinase Activity in the Evaluation of Remodeling Tissue-Engineered Vascular Grafts Implanted in a Growing Lamb Model

    PubMed Central

    Stacy, Mitchel R.; Naito, Yuji; Maxfield, Mark W.; Kurobe, Hirotsugu; Tara, Shuhei; Chan, Chung; Rocco, Kevin A.; Shinoka, Toshiharu; Sinusas, Albert J.; Breuer, Christopher K.

    2014-01-01

    Objective(s) The clinical translation of tissue-engineered vascular grafts has been demonstrated in children. The remodeling of biodegradable, cell-seeded scaffolds to functional neovessels is partially attributed to matrix metalloproteinases. Noninvasive assessment of matrix metalloproteinase activity may indicate graft remodeling and elucidate the progression of neovessel formation. Therefore, matrix metalloproteinase activity was evaluated in grafts implanted in lambs using in vivo and ex vivo hybrid imaging. Graft growth and remodeling was quantified using in vivo X-ray computed tomography angiography. Methods Cell-seeded and unseeded scaffolds were implanted in lambs (n=5) as inferior vena cava interposition grafts. At 2 and 6 months post-implantation, in vivo angiography assessed graft morphology. In vivo and ex vivo single photon emission tomography/X-ray computed tomography imaging was performed with a radiolabeled compound targeting matrix metalloproteinase activity at 6 months. Neotissue was examined at 6 months using qualitative histologic and immunohistochemical staining and quantitative biochemical analysis. Results Seeded grafts demonstrated significant luminal and longitudinal growth from 2 to 6 months. In vivo imaging revealed subjectively higher matrix metalloproteinase activity in grafts vs. native tissue. Ex vivo imaging confirmed a quantitative increase in matrix metalloproteinase activity and demonstrated higher activity in unseeded vs. seeded grafts. Glycosaminoglycan content was increased in seeded grafts vs. unseeded grafts, without significant differences in collagen content. Conclusions Matrix metalloproteinase activity remains elevated in tissue-engineered grafts 6 months post-implantation and may indicate remodeling. Optimization of in vivo imaging to noninvasively evaluate matrix metalloproteinase activity may assist in serial assessment of vascular graft remodeling. PMID:24952823

  6. [Effects of antiresorptive therapy on the structural and material properties of bone strength].

    PubMed

    Kishimoto, Hideaki

    2016-01-01

    Bone strength depends on its structural and material properties. Structural properties are determined by the size and shape of bone and also the microarchitecture. Material properties are determined by mineral crystallinity, collagen structure and microdamage in bone. The strength of bone is adapted to the needs of physical activities by biologic mechanisms, bone modeling and remodeling. The deterioration of bone strength in postmenopausal women is characterized by a trabecular bone deficit with poor trabecular connectivity and followed by a cortical bone deficit with trabeculation of endocortical bone and intracortical porosity due to accelerated bone remodeling. In high turnover osteoporosis antiresorptive therapy is effective in preventing the structural deficit and in increasing the stiffness and the toughness(bone strength)by increasing the mean degree of mineralization of bone tissue through the prolongation of secondary mineralization. But the long-term use of strong antiresorber, i.e. bisphosphonate or denosumab, would result in highly mineralized bone and disturbed repair of microcracks by inhibition of bone remodeling. Intermittent use or discontinuation of strong antiresorber after about 3-5 years of administration could be recommended to avoid the deterioration of bone strength. PMID:26728537

  7. Links Between the Microbiome and Bone.

    PubMed

    Hernandez, Christopher J; Guss, Jason D; Luna, Marysol; Goldring, Steven R

    2016-09-01

    The human microbiome has been shown to influence a number of chronic conditions associated with impaired bone mass and bone quality, including obesity, diabetes, and inflammatory bowel disease. The connection between the microbiome and bone health, however, has not been well studied. The few studies available demonstrate that the microbiome can have a large effect on bone remodeling and bone mass. The gut microbiome is the largest reservoir of microbial organisms in the body and consists of more than a thousand different species interacting with one another in a stable, dynamic equilibrium. How the microbiome can affect organs distant from the gut is not well understood but is believed to occur through regulation of nutrition, regulation of the immune system, and/or translocation of bacterial products across the gut endothelial barrier. Here we review each of these mechanisms and discuss their potential effect on bone remodeling and bone mass. We discuss how preclinical studies of bone-microbiome interactions are challenging because the microbiome is sensitive to genetic background, housing environment, and vendor source. Additionally, although the microbiome exhibits a robust response to external stimuli, it rapidly returns to its original steady state after a disturbance, making it difficult to sustain controlled changes in the microbiome over time periods required to detect alterations in bone remodeling, mass, or structure. Despite these challenges, an understanding of the mechanisms by which the gut microbiome affects bone has the potential to provide insights into the dissociation between fracture risk and bone mineral density in patients including those with obesity, diabetes, or inflammatory bowel disease. In addition, alteration of the gut microbiome has the potential to serve as a biomarker of bone metabolic activity as well as a target for therapies to improve bone structure and quality using pharmaceutical agents or pre- or probiotics. © 2016 American

  8. Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout

    PubMed Central

    Rajan, Sudarsan; Pena, James R.; Jegga, Anil G.; Aronow, Bruce J.; Wolska, Beata M.

    2013-01-01

    Familial hypertrophic cardiomyopathy (FHC) is a disease characterized by ventricular hypertrophy, fibrosis, and aberrant systolic and/or diastolic function. Our laboratories have previously developed two mouse models that affect cardiac performance. One mouse model encodes an FHC-associated mutation in α-tropomyosin: Glu → Gly at amino acid 180, designated as Tm180. These mice display a phenotype that is characteristic of FHC, including severe cardiac hypertrophy with fibrosis and impaired physiological performance. The other model was a gene knockout of phospholamban (PLN KO), a regulator of calcium uptake in the sarcoplasmic reticulum of cardiomyocytes; these hearts exhibit hypercontractility with no pathological abnormalities. Previous work in our laboratories shows that when mice were genetically crossed between the PLN KO and Tm180, the progeny (PLN KO/Tm180) display a rescued hypertrophic phenotype with improved morphology and cardiac function. To understand the changes in gene expression that occur in these models undergoing cardiac remodeling (Tm180, PLN KO, PLN KO/Tm180, and nontransgenic control mice), we conducted microarray analyses of left ventricular tissue at 4 and 12 mo of age. Expression profiling reveals that 1,187 genes changed expression in direct response to the three genetic models. With these 1,187 genes, 11 clusters emerged showing normalization of transcript expression in the PLN KO/Tm180 hearts. In addition, 62 transcripts are highly involved in suppression of the hypertrophic phenotype. Confirmation of the microarray analysis was conducted by quantitative RT-PCR. These results provide insight into genes that alter expression during cardiac remodeling and are active during modulation of the cardiomyopathic phenotype. PMID:23800848

  9. 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

  10. Glycosphingolipid synthesis inhibition limits osteoclast activation and myeloma bone disease

    PubMed Central

    Ersek, Adel; Xu, Ke; Antonopoulos, Aristotelis; Butters, Terry D.; Santo, Ana Espirito; Vattakuzhi, Youridies; Williams, Lynn M.; Goudevenou, Katerina; Danks, Lynett; Freidin, Andrew; Spanoudakis, Emmanouil; Parry, Simon; Papaioannou, Maria; Hatjiharissi, Evdoxia; Chaidos, Aristeidis; Alonzi, Dominic S.; Twigg, Gabriele; Hu, Ming; Dwek, Raymond A.; Haslam, Stuart M.; Roberts, Irene; Dell, Anne; Rahemtulla, Amin; Horwood, Nicole J.; Karadimitris, Anastasios

    2015-01-01

    Glycosphingolipids (GSLs) are essential constituents of cell membranes and lipid rafts and can modulate signal transduction events. The contribution of GSLs in osteoclast (OC) activation and osteolytic bone diseases in malignancies such as the plasma cell dyscrasia multiple myeloma (MM) is not known. Here, we tested the hypothesis that pathological activation of OCs in MM requires de novo GSL synthesis and is further enhanced by myeloma cell–derived GSLs. Glucosylceramide synthase (GCS) inhibitors, including the clinically approved agent N-butyl-deoxynojirimycin (NB-DNJ), prevented OC development and activation by disrupting RANKL-induced localization of TRAF6 and c-SRC into lipid rafts and preventing nuclear accumulation of transcriptional activator NFATc1. GM3 was the prevailing GSL produced by patient-derived myeloma cells and MM cell lines, and exogenous addition of GM3 synergistically enhanced the ability of the pro-osteoclastogenic factors RANKL and insulin-like growth factor 1 (IGF-1) to induce osteoclastogenesis in precursors. In WT mice, administration of GM3 increased OC numbers and activity, an effect that was reversed by treatment with NB-DNJ. In a murine MM model, treatment with NB-DNJ markedly improved osteolytic bone disease symptoms. Together, these data demonstrate that both tumor-derived and de novo synthesized GSLs influence osteoclastogenesis and suggest that NB-DNJ may reduce pathological OC activation and bone destruction associated with MM. PMID:25915583

  11. AMPK Activation by Metformin Suppresses Abnormal Extracellular Matrix Remodeling in Adipose Tissue and Ameliorates Insulin Resistance in Obesity.

    PubMed

    Luo, Ting; Nocon, Allison; Fry, Jessica; Sherban, Alex; Rui, Xianliang; Jiang, Bingbing; Xu, X Julia; Han, Jingyan; Yan, Yun; Yang, Qin; Li, Qifu; Zang, Mengwei

    2016-08-01

    Fibrosis is emerging as a hallmark of metabolically dysregulated white adipose tissue (WAT) in obesity. Although adipose tissue fibrosis impairs adipocyte plasticity, little is known about how aberrant extracellular matrix (ECM) remodeling of WAT is initiated during the development of obesity. Here we show that treatment with the antidiabetic drug metformin inhibits excessive ECM deposition in WAT of ob/ob mice and mice with diet-induced obesity, as evidenced by decreased collagen deposition surrounding adipocytes and expression of fibrotic genes including the collagen cross-linking regulator LOX Inhibition of interstitial fibrosis by metformin is likely attributable to the activation of AMPK and the suppression of transforming growth factor-β1 (TGF-β1)/Smad3 signaling, leading to enhanced systemic insulin sensitivity. The ability of metformin to repress TGF-β1-induced fibrogenesis is abolished by the dominant negative AMPK in primary cells from the stromal vascular fraction. TGF-β1-induced insulin resistance is suppressed by AMPK agonists and the constitutively active AMPK in 3T3L1 adipocytes. In omental fat depots of obese humans, interstitial fibrosis is also associated with AMPK inactivation, TGF-β1/Smad3 induction, aberrant ECM production, myofibroblast activation, and adipocyte apoptosis. Collectively, integrated AMPK activation and TGF-β1/Smad3 inhibition may provide a potential therapeutic approach to maintain ECM flexibility and combat chronically uncontrolled adipose tissue expansion in obesity. PMID:27207538

  12. Crosstalk between cartilage and bone: when bone cytokines matter.

    PubMed

    Funck-Brentano, Thomas; Cohen-Solal, Martine

    2011-04-01

    The cartilage damage which characterizes osteoarthritis is often accompanied by bone lesions. Joint integrity results from the balance in the physiological interactions between bone and cartilage. Several local factors regulate the physiological remodeling of cartilage, the disequilibrium of these leading to a higher cartilage catabolism. Several cytokines secreted by bone cells can induce chondrocyte differentiation, which suggests their role in the dialogue between both cells. Accumulative in vivo evidence shows that increased bone resorption occurs at an early stage in the development of osteoarthritis and that blocking bone-resorbing cytokines prevents cartilage damage, confirming the role of bone factors in the crosstalk of both tissues. Recently, molecules of the Wnt pathway have emerged as key regulators of bone and cartilage. Activation of Wnt/βcatenin induces an imbalance in cartilage homeostasis, and agonists/antagonists of Wnt are potential candidates for this interaction. This review will summarize what is known about the contribution of bone cytokines to the physiological remodeling of cartilage and in the pathophysiology of osteoarthritis. PMID:21596615

  13. Effect of acceleration on osteoblastic and osteoclastic activities: Analysis of bone metabolism using goldfish scale as a model for bone

    NASA Astrophysics Data System (ADS)

    Suzuki, S.; Kitamura, K.; Nemoto, N.; Shimizu, S.; Wada, W.; Kondo, K.; Tabata, T.; Sodeyama, S.; Ijiri, I.; Hattori, H.

    It is well known that hypo-gravity and hyper-gravity influence bone metabolism However basic data concerning the mechanism are a few because no in vitro model system of human bone is available Human bone consists of osteoblasts osteoclasts and the bone matrix No technique for the co-culture of these components has ever been developed Fish scale is a calcified tissue that contains osteoblasts osteoclasts and bone matrix all of which are similar to those found in human bone Recently we developed a new in vitro model system using goldfish scale This system can simultaneously detect the activities of both scale osteoclasts and osteoblasts with tartrate-resistant acid phosphatase and alkaline phosphatase as the respective markers Using this system we analyzed the bone metabolism under acceleration with a custom-made G-load apparatus Osteoclastic activity in the goldfish scales was suppressed under low-acceleration 0 5-G while osteoblastic activity did not change under this acceleration Under high-acceleration 6-G however the osteoblastic activity of the scales increased In addition the osteoclastic activity of the scales decreased These results suggest that both osteoblastic and osteoclastic activities are regulated by the strength of acceleration Therefore we strongly believe that our in vitro system is useful for analysis of bone metabolism under acceleration

  14. Physical activity completed when young has residual bone benefits at 94 years of age: a within-subject controlled case study

    PubMed Central

    Warden, Stuart J.; Mantila Roosa, Sara M.

    2014-01-01

    Physical activity is recommended for skeletal health because bones adapt to mechanical loading. The young skeleton shows greatest plasticity to physical activity-related mechanical loads, but bones are most at risk of failure later in life. The discrepancy raises the question of whether the skeletal benefits of physical activity completed when young persist with aging. Here we present a unique case wherein the cortical bone benefit of physical activity completed over five decades earlier could be established within an individual aged in their tenth decade of life. Specifically, we compared bone properties at the midshaft humerus between the throwing and nonthrowing arms of a 94-year-old former Major League Baseball player who ceased throwing 55 years earlier. By performing analyses within-subject, the long-term skeletal benefit of physical activity completed when young could be assessed independent of inherited and systemic traits. Also, as the subject threw left-handed during his throwing career, but was right-hand dominant in all other activities throughout life, any lasting skeletal benefits in favor of the throwing arm could not be attributable to simple arm dominance. Analyses indicated that any cortical bone mass, area and thickness benefits of throwing-related physical activity completed when young were lost with aging, possibly due to accelerated intracortical remodeling. In contrast, the subject’s throwing (nondominant) arm had greater total cross-sectional area and estimated strength (polar moment of inertia) than in his dominant arm, despite muscle indices favoring the latter. These data indicate that physical activity completed when young can have lasting benefits on bone size and strength, independent of the maintenance of bone mass benefits. PMID:24879028

  15. A novel peptide-modified and gene-activated biomimetic bone matrix accelerating bone regeneration.

    PubMed

    Pan, Haitao; Zheng, Qixin; Yang, Shuhua; Guo, Xiaodong; Wu, Bin; Zou, Zhenwei; Duan, Zhixia

    2014-08-01

    The osteogenic differentiation of bone marrow stromal cells (BMSCs) can be regulated by systemic or local growth factor, especially by transforming growth factor beta 1 (TGF-β1). However, how to maintain the bioactivity of exogenous TGF-β1 is a great challenge due to its short half-life time. The most promising solution is to transfer TGF-β1 gene into seed cells through transgenic technology and then transgenic cells to continuously secret endogenous TGF-β1 protein via gene expression. In this study, a novel non-viral vector (K)16GRGDSPC was chemically linked to bioactive bone matrices PLGA-[ASP-PEG]n using cross-linker to construct a novel non-viral gene transfer system. TGF-β1 gene was incubated with this system and subsequently rabbit-derived BMSCs were co-cultured with this gene-activated PLGA-[ASP-PEG]n, while co-cultured with PLGA-[ASP-PEG]n modified with (K)16GRGDSPC only and original PLGA-[ASP-PEG]n as control. Thus we fabricated three kinds of composites: Group A (BMSCs-TGF-β1DNA-(K)16GRGDSPC-PLGA-[ASP-PEG]n composite); Group B (BMSCs-(K)16GRGDSPC-PLGA-[ASP-PEG]n composite); and Group C (BMSCs-PLGA-[ASP-PEG]n composite). TGF-β1 and other osteogenic phenotype markers of alkaline phosphatase, osteocalcin, osteopontin and type I collagen in Group A were all significantly higher than the other two groups ex vivo. In vivo, 15-mm long segmental rabbit bone defects were created and randomly implanted the aforementioned composites separately, and then fixed with plate-screws. The results demonstrated that the implants in Group A significantly accelerated bone regeneration compared with the other implants based on X-rays, histological and biomechanical examinations. Therefore, we conclude this novel peptide-modified and gene-activated biomimetic bone matrix of TGF-β1DNA-(K)16GRGDSPC-PLGA-[ASP-PEG]n is a very promising scaffold biomaterial for accelerating bone regeneration. PMID:24115366

  16. The osteoimmunology of alveolar bone loss.

    PubMed

    Tompkins, Kevin A

    2016-03-01

    The mineralized structure of bone undergoes constant remodeling by the balanced actions of bone-producing osteoblasts and bone-resorbing osteoclasts (OCLs). Physiologic bone remodeling occurs in response to the body's need to respond to changes in electrolyte levels, or mechanical forces on bone. There are many pathological conditions, however, that cause an imbalance between bone production and resorption due to excessive OCL action that results in net bone loss. Situations involving chronic or acute inflammation are often associated with net bone loss, and research into understanding the mechanisms regulating this bone loss has led to the development of the field of osteoimmunology. It is now evident that the skeletal and immune systems are functionally linked and share common cells and signaling molecules. This review discusses the signaling system of immune cells and cytokines regulating aberrant OCL differentiation and activity. The role of these cells and cytokines in the bone loss occurring in periodontal disease (PD) (chronic inflammation) and orthodontic tooth movement (OTM) (acute inflammation) is then described. The review finishes with an exploration of the emerging role of Notch signaling in the development of the immune cells and OCLs that are involved in osteoimmunological bone loss and the research into Notch signaling in OTM and PD. PMID:26950207

  17. The IKAROS Interaction with a Complex Including Chromatin Remodeling and Transcription Elongation Activities Is Required for Hematopoiesis

    PubMed Central

    Bottardi, Stefania; Mavoungou, Lionel; Pak, Helen; Daou, Salima; Bourgoin, Vincent; Lakehal, Yahia A.; Affar, El Bachir; Milot, Eric

    2014-01-01

    IKAROS is a critical regulator of hematopoietic cell fate and its dynamic expression pattern is required for proper hematopoiesis. In collaboration with the Nucleosome Remodeling and Deacetylase (NuRD) complex, it promotes gene repression and activation. It remains to be clarified how IKAROS can support transcription activation while being associated with the HDAC-containing complex NuRD. IKAROS also binds to the Positive-Transcription Elongation Factor b (P-TEFb) at gene promoters. Here, we demonstrate that NuRD and P-TEFb are assembled in a complex that can be recruited to specific genes by IKAROS. The expression level of IKAROS influences the recruitment of the NuRD-P-TEFb complex to gene regulatory regions and facilitates transcription elongation by transferring the Protein Phosphatase 1α (PP1α), an IKAROS-binding protein and P-TEFb activator, to CDK9. We show that an IKAROS mutant that is unable to bind PP1α cannot sustain gene expression and impedes normal differentiation of IkNULL hematopoietic progenitors. Finally, the knock-down of the NuRD subunit Mi2 reveals that the occupancy of the NuRD complex at transcribed regions of genes favors the relief of POL II promoter-proximal pausing and thereby, promotes transcription elongation. PMID:25474253

  18. A p21-activated kinase (PAK1) signaling cascade coordinately regulates F-actin remodeling and insulin granule exocytosis in pancreatic β cells

    PubMed Central

    Kalwat, Michael A.; Yoder, Stephanie M.; Wang, Zhanxiang; Thurmond, Debbie C.

    2012-01-01

    Human islet studies implicate an important signaling role for the Cdc42 effector protein p21-activated kinase (PAK1) in the sustained/second-phase of insulin secretion. Because human islets from type 2 diabetic donors lack ~80% of normal PAK1 protein levels, the mechanistic requirement for PAK1 signaling in islet function was interrogated. Similar to MIN6 β cells, human islets elicited glucose-stimulated PAK1 activation that was sensitive to the PAK1 inhibitor, IPA3. Given that sustained insulin secretion has been correlated with glucose-induced filamentous actin (F-actin) remodeling, we tested the hypothesis that a Cdc42-activated PAK1 signaling cascade is required to elicit F-actin remodeling to mobilize granules to the cell surface. Live-cell imaging captured the glucose-induced cortical F-actin remodeling in MIN6 β cells; IPA3-mediated inhibition of PAK1 abolished this remodeling. IPA3 also ablated glucose-stimulated insulin granule accumulation at the plasma membrane, consistent with its role in sustained/second-phase insulin release. Both IPA3 and a selective inhibitor of the Cdc42 GTPase, ML-141, blunted the glucose-stimulated activation of Raf-1, suggesting Raf-1 to be downstream of Cdc42→PAK1. IPA3 also inhibited MEK1/2 activation, implicating the MEK1/2→ERK1/2 cascade to occur downstream of PAK1. Importantly, PD0325901, a new selective inhibitor of MEK1/2→ERK1/2 activation, impaired F-actin remodeling and the sustained/amplification pathway of insulin release. Taken together, these data suggest that glucose-mediated activation of Cdc42 leads to activation of PAK1 and prompts activation of its downstream targets Raf-1, MEK1/2 and ERK1/2 to elicit F-actin remodeling and recruitment of insulin granules to the plasma membrane to support the sustained phase of insulin release. PMID:23246867

  19. A unique nucleosome arrangement, maintained actively by chromatin remodelers facilitates transcription of yeast tRNA genes

    PubMed Central

    2013-01-01

    Background RNA polymerase (pol) III transcribes a unique class of genes with intra-genic promoters and high transcriptional activity. The major contributors to the pol III transcriptome, tRNAs genes are found scattered on all chromosomes of yeast. A prototype tDNA of <150 bp length, is generally considered nucleosome-free while some pol III-transcribed genes have been shown to have nucleosome-positioning properties. Results Using high resolution ChIP-chip and ChIP-seq methods, we found several unique features associated with nucleosome profiles on all tRNA genes of budding yeast, not seen on nucleosome-dense counterparts in fission yeast and resting human CD4+ T cells. The nucleosome-free region (NFR) on all but three yeast tDNAs is found bordered by an upstream (US) nucleosome strongly positioned at −140 bp position and a downstream (DS) nucleosome at variable positions with respect to the gene terminator. Perturbation in this nucleosomal arrangement interferes with the tRNA production. Three different chromatin remodelers generate and maintain the NFR by targeting different gene regions. Isw1 localizes to the gene body and makes it nucleosome-depleted, Isw2 maintains periodicity in the upstream nucleosomal array, while RSC targets the downstream nucleosome. Direct communication of pol III with RSC serves as a stress-sensory mechanism for these genes. In its absence, the downstream nucleosome moves towards the gene terminator. Levels of tRNAs from different families are found to vary considerably as different pol III levels are seen even on isogenes within a family. Pol III levels show negative correlation with the nucleosome occupancies on different genes. Conclusions Budding yeast tRNA genes maintain an open chromatin structure, which is not due to sequence-directed nucleosome positioning or high transcription activity of genes. Unlike 5′ NFR on pol II-transcribed genes, the tDNA NFR, which facilitates tDNA transcription, results from action of chromatin

  20. Mathematical approaches to bone reformation phenomena and numerical simulations

    NASA Astrophysics Data System (ADS)

    Matsuura, Yoshinori; Oharu, Shinnosuke; Takata, Takashi; Tamura, Akio

    2003-09-01

    Bone remodeling is metabolism of the bone through repetition of the resorption by osteoclasts and formation by osteoblasts. Osteoblasts produce inorganic calcium phosphate, which is converted to hydroxyapatite, and organic matrix consisting mainly of type I collagen, and then they deposit new bone to the part of the bone resorbed by osteoclasts. Osteoclasts dissociate calcium by secreting acid and degrade organic components by releasing lysosomal enzymes. Moreover, osteocytes in the bone play an important role in sensing various physical loads and conveying signals to activate osteoblasts. These three kinds of cells are linked to each other and perform the bone remodeling. Appropriate parameters representing the states of the bone and marrow are introduced and a mathematical model describing the bone remodeling phenomena is presented. The model involves an interface equation which determines the surface of the bone. The associated discrete model is formulated and its stable solvability is verified. Results of numerical simulations on a computer aided design system are visualized and then compared to clinical bone data. This work may be applied to medical science and in particular to dentistry.

  1. Chronic activation of the low affinity site of β1-adrenoceptors stimulates haemodynamics but exacerbates pressure-overload cardiac remodelling

    PubMed Central

    Kiriazis, Helen; Tugiono, Niquita; Xu, Qi; Gao, Xiao-Ming; Jennings, Nicole L; Ming, Ziqui; Su, Yidan; Klenowski, Paul; Summers, Roger J; Kaumann, Alberto; Molenaar, Peter; Du, Xiao-Jun

    2013-01-01

    BACKGROUND AND PURPOSE The β1-adrenoceptor has at least two binding sites, high and low affinity sites (β1H and β1L, respectively), which mediate cardiostimulation. While β1H-adrenoceptor can be blocked by all clinically used β-blockers, β1L-adrenoceptor is relatively resistant to blockade. Thus, chronic β1L-adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of β1H-adrenoceptors. Hence, it is important to determine the potential significance of β1L-adrenoceptors in vivo, particularly in pathological situations. EXPERIMENTAL APPROACH C57Bl/6 male mice were used. Chronic (4 or 8 weeks) β1L-adrenoceptor activation was achieved by treatment, via osmotic mini pumps, with (-)-CGP12177 (10 mg·kg−1·day−1). Cardiac function was assessed by echocardiography and micromanometry. KEY RESULTS (-)-CGP12177 treatment of healthy mice increased heart rate and left ventricular (LV) contractility. (-)-CGP12177 treatment of mice subjected to transverse aorta constriction (TAC), during weeks 4–8 or 4–12 after TAC, led to a positive inotropic effect and exacerbated fibrogenic signalling while cardiac hypertrophy tended to be more severe. (-)-CGP12177 treatment of mice with TAC also exacerbated the myocardial expression of hypertrophic, fibrogenic and inflammatory genes compared to untreated TAC mice. Washout of (-)-CGP12177 revealed a more pronounced cardiac dysfunction after 12 weeks of TAC. CONCLUSIONS AND IMPLICATIONS β1L-adrenoceptor activation provides functional support to the heart, in both normal and pathological (pressure overload) situations. Sustained β1L-adrenoceptor activation in the diseased heart exacerbates LV remodelling and therefore may promote disease progression from compensatory hypertrophy to heart failure. PMID:23750586

  2. OASIS modulates hypoxia pathway activity to regulate bone angiogenesis

    PubMed Central

    Cui, Min; Kanemoto, Soshi; Cui, Xiang; Kaneko, Masayuki; Asada, Rie; Matsuhisa, Koji; Tanimoto, Keiji; Yoshimoto, Yuki; Shukunami, Chisa; Imaizumi, Kazunori

    2015-01-01

    OASIS/CREB3L1, an endoplasmic reticulum (ER)-resident transcription factor, plays important roles in osteoblast differentiation. In this study, we identified new crosstalk between OASIS and the hypoxia signaling pathway, which regulates vascularization during bone development. RT-PCR and real-time PCR analyses revealed significant decreases in the expression levels of hypoxia-inducible factor-1α (HIF-1α) target genes such as vascular endothelial growth factor A (VEGFA) in OASIS-deficient (Oasis−/−) mouse embryonic fibroblasts. In coimmunoprecipitation experiments, the N-terminal fragment of OASIS (OASIS-N; activated form of OASIS) bound to HIF-1α through the bZIP domain. Luciferase assays showed that OASIS-N promoted the transcription activities of a reporter gene via a hypoxia-response element (HRE). Furthermore, the expression levels of an angiogenic factor Vegfa was decreased in Oasis−/− osteoblasts. Immunostaining and metatarsal angiogenesis assay showed retarded vascularization in bone tissue of Oasis−/− mice. These results suggest that OASIS affects the expression of HIF-1α target genes through the protein interaction with HIF-1α, and that OASIS-HIF-1α complexes may play essential roles in angiogenesis during bone development. PMID:26558437

  3. Top 10 Research Questions Related to Physical Activity and Bone Health in Children and Adolescents

    ERIC Educational Resources Information Center

    Janz, Kathleen F.; Thomas, David Q.; Ford, M. Allison; Williams, Skip M.

    2015-01-01

    Evidence strongly supports a positive, causal effect of physical activity on bone strength and suggests long-term benefits of childhood physical activity to the prevention of osteoporosis. The contribution of healthy bone development in youth is likely to be as important to fracture prevention as the amount of late adulthood bone loss. Families,…

  4. Quantifying Leisure Physical Activity and Its Relation to Bone Density and Strength

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Purpose: Compare three published methods of quantifying physical activity (total activity, peak strain, and bone loading exposure [BLE] scores) and identify their associations with areal bone mineral density (aBMD), volumetric BMD (vBMD), and bone strength. Methods: Postmenopausal women (N = 239; me...

  5. Biomechanical insult switches PEA-15 activity to uncouple its anti-apoptotic function and promote erk mediated tissue remodeling.

    PubMed

    Exler, Rachel E; Guo, Xiaoxin; Chan, Darren; Livne-Bar, Izhar; Vicic, Nevena; Flanagan, John G; Sivak, Jeremy M

    2016-01-15

    Biomechanical insult contributes to many chronic pathological processes, yet the resulting influences on signal transduction mechanisms are poorly understood. The retina presents an excellent mechanotransduction model, as mechanical strain on sensitive astrocytes of the optic nerve head (ONH) is intimately linked to chronic tissue remodeling and excavation by matrix metalloproteinases (MMPs), and apoptotic cell death. However, the mechanism by which these effects are induced by biomechanical strain is unclear. We previously identified the small adapter protein, PEA-15 (phosphoprotein enriched in astrocytes), through proteomic analyses of human ONH astrocytes subjected to pathologically relevant biomechanical insult. Under resting conditions PEA-15 is regulated through phosphorylation of two key serine residues to inhibit extrinsic apoptosis and ERK1/2 signaling. However, we surprisingly observed that biomechanical insult dramatically switches PEA-15 phosphorylation and function to uncouple its anti-apoptotic activity, and promote ERK1/2-dependent MMP-2 and MMP-9 secretion. These results reveal a novel cell autonomous mechanism by which biomechanical strain rapidly modifies this signaling pathway to generate altered tissue injury responses. PMID:26615958

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

    PubMed

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

    2008-02-01

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

  7. Integrin-extracellular matrix interactions in connective tissue remodeling and osteoblast differentiation

    NASA Technical Reports Server (NTRS)

    Globus, R. K.; Moursi, A.; Zimmerman, D.; Lull, J.; Damsky, C.

    1995-01-01

    The differentiaton of bone cells is a complex multistep process. Bone is somewhat unusual in that it is very actively and continually remodeled in the adult and that maintenance of its mass in the mature organism is exquisitely sensitive to mechanical as well as chemical signals. Bone is also unique because it consists of a very large amount of extracellular matrix (ECM) that is mineralized. The integrin family of ECM receptors has been shown to play an important role in tissue morphogenesis in several systems. Our studies on the regulation of matrix remodeling enzymes by integrins in rabbit synovial fibroblasts show that two b1 integrin fibronectin (FN) receptor complexes (alpha 5 beta 1 and alpha 4 beta 1) cooperate in detecting subtle changes in the composition of the ECM. As a result of signal transduction by these integrins, the levels of mRNA and protein for several members of the metalloproteinase family are regulated in these cells. We have also used antibody and RGD peptide perturbation studies to determine the significance of cell/ECM interactions to normal osteogenesis. We found that interactions between the cell binding domain of FN and integrins are required for both normal morphogenesis and gene expression in cultured osteoblasts that differentiate to form bone-like tissue in culture. These data lead us to propose that beta 1 integrins play an important role in osteoblast differentiation as well as in bone remodeling.

  8. Evolution of a designed retro-aldolase leads to complete active site remodeling

    PubMed Central

    Giger, Lars; Caner, Sami; Obexer, Richard; Kast, Peter; Baker, David; Ban, Nenad; Hilvert, Donald

    2013-01-01

    Evolutionary advances are often fueled by unanticipated innovation. Directed evolution of a computationally designed enzyme suggests that dramatic molecular changes can also drive the optimization of primitive protein active sites. The specific activity of an artificial retro-aldolase was boosted >4,400 fold by random mutagenesis and screening, affording catalytic efficiencies approaching those of natural enzymes. However, structural and mechanistic studies reveal that the engineered catalytic apparatus, consisting of a reactive lysine and an ordered water molecule, was unexpectedly abandoned in favor of a new lysine residue in a substrate binding pocket created during the optimization process. Structures of the initial in silico design, a mechanistically promiscuous intermediate, and one of the most evolved variants highlight the importance of loop mobility and supporting functional groups in the emergence of the new catalytic center. Such internal competition between alternative reactive sites may have characterized the early evolution of many natural enzymes. PMID:23748672

  9. Promotion of the induction of cell pluripotency through metabolic remodeling by thyroid hormone triiodothyronine-activated PI3K/AKT signal pathway

    PubMed Central

    Chen, Mengfei; Zhang, He; Wu, Jie; Xu, Liang; Xu, Di; Sun, Jinglan; He, Yixin; Zhou, Xin; Wang, Zhaojing; Wu, Lifang; Xu, Shaokun; Wang, Jinsong; Jiang, Shu; Zhou, Xiangjun; Hoffman, Andrew R.; Hu, Xiang; Hu, Jifan; Li, Tao

    2012-01-01

    Generation of induced pluripotent stem cells (iPSCs) from somatic cells by defined factors is a mechanism-unknown, yet extremely time-consuming process. Inefficient reprogramming leads to prolonged periods of in vitro iPSC selection, resulting in subtle genetic and epigenetic abnormalities. To facilitate pluripotent reprogramming, we have identified the thyroid hormone triiodothyronine (T3) as an endogenous factor that can enhance reprogramming of human dermal fibroblasts (HDF) and umbilical cord mesenchymal stem cells (UCMSC). This potentiation of iPSC induction is associated with metabolic remodeling activity, including up-regulation of key glycolytic genes, an increase in cell proliferation, and the induction of mesenchymal-epithelial transition (MET). We further identify the activation of the PI3K/AKT signal pathway by T3 as an underlying mechanism for the enhanced conversion to cell pluripotency in this model. These studies demonstrate that T3 enhances metabolic remodeling of donor cells in potentiating cell reprogramming. PMID:22575839

  10. Bone formation: roles of genistein and daidzein

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bone remodeling consists of a balance between bone formation by osteoblasts and bone resorption by osteoclasts. Osteoporosis is the result of increased bone resorption and decreased bone formation causing a decreased bone mass density, loss of bone microarchitecture, and an increased risk of fractu...

  11. Biocomposite macroporous cryogels as potential carrier scaffolds for bone active agents augmenting bone regeneration.

    PubMed

    Raina, Deepak Bushan; Isaksson, Hanna; Teotia, Arun Kumar; Lidgren, Lars; Tägil, Magnus; Kumar, Ashok

    2016-08-10

    Osteoinduction can be enhanced by combining scaffolds with bone morphogenic protein-2 (BMP-2). However, BMP's are known to also cause bone resorption. This can be controlled using bisphosphonates like zoledronic acid (ZA). In this study, we produced two different scaffolds containing silk-fibroin, chitosan, agarose and hydroxyapatite (HA) with and without bioactive glass. The aims of the study were to fabricate, physico-chemically characterize and evaluate the carrier properties of the scaffolds for recombinant human BMP-2 (rhBMP-2) and ZA. Scaffolds were characterized using various methods to confirm their composition. During cell-material interactions, both scaffolds exhibited gradual but sustained proliferation of both C2C12 and MSCs for a period of 6weeks with augmentative effects on their phenotype indicated by elevated levels of alkaline phosphatase (ALP) cuing towards osteogenic differentiation. In-vitro effects of rhBMP-2 and ZA contained within both the scaffolds was assessed on MC3T3 preosteoblast cells and the results show a significant increase in the ALP activity of the cells seeded on scaffolds with rhBMP-2. Further, the scaffold with both HA and bioactive glass was considered for the animal study. In-vitro, this scaffold released nearly 25% rhBMP-2 in 21-days and the addition of ZA did not affect the release. In the animal study, the scaffolds were combined with rhBMP-2 and ZA, rhBMP-2 or implanted alone in an ectopic muscle pouch model. Significantly higher bone formation was observed in the scaffold loaded with both rhBMP-2 and ZA as seen from micro-computed tomography, histomorphometry and energy dispersive X-ray spectroscopy. PMID:27252151

  12. Thermally Induced Osteocyte Damage Initiates a Remodelling Signaling Cascade

    PubMed Central

    Dolan, Eimear B.; McNamara, Laoise M.

    2015-01-01

    Thermal elevations experienced by bone during orthopaedic procedures, such as cutting and drilling, exothermal reactions from bone cement, and thermal therapies such as tumor ablation, can result in thermal damage leading to death of native bone cells (osteocytes, osteoblasts, osteoclasts and mesenchymal stem cells). Osteocytes are believed to be the orchestrators of bone remodeling, which recruit nearby osteoclast and osteoblasts to control resorption and bone growth in response to mechanical stimuli and physical damage. However, whether heat-induced osteocyte damage can directly elicit bone remodelling has yet to be determined. This study establishes the link between osteocyte thermal damage and the remodeling cascade. We show that osteocytes directly exposed to thermal elevations (47°C for 1 minute) become significantly apoptotic and alter the expression of osteogenic genes (Opg and Cox2). The Rankl/Opg ratio is consistently down-regulated, at days 1, 3 and 7 in MLO-Y4s heat-treated to 47°C for 1 minute. Additionally, the pro-osteoblastogenic signaling marker Cox2 is significantly up-regulated in heat-treated MLO-Y4s by day 7. Furthermore, secreted factors from heat-treated MLO-Y4s administered to MSCs using a novel co-culture system are shown to activate pre-osteoblastic MSCs to increase production of the pro-osteoblastic differentiation marker, alkaline phosphatase (day 7, 14), and calcium deposition (day 21). Most interestingly, an initial pro-osteoclastogenic signaling response (increase Rankl and Rankl/Opg ratio at day 1) followed by later stage pro-osteoblastogenic signaling (down-regulation in Rankl and the Rankl/Opg ratio and an up-regulation in Opg and Cox2 by day 7) was observed in non-heat-treated MLO-Y4s in co-culture when these were exposed to the biochemicals produced by heat-treated MLO-Y4s. Taken together, these results elucidate the vital role of osteocytes in detecting and responding to thermal damage by means of thermally induced apoptosis

  13. Thermally induced osteocyte damage initiates a remodelling signaling cascade.

    PubMed

    Dolan, Eimear B; Haugh, Matthew G; Voisin, Muriel C; Tallon, David; McNamara, Laoise M

    2015-01-01

    Thermal elevations experienced by bone during orthopaedic procedures, such as cutting and drilling, exothermal reactions from bone cement, and thermal therapies such as tumor ablation, can result in thermal damage leading to death of native bone cells (osteocytes, osteoblasts, osteoclasts and mesenchymal stem cells). Osteocytes are believed to be the orchestrators of bone remodeling, which recruit nearby osteoclast and osteoblasts to control resorption and bone growth in response to mechanical stimuli and physical damage. However, whether heat-induced osteocyte damage can directly elicit bone remodelling has yet to be determined. This study establishes the link between osteocyte thermal damage and the remodeling cascade. We show that osteocytes directly exposed to thermal elevations (47°C for 1 minute) become significantly apoptotic and alter the expression of osteogenic genes (Opg and Cox2). The Rankl/Opg ratio is consistently down-regulated, at days 1, 3 and 7 in MLO-Y4s heat-treated to 47°C for 1 minute. Additionally, the pro-osteoblastogenic signaling marker Cox2 is significantly up-regulated in heat-treated MLO-Y4s by day 7. Furthermore, secreted factors from heat-treated MLO-Y4s administered to MSCs using a novel co-culture system are shown to activate pre-osteoblastic MSCs to increase production of the pro-osteoblastic differentiation marker, alkaline phosphatase (day 7, 14), and calcium deposition (day 21). Most interestingly, an initial pro-osteoclastogenic signaling response (increase Rankl and Rankl/Opg ratio at day 1) followed by later stage pro-osteoblastogenic signaling (down-regulation in Rankl and the Rankl/Opg ratio and an up-regulation in Opg and Cox2 by day 7) was observed in non-heat-treated MLO-Y4s in co-culture when these were exposed to the biochemicals produced by heat-treated MLO-Y4s. Taken together, these results elucidate the vital role of osteocytes in detecting and responding to thermal damage by means of thermally induced apoptosis

  14. New Mechanism of Bone Cancer Pain: Tumor Tissue-Derived Endogenous Formaldehyde Induced Bone Cancer Pain via TRPV1 Activation.

    PubMed

    Wan, You

    2016-01-01

    In recent years, our serial investigations focused on the role of cancer cells-derived endogenous formaldehyde in bone cancer pain. We found that cancer cells produced formaldehyde through demethylation process by serine hydroxymethyltransferase (SHMT1 and SHMT2) and lysine-specific histone demethylase 1 (LSD1). When the cancer cells metastasized into bone marrow, the elevated endogenous formaldehyde induced bone cancer pain through activation on the transient receptor potential vanilloid subfamily member 1 (TRPV1) in the peripheral nerve fibers. More interestingly, TRPV1 expressions in the peripheral fibers were upregulated by the local insulin-like growth factor I (IGF-I) produced by the activated osteoblasts. In conclusion, tumor tissue-derived endogenous formaldehyde induced bone cancer pain via TRPV1 activation. PMID:26900062

  15. Adipogenic role of alternatively activated macrophages in β-adrenergic remodeling of white adipose tissue.

    PubMed

    Lee, Yun-Hee; Kim, Sang-Nam; Kwon, Hyun-Jung; Maddipati, Krishna Rao; Granneman, James G

    2016-01-01

    De novo brown adipogenesis involves the proliferation and differentiation of progenitors, yet the mechanisms that guide these events in vivo are poorly understood. We previously demonstrated that treatment with a β3-adrenergic receptor (ADRB3) agonist triggers brown/beige adipogenesis in gonadal white adipose tissue following adipocyte death and clearance by tissue macrophages. The close physical relationship between adipocyte progenitors and tissue macrophages suggested that the macrophages that clear dying adipocytes might generate proadipogenic factors. Flow cytometric analysis of macrophages from mice treated with CL 316,243 identified a subpopulation that contained elevated lipid and expressed CD44. Lipidomic analysis of fluorescence-activated cell sorting-isolated macrophages demonstrated that CD44+ macrophages contained four- to five-fold higher levels of the endogenous peroxisome-proliferator activated receptor gamma (PPARγ) ligands 9-hydroxyoctadecadienoic acid (HODE), and 13-HODE compared with CD44- macrophages. Gene expression profiling and immunohistochemistry demonstrated that ADRB3 agonist treatment upregulated expression of ALOX15, the lipoxygenase responsible for generating 9-HODE and 13-HODE. Using an in vitro model of adipocyte efferocytosis, we found that IL-4-primed tissue macrophages accumulated lipid from dying fat cells and upregulated expression of Alox15. Furthermore, treatment of differentiating adipocytes with 9-HODE and 13-HODE potentiated brown/beige adipogenesis. Collectively, these data indicate that noninflammatory removal of adipocyte remnants and coordinated generation of PPARγ ligands by M2 macrophages provides localized adipogenic signals to support de novo brown/beige adipogenesis. PMID:26538237

  16. Synthetic remodeling of the chartreusin pathway to tune antiproliferative and antibacterial activities.

    PubMed

    Ueberschaar, Nico; Xu, Zhongli; Scherlach, Kirstin; Metsä-Ketelä, Mikko; Bretschneider, Tom; Dahse, Hans-Martin; Görls, Helmar; Hertweck, Christian

    2013-11-20

    Natural products of the benzonaphthopyranone class, such as chartreusin, elsamicin A, gilvocarcin, and polycarcin, represent potent leads for urgently needed anticancer therapeutics and antibiotics. Since synthetic protocols for altering their architectures are limited, we harnessed enzymatic promiscuity to generate a focused library of chartreusin derivatives. Pathway engineering of the chartreusin polyketide synthase, mutational synthesis, and molecular modeling were employed to successfully tailor the structure of chartreusin. For the synthesis of the aglycones, improved synthetic avenues to substituted coumarin building blocks were established. Using an engineered mutant, in total 11 new chartreusin analogs (desmethyl, methyl, ethyl, vinyl, ethynyl, bromo, hydroxy, methoxy, and corresponding (1→2) abeo-chartreusins) were generated and fully characterized. Their biological evaluation revealed an unexpected impact of the ring substituents on antiproliferative and antibacterial activities. Irradiation of vinyl- and ethynyl-substituted derivatives with blue light resulted in an improved antiproliferative potency against a colorectal cancer cell line. In contrast, the replacement of a methyl group by hydrogen caused a drastically decreased cytotoxicity but markedly enhanced antimycobacterial activity. Furthermore, mutasynthesis of bromochartreusin led to the first crystal structure of a chartreusin derivative that is not modified in the glycoside residue. Beyond showcasing the possibility of converting diverse, fully synthetic polyphenolic aglycones into the corresponding glycosides in a whole-cell approach, this work identified new chartreusins with fine-tuned properties as promising candidates for further development as therapeutics. PMID:24143864

  17. Chloroplast Membrane Remodeling during Freezing Stress Is Accompanied by Cytoplasmic Acidification Activating SENSITIVE TO FREEZING2.

    PubMed

    Barnes, Allison C; Benning, Christoph; Roston, Rebecca L

    2016-07-01

    Low temperature is a seasonal abiotic stress that restricts native plant ranges and crop distributions. Two types of low-temperature stress can be distinguished: chilling and freezing. Much work has been done on the mechanisms by which chilling is sensed, but relatively little is known about how plants sense freezing. Recently, Arabidopsis (Arabidopsis thaliana) SENSITIVE TO FREEZING2 (SFR2) was identified as a protein that responds in a nontranscriptional manner to freezing. Here, we investigate the cellular conditions that allow SFR2 activation. Using a combination of isolated organelle, whole-tissue, and whole-plant assays, we provide evidence that SFR2 is activated by changes in cytosolic pH and Mg(2+) Manipulation of pH and Mg(2+) in cold-acclimated plants is shown to cause changes similar to those of freezing. We conclude that pH and Mg(2+) are perceived as intracellular cues as part of the sensing mechanism for freezing conditions. This evidence provides a specific molecular mechanism to combat freezing. PMID:27233750

  18. Endothelial Msx1 transduces hemodynamic changes into an arteriogenic remodeling response

    PubMed Central

    Vandersmissen, Ine; Craps, Sander; Depypere, Maarten; Coppiello, Giulia; van Gastel, Nick; Maes, Frederik; Carmeliet, Geert; Schrooten, Jan; Jones, Elizabeth A.V.; Umans, Lieve; Devlieger, Roland; Koole, Michel; Gheysens, Olivier; Zwijsen, An; Aranguren, Xabier L.

    2015-01-01

    Collateral remodeling is critical for blood flow restoration in peripheral arterial disease and is triggered by increasing fluid shear stress in preexisting collateral arteries. So far, no arterial-specific mediators of this mechanotransduction response have been identified. We show that muscle segment homeobox 1 (MSX1) acts exclusively in collateral arterial endothelium to transduce the extrinsic shear stimulus into an arteriogenic remodeling response. MSX1 was specifically up-regulated in remodeling collateral arteries. MSX1 induction in collateral endothelial cells (ECs) was shear stress driven and downstream of canonical bone morphogenetic protein–SMAD signaling. Flow recovery and collateral remodeling were significantly blunted in EC-specific Msx1/2 knockout mice. Mechanistically, MSX1 linked the arterial shear stimulus to arteriogenic remodeling by activating the endothelial but not medial layer to a proinflammatory state because EC but not smooth muscle cellMsx1/2 knockout mice had reduced leukocyte recruitment to remodeling collateral arteries. This reduced leukocyte infiltration in EC Msx1/2 knockout mice originated from decreased levels of intercellular adhesion molecule 1 (ICAM1)/vascular cell adhesion molecule 1 (VCAM1), whose expression was also in vitro driven by promoter binding of MSX1. PMID:26391659

  19. Intracellular Shigella remodels its LPS to dampen the innate immune recognition and evade inflammasome activation

    PubMed Central

    Paciello, Ida; Silipo, Alba; Lembo-Fazio, Luigi; Curcurù, Laura; Zumsteg, Anna; Noël, Gaëlle; Ciancarella, Valeria; Sturiale, Luisa; Molinaro, Antonio; Bernardini, Maria Lina

    2013-01-01

    LPS is a potent bacterial effector triggering the activation of the innate immune system following binding with the complex CD14, myeloid differentiation protein 2, and Toll-like receptor 4. The LPS of the enteropathogen Shigella flexneri is a hexa-acylated isoform possessing an optimal inflammatory activity. Symptoms of shigellosis are produced by severe inflammation caused by the invasion process of Shigella in colonic and rectal mucosa. Here we addressed the question of the role played by the Shigella LPS in eliciting a dysregulated inflammatory response of the host. We unveil that (i) Shigella is able to modify the LPS composition, e.g., the lipid A and core domains, during proliferation within epithelial cells; (ii) the LPS of intracellular bacteria (iLPS) and that of bacteria grown in laboratory medium differ in the number of acyl chains in lipid A, with iLPS being the hypoacylated; (iii) the immunopotential of iLPS is dramatically lower than that of bacteria grown in laboratory medium; (iv) both LPS forms mainly signal through the Toll-like receptor 4/myeloid differentiation primary response gene 88 pathway; (v) iLPS down-regulates the inflammasome-mediated release of IL-1β in Shigella-infected macrophages; and (vi) iLPS exhibits a reduced capacity to prime polymorfonuclear cells for an oxidative burst. We propose a working model whereby the two forms of LPS might govern different steps of the invasive process of Shigella. In the first phases, the bacteria, decorated with hypoacylated LPS, are able to lower the immune system surveillance, whereas, in the late phases, shigellae harboring immunopotent LPS are fully recognized by the immune system, which can then successfully resolve the infection. PMID:24167293

  20. Expression of peptide fragments from proADM and involvement of mitogen-activated protein kinase signaling pathways in pulmonary remodeling induced by high pulmonary blood flow.

    PubMed

    Li, Wei; Guo, Aili; Wang, Lijuan; Kong, Qingyu; Wang, Rong; Han, Li; Zhao, Cuifen

    2016-01-01

    Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive pulmonary arterial remodeling and right ventricular failure. Despite recent advances in pathophysiological mechanism exploration and new therapeutic approaches, PAH remains a challenging condition. In this study, we investigated the roles of the peptide fragments from proadrenomedullin (proADM) such as adrenomedullin (ADM), adrenotensin (ADT), and proadrenomedullin N-terminal 20 peptide (PAMP) during pulmonary remodeling caused by high pulmonary blood flow, and probed the possible involvement of mitogen-activated protein kinase (MAPK) signal transduction pathways. Sixteen rat models of PAH were artificially established by surgically connecting the left common carotid artery to the external jugular vein. We subcutaneously injected an extracellular signal-regulated protein kinase (ERK1/2) inhibitor, PD98059, in eight rats, treated another eight rats with an equal volume of saline. Eight rats without connections served as the control group. We observed that mRNA expression levels of ADM, stress-activated protein kinase (SAPK), and ERK1/2 were significantly elevated in the shunted rats; furthermore, ERK1/2 levels were significantly inhibited by PD98059. Protein levels of ADM, PAMP, p-SAPK, and p-ERK1/2 were significantly higher ADT was lower, and p-p38 remained unchanged in the rat models compared with the controls. However, the protein expression of both ADM and p-ERK1/2 was significantly inhibited by PD98059. Our results suggest that levels of ADM, ADT, and PAMP respond to pulmonary remodeling, and that activation of the SAPK and ERK1/2 signaling pathways is involved in pulmonary hypertension and artery remodeling caused by high pulmonary blood flow. PMID:25990643

  1. Alterations in calcium homeostasis and bone during actual and simulated space flight.

    PubMed

    Wronski, T J; Morey, E R

    1983-01-01

    The weightlessness experienced in space produces alterations in calcium homeostasis. Gemini, Apollo, and Skylab astronauts exhibited a negative calcium balance due primarily to hypercalciuria. In addition, the bone mineral density of the calcaneus declined by approximately 4% in Skylab crew members after 84 d of orbital flight. The negative calcium balance and loss of calcaneal bone mineral in normal adults subjected to prolonged bed rest was comparable to that observed in space. The pathogenesis of bone loss during space flight and bed rest is not well understood due to the lack of histomorphometric data. It is also uncertain whether osteoporotic changes in astronauts are corrected postflight. The observed bone loss would be reversible and of no long-term consequence if the only abnormality was an increased remodeling rate. However, altered bone cell activity would probably result in irreversible bone loss with the premature development of senile osteoporosis many years after space flight. The main skeletal defect in growing rats placed in orbit aboard Soviet Cosmos biosatellites appears to be diminished bone formation. Bone resorption was not elevated during weightlessness. Although cortical bone returned to normal postflight, the decline in trabecular bone mass was somewhat persistent. These studies established that the modeling of a growing skeleton was altered in a weightless environment, but do not necessarily imply that a remodeling imbalance occurs in adults during space flight. However, various forms of simulated space flight inhibited bone formation during both skeletal modeling and the remodeling of adult bone.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:6645871

  2. PTH signaling mediates perilacunar remodeling during exercise.

    PubMed

    Gardinier, Joseph D; Al-Omaishi, Salam; Morris, Michael D; Kohn, David H

    2016-01-01

    Mechanical loading and release of endogenous parathyroid hormone (PTH) during exercise facilitate the adaptation of bone. However, it remains unclear how exercise and PTH influence the composition of bone and how exercise and PTH-mediated compositional changes influence the mechanical properties of bone. Thus, the primary purpose of this study was to establish compositional changes within osteocytes' perilacunar region of cortical bone following exercise, and evaluate the influence of endogenous PTH signaling on this perilacunar adaptation. Raman spectroscopy, scanning electron microscopy (SEM), and energy dispersive X-ray spectroscopy (EDS) were used to evaluate tissue composition surrounding individual lacuna within the tibia of 19week old male mice exposed to treadmill running for 3weeks. As a result of exercise, tissue within the perilacunar region (within 0-5μm of the lacuna wall) had a lower mineral-to-matrix ratio (MMR) compared to sedentary controls. In addition, exercise also increased the carbonate-to-phosphate ratio (CPR) across both perilacunar and non-perilacunar regions (5-10μm and 10-15μm from the lacuna walls). Tibial post-yield work had a significant negative correlation with perilacunar MMR. Inhibition of PTH activity with PTH(7-34) demonstrated that perilacunar remodeling during exercise was dependent on the cellular response to endogenous PTH. The osteocytes' response to endogenous PTH during exercise was characterized by a significant reduction in SOST expression and significant increase in FGF-23 expression. The potential reduction in phosphate levels due to FGF-23 expression may explain the increase in carbonate substitution. Overall, this is the first study to demonstrate that adaptation in tissue composition is localized around individual osteocytes, may contribute to the changes in whole bone mechanics during exercise, and that PTH signaling during exercise contributes to these adaptations. PMID:26924474

  3. Understanding the local actions of lipids in bone physiology.

    PubMed

    During, Alexandrine; Penel, Guillaume; Hardouin, Pierre

    2015-07-01

    The adult skeleton is a metabolically active organ system that undergoes continuous remodeling to remove old and/or stressed bone (resorption) and replace it with new bone (formation) in order to maintain a constant bone mass and preserve bone strength from micro-damage accumulation. In that remodeling process, cellular balances--adipocytogenesis/osteoblastogenesis and osteoblastogenesis/osteoclastogenesis--are critical and tightly controlled by many factors, including lipids as discussed in the present review. Interest in the bone lipid area has increased as a result of in vivo evidences indicating a reciprocal relationship between bone mass and marrow adiposity. Lipids in bones are usually assumed to be present only in the bone marrow. However, the mineralized bone tissue itself also contains small amounts of lipids which might play an important role in bone physiology. Fatty acids, cholesterol, phospholipids and several endogenous metabolites (i.e., prostaglandins, oxysterols) have been purported to act on bone cell survival and functions, the bone mineralization process, and critical signaling pathways. Thus, they can be regarded as regulatory molecules important in bone health. Recently, several specific lipids derived from membrane phospholipids (i.e., sphingosine-1-phosphate, lysophosphatidic acid and different fatty acid amides) have emerged as important mediators in bone physiology and the number of such molecules will probably increase in the near future. The present paper reviews the current knowledge about: (1°) bone lipid composition in both bone marrow and mineralized tissue compartments, and (2°) local actions of lipids on bone physiology in relation to their metabolism. Understanding the roles of lipids in bone is essential to knowing how an imbalance in their signaling pathways might contribute to bone pathologies, such as osteoporosis. PMID:26118851

  4. Intracoronary infusion of autologous mononuclear cells from bone marrow or G-CSF mobilised apheresis product may not improve remodelling, contractile function, perfusion or infarct size in a swine model of large myocardial infarction

    PubMed Central

    de Silva, Ranil; Raval, Amish N.; Hadi, Mohiuddin; Gildea, Karena M.; Bonifacino, Aylin C.; Yu, Zu-Xi; Yau, Yu Ying; Leitman, Susan F.; Bacharach, Stephen L.; Donahue, Robert E.; Read, Elizabeth J.; Lederman, Robert J.

    2008-01-01

    Background In a blinded, placebo controlled study, we investigated whether intracoronary infusion of autologous mononuclear cells from G-CSF mobilised apheresis product or bone marrow (BM) improved sensitive outcome measures in a swine model of large MI. Methods and Results Four days after LAD occlusion and reperfusion, cells from BM or apheresis product of saline (Placebo) or G-CSF injected animals were infused into the LAD. Large infarcts were created: baseline ejection fraction (EF) by MRI of 35.3 ± 8.5%, no difference between the Placebo, G-CSF and BM groups (p=0.16 by ANOVA). At 6 weeks EF fell to a similar degree in the Placebo, G-CSF and BM groups (−7.9±6.0%, −8.5±8.8% and −10.9±7.6%, p=0.78 by ANOVA). Left ventricular volumes and infarct size by MRI deteriorated similarly in all 3 groups. Quantitative PET demonstrated significant decline in FDG uptake rate in the LAD territory at follow-up, with no histological, angiographic or PET perfusion evidence of functional neovascularisation. Immunofluorescence failed to demonstrate transdifferentiation of infused cells. Conclusion Intracoronary infusion of mononuclear cells from either bone marrow or G-CSF mobilised apheresis product may not improve or limit deterioration in systolic function, adverse ventricular remodelling, infarct size or perfusion in a swine model of large MI. PMID:18502738

  5. Local release of pioglitazone (a peroxisome proliferator-activated receptor γ agonist) accelerates proliferation and remodeling phases of wound healing.

    PubMed

    Sakai, Shigeki; Sato, Keisuke; Tabata, Yasuhiko; Kishi, Kazuo

    2016-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily known for its anti-inflammatory and macrophage differentiation effects, as well as its ability to promote fat cell differentiation and reduce insulin resistance. Pioglitazone (Pio) is a PPARγ agonist used clinically as an anti-diabetic agent for improving insulin sensitivity in patients with diabetes. The objective of this study was to develop a drug delivery system (DDS) for the local release of Pio to promote wound healing. Pio of low aqueous solubility was water-solubilized by micelles formed from gelatin grafted with L-lactic acid oligomers, and incorporated into a biodegradable gelatin hydrogel. An 8-mm punch biopsy tool was used to prepare two skin wounds on either side of the midline of 8-week-old mice. Wounds were treated by the hydrogels with (Pio-hydrogel group) or without (control group) Pio, and the wound area were observed 1, 4, 7, and 14 days after treatment. In addition, a protein assay and immunohistological stain were performed to determine the effects of the Pio-hydrogel on inflammation and macrophage differentiation. The Pio-hydrogels promote wound healing. Moreover, Western blotting analysis demonstrated that treatment with Pio-hydrogels resulted in decreased levels of the cytokines MIP-2 and TGF-β, and increased levels of glucose-regulating adiponectin. It is concluded that Pio-incorporated hydrogels promote the proliferation and remodeling phases of wound healing, and may prove to be effective as wound dressings. PMID:26710090

  6. Thyroid hormone activates Wnt/β-catenin signaling involved in adult epithelial development during intestinal remodeling in Xenopus laevis.

    PubMed

    Hasebe, Takashi; Fujimoto, Kenta; Kajita, Mitsuko; Ishizuya-Oka, Atsuko

    2016-08-01

    During amphibian intestinal remodeling, thyroid hormone (TH) induces some larval epithelial cells to dedifferentiate into adult stem cells, which newly generate the absorptive epithelium analogous to the mammalian epithelium. To clarify molecular mechanisms underlying adult epithelial development, we here focus on TH response genes that are associated with the canonical Wnt pathway. Our quantitative reverse transcription plus polymerase chain reaction and immunohistochemical analyses indicate that all of the genes examined, including β-catenin, c-Myc and secreted frizzle-related protein 2 (SFRP2), are up-regulated in Xenopus laevis intestine during both natural and TH-induced metamorphosis. Moreover, immunoreactivity for nuclear β-catenin becomes detectable in adult stem cells from the start of their appearance and then increases in intensity in adult epithelial primordia derived from the stem cells, which actively proliferate and coexpress Wnt target genes c-Myc and LGR5. These expression profiles strongly suggest the involvement of the canonical Wnt pathway in the maintenance and/or proliferation of adult stem/progenitor cells. More importantly, by using organ cultures of the tadpole intestine, we have experimentally shown that the addition of exogenous SFRP2 protein to the culture medium promotes cell proliferation of the adult epithelial primordia, whereas inhibition of endogenous SFRP2 by its antibody suppresses their proliferation. The inhibition of SFRP2 suppresses larval epithelial changes in shape from simple columnar to stem-cell-like roundish cells, resulting in the failure of epithelial dedifferentiation. Thus, TH-up-regulated SFRP2 in the postembryonic intestine promotes adult stem cell development, possibly by acting as an agonist of both canonical and non-canonical Wnt signaling. PMID:27068920

  7. C/EBPβ and Nuclear Factor of Activated T Cells Differentially Regulate Adamts-1 Induction by Stimuli Associated with Vascular Remodeling

    PubMed Central

    Oller, Jorge; Alfranca, Arántzazu; Méndez-Barbero, Nerea; Villahoz, Silvia; Lozano-Vidal, Noelia; Martín-Alonso, Mara; Arroyo, Alicia G.; Escolano, Amelia; Armesilla, Angel Luis

    2015-01-01

    Emerging evidence indicates that the metalloproteinase Adamts-1 plays a significant role in the pathophysiology of vessel remodeling, but little is known about the signaling pathways that control Adamts-1 expression. We show that vascular endothelial growth factor (VEGF), angiotensin-II, interleukin-1β, and tumor necrosis factor α, stimuli implicated in pathological vascular remodeling, increase Adamts-1 expression in endothelial and vascular smooth muscle cells. Analysis of the intracellular signaling pathways implicated in this process revealed that VEGF and angiotensin-II upregulate Adamts-1 expression via activation of differential signaling pathways that ultimately promote functional binding of the NFAT or C/EBPβ transcription factors, respectively, to the Adamts-1 promoter. Infusion of mice with angiotensin-II triggered phosphorylation and nuclear translocation of C/EBPβ proteins in aortic cells concomitantly with an increase in the expression of Adamts-1, further underscoring the importance of C/EBPβ signaling in angiotensin-II-induced upregulation of Adamts-1. Similarly, VEGF promoted NFAT activation and subsequent Adamts-1 induction in aortic wall in a calcineurin-dependent manner. Our results demonstrate that Adamts-1 upregulation by inducers of pathological vascular remodeling is mediated by specific signal transduction pathways involving NFAT or C/EBPβ transcription factors. Targeting of these pathways may prove useful in the treatment of vascular disease. PMID:26217013

  8. Development of an enzyme-linked immunosorbent assay for detection of chicken osteocalcin and its use in evaluation of perch effects on bone remodeling in caged White Leghorns

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Osteocalcin (OC) is a sensitive biochemical marker for evaluating bone turnover in mammals. The role of avian OC is less clear because of a need for a chicken assay. Our objectives were to develop an assay using indirect competitive ELISA for detecting chicken serum OC and use the assay to examine t...

  9. Grizzly bears (Ursus arctos horribilis) and black bears (Ursus americanus) prevent trabecular bone loss during disuse (hibernation).

    PubMed

    McGee-Lawrence, Meghan E; Wojda, Samantha J; Barlow, Lindsay N; Drummer, Thomas D; Castillo, Alesha B; Kennedy, Oran; Condon, Keith W; Auger, Janene; Black, Hal L; Nelson, O Lynne; Robbins, Charles T; Donahue, Seth W

    2009-12-01

    Disuse typically causes an imbalance in bone formation and bone resorption, leading to losses of cortical and trabecular bone. In contrast, bears maintain balanced intracortical remodeling and prevent cortical bone loss during disuse (hibernation). Trabecular bone, however, is more detrimentally affected than cortical bone in other animal models of disuse. Here we investigated the effects of hibernation on bone remodeling, architectural properties, and mineral density of grizzly bear (Ursus arctos horribilis) and black bear (Ursus americanus) trabecular bone in several skeletal locations. There were no differences in bone volume fraction or tissue mineral density between hibernating and active bears or between pre- and post-hibernation bears in the ilium, distal femur, or calcaneus. Though indices of cellular activity level (mineral apposition rate, osteoid thickness) decreased, trabecular bone resorption and formation indices remained balanced in hibernating grizzly bears. These data suggest that bears prevent bone loss during disuse by maintaining a balance between bone formation and bone resorption, which consequently preserves bone structure and strength. Further investigation of bone metabolism in hibernating bears may lead to the translation of mechanisms preventing disuse-induced bone loss in bears into novel treatments for osteoporosis. PMID:19703606

  10. Structural basis of growth-related gain and age-related loss of bone strength

    PubMed Central

    2008-01-01

    If bone strength was the only requirement of skeleton, it could be achieved with bulk, but bone must also be light. During growth, bone modelling and remodelling optimize strength, by depositing bone where it is needed, and minimize mass, by removing it from where it is not. The population variance in bone traits is established before puberty and the position of an individual's bone size and mass tracks in the percentile of origin. Larger cross-sections have a comparably larger marrow ca