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Results in Journal BoneKEy Reports: 537

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Sandra M Sacco, Caitlin Saint, Amanda B Longo, Charles B Wakefield, Phil L Salmon, Paul J Leblanc,
Published: 13 January 2017
BoneKEy Reports, Volume 6; https://doi.org/10.1038/bonekey.2016.87

The publisher has not yet granted permission to display this abstract.
Gloria Allocca, Anjali P Kusumbe, ,
Published: 7 December 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.84

Abstract:
Confocal and two-photon microscopy has been widely used in bone research to not only produce high quality, three-dimensional images but also to provide valuable structural and quantitative information. In this article, we describe step-by-step protocols for confocal and two-photon microscopy to investigate earlier cellular events during colonisation of cancer cells in bone using xenograft mouse models. This includes confocal/two-photon microscopy imaging of paraformaldehyde fixed thick bone sections and frozen bone samples.
, Greg D Gamble, Ian R Reid
Published: 7 December 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.85

Abstract:
Hyperparathyroidism may be associated with skeletal and cardiovascular abnormalities, but it is unclear whether these associations exist for high-normal levels of parathyroid hormone (PTH). We assessed relationships between PTH and anthropometric, skeletal and cardiometabolic indices in normal men. Body composition, blood pressure, biochemistry and bone mineral density (BMD) were evaluated in 151 healthy men. BMD was reassessed at 2 years, and coronary artery calcium (CAC) was measured at 3.5 years. Relationships between PTH and other baseline characteristics, CAC scores and change in BMD were evaluated. PTH correlated positively with baseline body mass index, fat mass, diastolic blood pressure, triglycerides, total and low-density lipoprotein (LDL) cholesterol, (r=0.19–0.25, P=0.02–0.002), and with category of CAC score. Relationships between PTH and cardiometabolic indices remained significant after adjustment for age, 25-hydroxyvitamin D and estimated glomerular filteration rate. Men in the top PTH tertile (⩾4.4 pmol l−1, n=51) were more likely to have LDL cholesterol ⩾3.5 mmol l−1, diastolic blood pressure ⩾85 mm Hg, and CAC score >0 than men in lower tertiles. PTH was not associated with history of fracture, baseline BMD, or change in BMD over 2 years. In summary, in this cohort of healthy men, PTH levels are linearly related to adiposity and to cardiometabolic indices, but not to BMD or bone loss. These findings suggest that adiposity should be considered as an independent cause of secondary hyperparathyroidism, and they may be relevant to patients with normocalcemic hyperparathyroidism, in whom high PTH levels may be a marker of adiposity and cardiometabolic risk rather than always indicating parathyroid autonomy.
Published: 7 December 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.86

Abstract:
The high incidence of secondary hip fractures and the associated markedly increased mortality call for preventive actions that could help to avoid these injuries. By providing immediate strengthening and not relying on patient compliance, internal prophylactic augmentation of the osteoporotic proximal femur may overcome the main limitations of systemic bone drugs and wearable protective pads. However, such a method would have to provide sufficient and reliable strengthening effect with minimal risks and side effects to justify the need of an invasive treatment. The requirements for an internal reinforcement approach are thus strict and include mechanical, biological, clinical, ethical and financial criteria. Here we first attempt to describe the properties of an ideal augmentation method. Previously published methodologies and techniques developed at our research institute, including approaches using cements, metals, other materials or combined approaches, are then reviewed and evaluated according to these aspects. We conclude that none of the discussed methodologies appears to be able to deliver a sufficiently high gain-versus-risk ratio that could justify the clinical application and thus augmentation of the osteoporotic proximal femur remains a challenge. Finally, we provide suggestions for the development and evaluation of future strategies.
, Nicole Y C Yu, Iman Jalilian, André F Pereira, Ulf R Knothe
Published: 30 November 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.70

The publisher has not yet granted permission to display this abstract.
, Jeffrey L Price
Published: 16 November 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.80

Abstract:
Deletion of proprotein convertase Mbtps1 in bone osteocytes leads to a significant postnatal increase in skeletal muscle size and contractile function, while causing only a 25% increase in stiffness in long bones. Concerns about leakiness in skeletal muscle were discounted since Cre recombinase expression does not account for our findings, and, Mbtps1 protein and mRNA is not deleted. Interestingly, the response of normal skeletal muscle to exercise and the regenerative response of skeletal muscle to the deletion of Mbtps1 in bone share some key regulatory features including a preference for slow twitch muscle fibers. In addition, transcriptional regulators PPAR, PGC-1α, LXR, and repressors DEC1 and DEC2 all occupy central positions within these two pathways. We hypothesize that the age-dependent muscle phenotype in Dmp1-Cre Mbtps1 cKO mice is due to bone→muscle crosstalk. Many of the myogenic genes altered in this larger and functionally improved muscle are regulated by circadian core transcriptional repressors DEC1 and DEC2, and furthermore, display a temporal coordination with Dec1 and Dec2 expression consistent with a regulatory co-dependency. These considerations lead us to propose that Dmp1-Cre Mbtps1 cKO osteocytes activate myogenesis by increased release of an activator of muscle PPAR-gamma, for example, PGE2 or sphingosine-1-P, or, by diminished release of an inhibitor of LXR, for example, long-chain polyunsaturated fatty acids. We hope that further investigation of these interacting pathways in the Dmp1-Cre Mbtps1 cKO model will lead to clinically translatable findings applicable to age-related sarcopenia and other muscle wasting syndromes.
, Carolyne Falank, Heather Fairfield, Sarah Linehan, Clifford J Rosen, David L Kaplan, Julie Sterling,
Published: 19 October 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.75

The publisher has not yet granted permission to display this abstract.
, Matt M Stern, Amber R Stern, Janak L Pathak, Nathalie Bravenboer,
Published: 14 September 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.65

Abstract:
The aim of this paper is to present several popular methods for in vitro culture of osteocytes and osteocyte cell lines. Osteocytes are located extremely suitably within the calcified bone matrix to sense mechanical signals, and are equipped with a multitude of molecular features that allow mechanosensing. However, osteocytes are more than specialized mechanosensing cells. Several signaling molecules are preferentially produced by osteocytes, and osteocytes hold a tight reign over osteoblast and osteoclast formation and activity, but also have a role as endocrine cell, communicating with muscles or organs as remote as the kidneys. In order to facilitate further research into this fascinating cell type, three protocols will be provided in this paper. The first protocol will be on the culture of mouse (early) osteocyte cell lines, the second on the isolation and culture of primary mouse bone cells, and the third on the culture of fully embedded human osteocytes within their own three-dimensional bone matrix.
Meghan M Moran, Kotaro Sena, Margaret A McNulty, ,
Published: 7 September 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.61

Abstract:
In this paper, we provide a detailed protocol for a model of long bone mechanical marrow ablation in the rodent, including surgical procedure, anesthesia, and pre- and post-operative care. In addition, frequently used experimental end points are briefly discussed. This model was developed to study intramembranous bone regeneration following surgical disruption of the marrow contents of long bones. In this model, the timing of the appearance of bone formation and remodeling is well-characterized and therefore the model is well-suited to evaluate the in vivo effects of various agents which influence these processes. When biomaterials such as tissue engineering scaffolds or metal implants are placed in the medullary cavity after marrow ablation, end points relevant to tissue engineering and implant fixation can also be analyzed. By sharing a detailed protocol, we hope to improve inter-laboratory reproducibility.
, , Serge Ferrari
Published: 31 August 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.59

Abstract:
With the development of new non-invasive analytical techniques and particularly the advent of high-resolution peripheral quantitative computed tomography (HRpQCT) it is possible to assess cortical and trabecular bone changes under the effects of ageing, diseases and treatments. In the present study, we reviewed the treatment-related effects on bone parameters assessed by HRpQCT imaging. We identified 12 full-length articles published in peer-reviewed journals describing treatment-induced changes assessed by HRpQCT. The design of these studies varied a lot in terms of duration and methodology: some of them were open-labelled, others were double-blind, placebo-controlled or double-blind, double-dummy, active controlled. In addition, the sample size in these studies ranged from 11 to 324 patients. Motion artifacts occurring during data acquisition were sometimes a real challenge particularly at the radius leading sometimes to exclude the analysis at the radius due to the uninterpretability of microstructural parameters. Responses to therapies were treatment-specific and divergent effects in cortical and trabecular bone with antiresorptive or anabolic agents were observed. Standardization of bone microarchitecture parameters (including porosity) and bone strength estimates by finite element analysis (FEA) are mandatory. The additional value of microarchitecture and FEA estimates changes with therapies in terms of improvement in fracture outcomes which have to be adequately assessed in clinical trials with fracture end point. Data from these reviewed studies advance our understanding of the microstructural consequences of osteoporosis and highlight potential differences in bone quality outcomes within therapies.
Published: 24 August 2016
BoneKEy Reports, Volume 5, pp 829-829; https://doi.org/10.1038/bonekey.2016.60

Abstract:
Ageing and associated skeletal diseases pose a significant challenge for health care systems worldwide. Age-related fractures have a serious impact on personal, social and economic wellbeing. A significant proportion of physiological loading is carried by the cortical shell. Its role in the fracture resistance and strength of whole bones in the ageing skeleton is of utmost importance. Even though a large body of knowledge has been accumulated on this topic on the macroscale, the underlying micromechanical material behaviour and the scale transition of bone's mechanical properties are yet to be uncovered. Therefore, this review aims at providing an overview of the state-of-the-art of the post-yield and failure properties of cortical bone at the extracellular matrix and the tissue level.
, Marcella Greco, Aurélia Bertholet-Thomas, François Nobili, Jozef Zustin, Pierre Cochat, Francesco Emma, Georges Boivin
Published: 17 August 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.55

Abstract:
Hypophosphatemic rickets and short stature are observed in nephropathic cystinosis, an orphan autosomal recessive lysosomal storage disease due to a deficiency of cystinosin (CTNS gene). Although bone impairment is not common, it nevertheless appears to be more and more discussed by experts, even though the exact underlying pathophysiology is unclear. Four hypotheses are currently discussed to explain such impairment: copper deficiency, bone consequences of severe hypophosphatemic rickets during infancy, cysteamine toxicity and abnormal thyroid metabolism. In murine models, the invalidation of the CTNS gene is associated neither with renal phosphate wasting nor with renal failure, but causes severe osteopenia and growth retardation, thus raising the hypothesis of a specific underlying bone defect in cystinosis. Moreover, the in vitro ability of mesenchymal stromal cells isolated from bone marrow to differentiate along the osteoblastic lineage is reduced in patients with cystinosis as compared with cells obtained from healthy controls, this cellular abnormality being reverted after cysteamine treatment. From our experience of three pediatric patients with cystinosis and severe bone deformations having undergone a thorough biochemical evaluation, as well as a bone biopsy, we conclude that even though copper deficiency, high-doses cysteamine regimens and abnormal thyroid metabolism may worsen the bone picture in cystinosis patients, the exact pathophysiology of such impairment remains to be defined. The role of chronic hypoparathyroidism due to chronic phosphate wasting could also be discussed. In the future, larger and prospective studies should focus on this topic because of the potential major impact on patients' quality of life.
Kathrin Sinningen, Sylvia Thiele, ,
Published: 20 July 2016
BoneKEy Reports, Volume 5, pp 820-820; https://doi.org/10.1038/bonekey.2016.52

Abstract:
Milk fat globule-epidermal growth factor 8 (MFG-E8) is a glycoprotein that is abundantly expressed in various tissues and has a pivotal role in the phagocytic clearance of apoptotic cells. However, MFG-E8 has also gained significant attention because of its wide range of functions in autoimmunity, inflammation and tissue homeostasis. More recently, MFG-E8 has been identified as a critical regulator of bone homeostasis, being expressed in both, osteoblasts and osteoclasts. In addition, it was shown that MFG-E8 fulfils an active role in modulating inflammatory processes, suggesting an anti-inflammatory role of MFG-E8 and proposing it as a novel therapeutic target for inflammatory diseases. This concise review focusses on the expression and regulation of MFG-E8 in the context of inflammatory bone diseases, highlights its role in the pathophysiology of osteoimmune diseases and discusses the therapeutic potential of MFG-E8.
Published: 20 July 2016
BoneKEy Reports, Volume 5, pp 826-826; https://doi.org/10.1038/bonekey.2016.48

The publisher has not yet granted permission to display this abstract.
Jonathan A Mitchell, Diana L Cousminer, Babette S Zemel, ,
Published: 20 July 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.50

Abstract:
Osteoporosis is one of the most common chronic forms of disability in postmenopausal women and represents a major health burden around the world. Bone fragility is affected by bone mineral density (BMD), and, one of the most important factors in preventing osteoporosis is optimizing peak bone mass, which is achieved during growth in childhood and adolescence. BMD is a complex trait resulting from environmental and genetic factors. Genome-wide association studies have discovered robust genetic signals influencing BMD in adults, and similar studies have also been conducted to investigate the genetics of BMD in the pediatric setting. These latter studies have revealed that many adult osteoporosis-related loci also regulate BMD during growth. These investigations have the potential to profoundly impact public health and will allow for the eventual development of effective interventions for the prevention of osteoporosis.
Silvia Marino, , Genevieve Brown, Rachel Anne Howard-Jones,
Published: 29 June 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.49

Abstract:
Ex vivo explant culture models are powerful tools in bone research. They allow investigation of bone and cartilage responses to specific stimuli in a controlled manner that closely mimics the in vivo processes. Because of limitations in obtaining healthy human bone samples the explant growth of animal tissue serves as a platform to study the complex physico-chemical properties of the bone. Moreover, these models enable preserving important cell–cell and cell–matrix interactions in order to better understand the behaviour of cells in their natural three-dimensional environment. Thus, the use of bone ex vivo explant cultures can frequently be of more physiological relevance than the use of two-dimensional primary cells grown in vitro. Here, we describe isolation and ex vivo growth of different animal bone explant models including metatarsals, femoral heads, calvaria, mandibular slices and trabecular cores. We also describe how these explants are utilised to study bone development, cartilage and bone metabolism, cancer-induced bone diseases, stem cell-driven bone repair and mechanoadaptation. These techniques can be directly used to understand mechanisms linked with bone physiology or bone-associated diseases. The bone is a complex and specialised connective tissue in a state of dynamic equilibrium that, together with cartilage, forms the skeletal system. Active reorganisation of bone microstructure is achieved through bone remodelling or modelling, processes that are mediated by osteoclasts, osteoblasts and osteocytes.1 Remodelling represents coordinated changes in bone resorption and formation, which occur throughout life, in order to maintain health and integrity of the skeleton. Bone modelling is an adaptation of bone to external stimuli and is generally limited to growth and responses to mechanical loading. Ex vivo growth of bone explants offers a unique opportunity to study these mechanisms in a controlled experimental setting where both the three-dimensional organisation as well as the cellular diversity of the bone are preserved. In addition, the ex vivo cultures can help the investigation of mechanisms underlying bone growth, bone and cartilage matrix turnover, mechanical loading, or interactions with other cell types and advance our understanding of bone physiology. The aim of this collective protocol is to provide a detailed description of the procedures that are currently used to isolate, culture and characterise a variety of animal bone explant culture models and include the applications of these models in bone research (Figure 1). This protocol combines previously published protocols and those optimised in our laboratories and offers the technical hints and suggestions for each of the methods. This protocol also provides a list of additional reading that should help the researcher with establishing these procedures at their home institution. The mouse metatarsal culture model can be used to improve our understanding of bone development. This model, pioneered by Burger and Van-Delft in the Netherlands (1976),2 is a highly physiological ex vivo model for studying endochondral ossification, the process by which the cartilage scaffold is replaced by mineralised bone. This process is tightly regulated in healthy individuals in order to prevent abnormal development and/or longitudinal bone growth.3 The metatarsal model allows for the study of linear bone growth, as the growth rate of the bones in culture mimics that seen in vivo. Moreover, this model enables investigation of chondrocyte proliferation and hypertrophy, extracellular matrix production and tissue mineralisation. The method described in this protocol relates to murine metatarsal explant cultures; however, there are numerous papers detailing similar cultures in rats4 (Method 1). The mouse femoral head culture model can be used to investigate the expression and turnover of specific markers within bone and cartilage. This is useful to help understand the mechanisms linked with pathogenesis of osteoarthritis, where there is a clear association between articular cartilage degeneration and subchondral bone changes.5, 6 This model was developed by Stanescu and Leibovich (1982),7 and over the years it has been primarily used to understand mechanisms of cartilage breakdown. For instance, this model was effectively applied by Glasson et al.8 to demonstrate the importance of aggrecan proteolytical cleavage and neoepitope formation during osteoarthritis progression.8 Uniquely, the mouse femoral head culture model can also be used for simultaneous investigation of bone modelling and cartilage extracellular matrix degradation occurring during explant culture9 (Method 2). The mouse calvaria ex vivo culture model has been routinely used to investigate bone resorption,10 bone formation11 and bone regeneration/healing process.12 By using an adaptation of the calvaria explant culture model, it is also possible to study cancer-induced bone metastases ex vivo as shown by Sophocleous et al.13 and others. Cancer to bone metastasis is mediated by the secretion of soluble factors by cancer cells, which stimulate the proliferation and activity of osteoblasts and osteoclasts, affecting both bone formation as well as bone resorption. The method described in this protocol gives an example of the isolation and culture of calvaria derived from mouse pups; however, similar cultures can be established using the calvarial bones obtained from rats14 or chicken embryos15 (Method 3). A rat mandible slice model was initially established to investigate inflammatory bone destruction.16 This model was adapted by Colombo and colleagues to enable the study of dental pulp stem cell (DPSC) behaviour in an ex vivo environment.17 DPSCs have characteristics similar to mesenchymal stem cells18, 19 and display migratory and odontoblast differentiation capacity in response to tissue damage.19, 20, 21 Studying DPSC behaviour in an ex vivo mandible slice...
Constance B Hilliard
Published: 29 June 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.30

Abstract:
This ecological correlation study explores the marked differential in osteoporosis susceptibility between East and West Africans. African tsetse belt populations are lactase non-persistent (lactose intolerant) and possess none of the genetic polymorphisms carried by lactase persistent (lactose tolerant) ethnic populations. What appears paradoxical, however, is the fact that Niger-Kordofanian (NK) West African ethnicities are also at minimal risk of osteoporosis. Although East Africans share a genetic affinity with NK West Africans, they display susceptibility rates of the bone disorder closer to those found in Europe. Similar to Europeans, they also carry alleles conferring the lactase persistence genetic traits. Hip fracture rates of African populations are juxtaposed with a global model to determine whether it is the unique ecology of the tsetse-infested zone or other variables that may be at work. This project uses MINITAB 17 software for regression analyses. The research data are found on AJOL (African Journals Online), PUBMED and JSTOR (Scholarly Journal Archive). Data showing the risk of osteoporosis to be 80 times higher among East Africans with higher levels of lactase persistence than lactase non-persistence West Africans are compared with global statistics. Hip fracture rates in 40 countries exhibit a high Pearson's correlation of r=0.851, with P-value=0.000 in relation to dairy consumption. Lower correlations are seen for hip fracture incidence vis-à-vis lactase persistence, per capita income and animal protein consumption. Ethnic populations who lack lactase persistence single-nucleotide polymorphisms may be at low risk of developing osteoporosis.
, , , Fernando Rivadeneira, David M Evans
Published: 25 May 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.23

Abstract:
Peak bone mass, the maximum amount of bone accrued at the end of the growth period, is an important predictor of future risk of osteoporosis and fracture. Hence, the contribution of genetic factors influencing bone accrual is of considerable interest to the osteoporosis research community. In this article, we review evidence that genetic factors play an important role in bone growth, describe the genetic loci implicated so far and briefly discuss lessons learned from the application of genome-wide association studies. Moreover, we attempt to make the case for genetic investigations of bone mineral density in paediatric and young adult populations, describing their potential to increase our knowledge of the process of bone metabolism throughout the life course, and in turn, identify novel targets for the pharmacological treatment of osteoporosis.
, Francesca Sassi
Published: 18 May 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.29

The publisher has not yet granted permission to display this abstract.
, , Nadia Rucci, , Gabriel M. Pagnotti, Antonella Chiechi, , Julie A. Sterling
Published: 11 May 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.31

The publisher has not yet granted permission to display this abstract.
Javier Riancho, , José A Riancho
Published: 4 May 2016
BoneKEy Reports, Volume 5, pp 797-797; https://doi.org/10.1038/bonekey.2016.24

The publisher has not yet granted permission to display this abstract.
, Ameya Bendre, Mervi Laanti, Kalman G Büki, , Päivi Tervola, Johanna Saarimäki, Matti Poutanen, Pirkko Härkönen, Kalervo Väänänen
Published: 6 April 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.14

The publisher has not yet granted permission to display this abstract.
Ramin Rohanizadeh, Yi Deng,
Published: 2 March 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.20

The publisher has not yet granted permission to display this abstract.
Hyungjin Jung,
Published: 2 March 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.5

Abstract:
Previous studies demonstrated that extracellular calcium efflux ([Ca2+]E) originates from the regions of bone extracellular matrix that are undergoing microdamage. Such [Ca2+]E is reported to induce the activation of intracellular calcium signaling ([Ca2+]I) in MC3T3-E1 cells. The current study investigated the association between microdamage and local activation of intracellular calcium signaling quantifiably in MC3T3-E1 cells. Cells were seeded on devitalized notched bovine bone samples to induce damage controllably within the field of observation. A sequential staining procedure was implemented to stain for intracellular calcium activation followed by staining for microdamage on the same sample. The increase in [Ca2+]I fluorescence in cells of mechanically loaded samples was greater than that of unloaded negative control cells. The results showed that more than 80% of the cells with increased [Ca2+]I fluorescence were located within the damage zone. In conclusion, the findings demonstrate that there are spatial proximity between diffuse microdamage induction and the activation of intracellular calcium ([Ca2+]I) signaling in MC3T3-E1 cells. The downstream responses to the observed activation in future research may help understand how bone cells repair microdamage.
Jinlu Dai, Janine Hensel, , , Yusuke Shiozawa
Published: 17 February 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.4

The publisher has not yet granted permission to display this abstract.
Concepción Fernández-Roldán, Fernanda Genre, Raquel López-Mejías, Begoña Ubilla, Verónica Mijares, , Concepción López Robles, José Luis Callejas-Rubio, Raquel Ríos Fernández, Manuela Expósito Ruiz, et al.
Published: 3 February 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2016.2

Abstract:
Systemic autoimmune diseases (SADs) are associated with lower bone mass and an increased risk of fractures. Sclerostin has a pivotal role in bone metabolism. Available data on circulating sclerostin levels in healthy subjects are limited, whereas those in SAD patients are absent. Our objective was to determine circulating sclerostin concentrations in systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and Crohn's disease (CD) patients, and to analyze the factors associated with sclerostin concentrations. In this cross-sectional case–control study, serum sclerostin levels were measured in 38 SLE patients, 20 CD patients, 8 SSc patients and 20 healthy controls using a sclerostin ELISA. The mean values of the sclerostin (95% confidence interval) were 35.36 pmol l−1 (12–101) in patients and 33.92 pmol l−1 (2.31–100) in control subjects. The mean sclerostin value was 36.4 pmol l−1 (22.1–48.5) in SLE patients, 26.7 pmol l−1 (17.3–36.3) in CD patients and 51.8 pmol l−1 (26.5–77.1) in SSc patients (P=0.001). Serum sclerostin levels were positively correlated with age (P<0.001), body mass index (BMI) (P=0.01) and lumbar spine Z-score (P=0.001) and negatively with creatinine clearance (P=0.001). Glucocorticoid treatment did not affect sclerostin levels. Sclerostin levels seem to have a heterogeneous pattern in different autoimmune diseases. SLE and SSc patients did not differ from healthy controls regarding sclerostin levels. The CD group had significantly lower values compared with SSc patients. Factors associated with sclerostin levels in autoimmune diseases seem to be the same than in the general population.
Seint T Lwin, , Rebecca Silbermann
Published: 3 February 2016
BoneKEy Reports, Volume 5; https://doi.org/10.1038/bonekey.2015.142

The publisher has not yet granted permission to display this abstract.
Published: 23 December 2015
BoneKEy Reports, Volume 4; https://doi.org/10.1038/bonekey.2015.138

Abstract:
The aim of this laboratory method is to describe two approaches for the investigation of bone responses to mechanical loading in mice in vivo. The first is running exercise, because it is easily translatable clinically, and the second is axial compression of the tibia, because it is precisely controllable. The effects of running exercise, and in general physical activity, on bone tissue have been shown to be both direct through mechanical loading (ground impact and muscle tension) and indirect through metabolic changes. Therefore, running exercise has been considered the most convenient preclinical model for demonstrating the general idea that exercise is good for bone health, either early in age for increasing peak bone mass or later in age by slowing down bone loss. However, numerous combinations of protocols have been reported, which makes it difficult to formulate a simple take-home message. This laboratory method also provides a detailed description of in vivo direct mechanical axial compression of the mouse tibia. The effects of mechanical loading depend on the force (strain), frequency, waveform and duration of application, and they range from bone anabolism with low bone remodeling, inducing lamellar bone accumulation, to bone catabolism with high bone remodeling, leading to microdamage, woven bone formation and bone loss. Direct in vivo loading models are extensively used to study mechanotransduction pathways, and contribute by this way to the development of new bone anabolism treatments. Although it is particularly difficult to assemble an internationally adopted protocol description, which would give reproducible bone responses, here we have attempted to provide a comprehensive guide for best practice in performing running exercise and direct in vivo mechanical loading in the laboratory.
Published: 23 December 2015
BoneKEy Reports, Volume 4; https://doi.org/10.1038/bonekey.2015.134

Abstract:
Irisin was originally recognized as a hormone-like myokine secreted as a product of fibronectin type III domain containing 5 from skeletal muscle in response to exercise both in mice and humans. The first role attributed to Irisin was its ability to induce trans-differentiation of white adipose tissue into brown, but we recently demonstrated that Irisin also has a central role in the control of bone mass, even at lower concentration than required to induce the browning response. Considering how physical exercise is important for the development of an efficient load-bearing skeleton, we can now consider this myokine as one of the molecules responsible for the positive correlation between exercise and healthy bone, linking to the well-established relationship between muscle and bone. Recombinant Irisin (r-Irisin), administered at low dose in young mice, increases cortical bone mineral density and positively modifies bone geometry. Irisin exerts its effect prevalently on osteoblast lineage by enhancing differentiation and activity of bone-forming cells, through the increase in activating transcription factor 4 expression. Low-dose r-Irisin also increases osteopontin and decreases sclerostin synthesis but did not affect Uncoupling protein 1 expression in white adipose tissue, whose upregulation is known to cause browning of fat, when Irisin is administered at a higher dose. These findings offer an explanation to the positive outcome on the skeleton triggered by skeletal muscle during physical activity and prove that the bone tissue is more sensitive than the adipose tissue to the Irisin action.
, Wafa A Alnahdi, Nabeel Alama, Gordon A Ferns
Published: 11 November 2015
BoneKEy Reports, Volume 4; https://doi.org/10.1038/bonekey.2015.127

Abstract:
BoneKEy is an online knowledge resource providing coverage of the field of bone and mineral metabolism. Covering both basic science research and clinical investigations, BoneKEy will provide the bone field with an online platform for scientific exchange and community growth based on expert scientific content
Published: 4 November 2015
BoneKEy Reports, Volume 4; https://doi.org/10.1038/bonekey.2015.125

Abstract:
Paget's disease of bone (PDB) is a common metabolic bone disease characterised by focal areas of increased bone turnover, which primarily affects people over the age of 55 years. Genetic factors have a fundamental role in the pathogenesis of PDB and are probably the main predisposing factor for the disease. The genetic contribution to PDB susceptibility ranges from rare pathogenic mutations in the single gene SQSTM1 to more common, small effect variants in at least seven genetic loci that predispose to the disease. These loci have additive effects on disease susceptibility and interact with SQSTM1 mutations to affect disease severity, making them a potentially useful tool in predicting disease risk and complication and in managing treatments. Many of these loci harbour genes that have important function in osteoclast differentiation such as CSF1, DCSTAMP and TNFRSF11A. Other susceptibility loci have highlighted new molecular pathways that have not been previously implicated in regulation of bone metabolism such as OPTN, which was recently found to negatively regulate osteoclast differentiation. PDB-susceptibility variants exert their effect either by affecting the protein coding sequence such as variants found in SQSTM1 and RIN3 or by influencing gene expression such as those found in OPTN and DCSTAMP. Epidemiological studies indicate that environmental triggers also have a key role in PDB and interact with genetic factors to influence manifestation and severity of the disease; however, further studies are needed to identify these triggers.
, Joseph Caverzasio
Published: 4 November 2015
BoneKEy Reports, Volume 4; https://doi.org/10.1038/bonekey.2015.126

Abstract:
Sclerostin inhibits bone formation mostly by antagonizing LRP5/6, thus inhibiting Wnt signaling. However, experiments with genetically modified mouse models suggest that a significant part of sclerostin-mediated inhibition of bone formation is due to interactions with other binding partners. The objective of the present work was to identify signaling pathways affected by sclerostin in relation with its inhibitory action on osteogenic differentiation of C3H10T1/2 cells, MC3T3-E1 cells and primary osteoblasts. Sclerostin inhibited BMP2-induced osteoblast differentiation without altering SMAD1/5 phosphorylation and transcriptional activity. Moreover, sclerostin prevented Wnt3a-mediated osteoblastogenesis without affecting LRP5/6 phosphorylation or β-catenin transcriptional activity. In addition, sclerostin inhibited mineralization promoted by GSK3 inhibition, which mimics canonical Wnt signaling without activation of LRP5/6, suggesting that sclerostin can prevent osteoblast differentiation without antagonizing LRP5/6. Finally, we found that sclerostin could activate platelet-derived growth factor receptor (PDGFR) and its downstream signaling pathways PLCγ, PKC, Akt and ERK1/2. PDGFR inhibition could reverse sclerostin-mediated inhibitory activity on BMP2-induced osteoblast differentiation. Therefore, our data suggest that sclerostin can activate PDGFR signaling by itself, and this functional interaction may be involved in the negative effect of sclerostin on osteoblast differentiation.
G. David Roodman, Rebecca Silbermann
Published: 28 October 2015
BoneKEy Reports, Volume 4; https://doi.org/10.1038/bonekey.2015.122

Abstract:
The bone is a frequent site for tumor metastasis, and cancer in the bone results in marked disturbances of bone remodeling that can be lytic, blastic or a combination of the two. Patients with advanced malignancies that have metastasized to the bone frequently suffer from debilitating skeletal-related events, including pathologic fractures, spinal cord compression syndromes, disorders of calcium and phosphate homeostasis and severe cancer-related pain. This review will discuss recent studies on the mechanisms responsible for osteolytic and osteoblastic metastasis and how their identification has resulted in the development of new agents for patients with metastatic bone disease
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