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Sclerostin

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https://www.readbyqxmd.com/read/29154967/bone-marrow-mechanotransduction-in-porcine-explants-alters-kinase-activation-and-enhances-trabecular-bone-formation-in-the-absence-of-osteocyte-signaling
#1
Kimberly J Curtis, Thomas R Coughlin, Devon E Mason, Joel D Boerckel, Glen L Niebur
Bone is a dynamic tissue that can adapt its architecture in response to mechanical signals under the control of osteocytes, which sense mechanical deformation of the mineralized bone. However, cells in the marrow are also mechanosensitive and may contribute to load-induced bone adaptation, as marrow is subjected to mechanical stress during bone deformation. We investigated the contribution of mechanotransduction in marrow cells to trabecular bone formation by applying low magnitude mechanical stimulation (LMMS) to porcine vertebral trabecular bone explants in an in situ bioreactor...
November 14, 2017: Bone
https://www.readbyqxmd.com/read/29149200/heterozygous-deletion-of-both-sclerostin-sost-and-connexin43-gja1-genes-in-mice-is-not-sufficient-to-impair-cortical-bone-modeling
#2
Susan K Grimston, Francesca Fontana, Marcus Watkins, Roberto Civitelli
Connexin43 (Cx43) is the main gap junction protein expressed in bone forming cells, where it modulates peak bone mass acquisition and cortical modeling. Genetic ablation of the Cx43 gene (Gja1) results in cortical expansion with accentuated periosteal bone formation associated with decreased expression of the Wnt inhibitor sclerostin. To determine whether sclerostin (Sost) down-regulation might contribute to periosteal expansion in Gja1 deficient bones, we took a gene interaction approach and crossed mice harboring germline null alleles for Gja1 or Sost to generate single Gja1+/-and Sost+/-and double Gja1+/-;Sost+/-heterozygous mice...
2017: PloS One
https://www.readbyqxmd.com/read/29142975/sclerostin%C3%A2-a-debutant-on-the-autosomal-dominant-polycystic-kidney-disease-scene
#3
Magdalena Jankowska, Mathias Haarhaus, Abdul Rashid Qureshi, Bengt Lindholm, Pieter Evenepoel, Peter Stenvinkel
Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease originating from a mutation in genes encoding polycystin 1 and 2. Recent evidence suggests that these polycystins mediate mechanosensation not only in the primary cilium of kidney cells but also in bone cells. The Wnt/β-catenin signaling pathway plays a central role in mechanotransduction in osteocytes. Mechanical unloading causes the upregulation of the Wnt inhibitor sclerostin. We tested the hypothesis that ADPKD associates with higher circulating sclerostin levels...
May 2017: KI Reports
https://www.readbyqxmd.com/read/29136947/the-effect-of-the-dipeptidyl-peptidase-4-inhibitor-sitagliptin-on-gentamicin-nephrotoxicity-in-mice
#4
Yousuf M Al Suleimani, Aly M Abdelrahman, Turan Karaca, Priyadarsini Manoj, Mohammed Ashique, Abderrahim Nemmar, Badreldin H Ali
This study aimed at investigating the possible ameliorative effects of sitagliptin in mice with gentamicin (GEN) nephrotoxicity. Sitagliptin was given to the animals at an oral dose of 10mgkg(-1) per day for 10days, and in some of these mice, GEN was injected intraperitoneally at a dose of 100mgkg(-1) per day during the last seven days of the treatment. Nephrotoxicity was evaluated histopathologically by light microscopy and biochemically by measuring several indices in plasma, urine and renal cortex homogenates...
November 9, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29129760/the-key-role-of-proinflammatory-cytokines-matrix-proteins-rankl-opg-and-wnt-%C3%AE-catenin-in-bone-healing-of-hip-arthroplasty-patients
#5
Jean Cassuto, Agnetha Folestad, Jan Göthlin, Henrik Malchau, Johan Kärrholm
INTRODUCTION: We still lack understanding of why some implants fail while most remain stable after decades of use. Proinflammatory cytokines, matrix proteins and bone regulating cytokines of the RANKL/OPG (receptor activator of nuclear factor kappa B ligand/osteoprotegerin) and Wnt/β-catenin pathways are mandatory for normal bone repair but their spatial and temporal role in the healing of primary total hip arthroplasties (THA) has not been previously shown. MATERIALS AND METHODS: Twenty-four osteoarthritis patients with one-sided well-fixed primary THA were prospectively monitored during 18years (18Y) with repeated blood samples, clinical variables and radiographs...
November 10, 2017: Bone
https://www.readbyqxmd.com/read/29129759/dampening-of-the-bone-formation-response-following-repeat-dosing-with-sclerostin-antibody-in-mice-is-associated-with-up-regulation-of-wnt-antagonists
#6
Gill Holdsworth, Kevin Greenslade, Joby Jose, Zofia Stencel, Hishani Kirby, Adrian Moore, Hua Zhu Ke, Martyn K Robinson
Administration of antibodies to sclerostin (Scl-Ab) has been shown to increase bone mass, bone mineral density (BMD) and bone strength by increasing bone formation and decreasing bone resorption in both animal studies and human clinical trials. In these studies, the magnitude and rate of increase in bone formation markers is attenuated upon repeat dosing with Scl-Ab despite a continuous and progressive increase in BMD. Here, we investigated whether the attenuation in the bone formation response following repeated administration of Scl-Ab was associated with increased expression of secreted antagonists of Wnt signalling and determined how the circulating marker of bone formation, P1NP, responded to single, or multiple doses, of Scl-Ab four days post-dosing...
November 9, 2017: Bone
https://www.readbyqxmd.com/read/29128813/effect-of-aromatase-inhibitors-on-learning-and-memory-and-modulation-of-hippocampal-dickkopf-1-and-sclerostin-in-female-mice
#7
Saima Zameer, Divya Vohora
BACKGROUND: There has been conflicting reports on the effect of third generation aromatase inhibitors on cognition in estrogen-deficient states. Since aromatase inhibitors themselves cause estrogen deprivation, the present work was designed to evaluate the comparative effect of three aromatase inhibitors on behavioral measures of learning and memory in female mice. Further, in view of the reports of estrogen and Wnt signaling pathway in cognition, the role of two Wnt signaling antagonists (dickkopf-1 and sclerostin) in mediation of cognitive effects of aromatase inhibitors was evaluated...
June 13, 2017: Pharmacological Reports: PR
https://www.readbyqxmd.com/read/29125417/loss-of-mechanosensitive-sclerostin-may-accelerate-cranial-bone-growth-and-regeneration
#8
Kyung Shin Kang, Jeff Lastfogel, Laurie L Ackerman, Andrew Jea, Alexander G Robling, Sunil S Tholpady
OBJECTIVE Cranial defects can result from trauma, infection, congenital malformations, and iatrogenic causes and represent a surgical challenge. The current standard of care is cranioplasty, with either autologous or allogeneic material. In either case, the intrinsic vascularity of the surrounding tissues allows for bone healing. The objective of this study was to determine if mechanotransductive gene manipulation would yield non-weight-bearing bone regeneration in a critical size calvarial defect in mice. METHODS A mouse model of Sost deletion in Sost knockout (KO) mice was created in which the osteocytes do not express sclerostin...
November 10, 2017: Journal of Neurosurgery
https://www.readbyqxmd.com/read/29113980/management-of-endocrine-disease-novel-anabolic-treatments-for-osteoporosis
#9
Ernesto Canalis
Skeletal anabolic agents enhance bone formation, which is determined by the number and function of osteoblasts. Signals that influence the differentiation and function of cells of the osteoblast lineage play a role in the mechanism of action of anabolic agents in the skeleton. Wnts induce the differentiation of mesenchymal stem cells toward osteoblasts, and insulin-like growth factor I (IGF-I) enhances the function of mature osteoblasts. The activity of Wnt and IGF-I is controlled by proteins that bind to the growth factor or to its receptors...
November 7, 2017: European Journal of Endocrinology
https://www.readbyqxmd.com/read/29113523/monoclonal-antibodies-for-treating-osteoporosis
#10
Maria Felicia Faienza, Mariangela Chiarito, Gabriele D'amato, Graziana Colaianni, Silvia Colucci, Maria Grano, Giacomina Brunetti
Osteoporosis is the most widespread skeletal disease requiring innovative therapeutic strategies for its management. The understanding of receptor activator of nuclear factor kappa-B ligand (RANKL) and sclerostin's role in bone cell biology is completely changing the therapeutic landscape. RANKL supports osteoclast formation and activity and is mainly produced by cells of osteoblastic lineage. Sclerostin, an antagonist of the Wnt pathway, has a key role in bone formation and is mainly secreted by osteocytes...
November 7, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/29109339/effects-of-surface-microtopography-of-titanium-disks-on-cell-proliferation-and-differentiation-of-osteoblast-like-cells-isolated-from-rat-calvariae
#11
Satoshi Yokose, Perry R Klokkevold, Henry H Takei, Hiroshi Kadokura, Tetsuya Kikui, Yasushi Hibino, Hirotaka Shigeta, Hiroshi Nakajima, Hiroshi Kawazu
The surface topography of implant fixture is an important factor affecting the osseointegration. We herein demonstrated the effects of surface microtopography of titanium disks on proliferation and differentiation of osteoblast-like cells isolated from rat calvariae. Titanium disks with machine surface (MS), rough surface (R1) and rough surface combined with small cavities (R2) were used in an in vitro culture system. Rough surfaces (R1 and R2 disks) induced stronger osteoblast proliferation and differentiation (BGP and sclerostin mRNA expressions and calcium content) than the smooth surface (MS disk)...
November 3, 2017: Dental Materials Journal
https://www.readbyqxmd.com/read/29105581/wnt-mediated-modulation-of-bone-metabolism-implications-for-wnt-targeting-to-treat-extraskeletal-disorders
#12
Whitney A Bullock, Alexander G Robling
The WNT-signaling pathway is involved in cellular and tissue functions that control such diverse processes as body axis patterning, cellular proliferation, differentiation, and life span. The long list of molecules that can participate or modify WNT signaling makes this pathway one of the most complex in cell biology. In bone tissues, WNT signaling is required for proper skeletal development, and human mutations in various components of the cascade revealed insights into pharmacologic targeting that can be harnessed to improve skeletal health...
January 1, 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/29104955/crosstalk-between-mlo-y4-osteocytes-and-c2c12-muscle-cells-is-mediated-by-the-wnt-%C3%AE-catenin-pathway
#13
Jian Huang, Sandra Romero-Suarez, Nuria Lara, Chenglin Mo, Simon Kaja, Leticia Brotto, Sarah L Dallas, Mark L Johnson, Katharina Jähn, Lynda F Bonewald, Marco Brotto
We examined the effects of osteocyte secreted factors on myogenesis and muscle function. MLO-Y4 osteocyte-like cell conditioned media (CM) (10%) increased ex vivo soleus muscle contractile force by ~25%. MLO-Y4 and primary osteocyte CM (1-10%) stimulated myogenic differentiation of C2C12 myoblasts, but 10% osteoblast CMs did not enhance C2C12 cell differentiation. Since WNT3a and WNT1 are secreted by osteocytes, and the expression level of Wnt3a is increased in MLO-Y4 cells by fluid flow shear stress, both were compared, showing WNT3a more potent than WNT1 in inducing myogenesis...
October 2017: JBMR Plus
https://www.readbyqxmd.com/read/29092060/evidence-for-bone-and-mineral-metabolism-alterations-in-children-with-autosomal-dominant-polycystic-kidney-disease
#14
Stéphanie De Rechter, Justine Bacchetta, Nathalie Godefroid, Laurence Dubourg, Pierre Cochat, Julie Maquet, Ann Raes, Jean De Schepper, Pieter Vermeersch, Maria Van Dyck, Elena Levtchenko, Patrick D'Haese, Pieter Evenepoel, Djalila Mekahli
Context: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. Hypophosphatemia was demonstrated in adult patients with preserved renal function, together with high fibroblast growth factor 23 (FGF23) and low soluble Klotho levels. The latter explained the relative FGF23 hyporesponsiveness in this cohort. Objective: Evaluating phosphate and bone mineral metabolism in children with ADPKD compared with what is known in adult ADPKD patients...
November 1, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29090474/sclerostin-antibody-augments-the-anabolic-bone-formation-response-in-a-mouse-model-of-mechanical-tibial-loading
#15
A Morse, A Schindeler, M M McDonald, M Kneissel, I Kramer, D G Little
Decreased activity or expression of sclerostin, an endogenous inhibitor of Wnt/β-catenin signaling, results in increased bone formation and mass. Antibodies targeting and neutralizing sclerostin (Scl-Ab) have been shown to increase bone mass and reduce fracture risk. Sclerostin is also important in modulating the response of bone to changes in its biomechanical environment. However, the effects of Scl-Ab on mechanotransduction are unclear, and it was speculated that the loading response may be altered for individuals receiving Scl-Ab therapy...
November 1, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/29080811/genetics-of-sost-sost-in-sclerosteosis-and-van-buchem-disease-animal-models
#16
Aimy Sebastian, Gabriela G Loots
Sclerosteosis and van Buchem disease (VBD) are two rare autosomal recessive disorders that results from osteoblast hyperactivity, in which progressive bone overgrowth leads to very dense bones, distortion of the face, and entrapment of cranial nerves. Sclerosteosis is caused by loss-of-function mutations in the SOST gene which encodes a secreted glycoprotein, sclerostin. VBD is caused by a noncoding deletion that removes a SOST-specific regulatory element in bone. In bone, SOST is expressed predominantly by osteocytes and sclerostin suppress bone formation by inhibiting the canonical Wnt signaling pathway...
October 25, 2017: Metabolism: Clinical and Experimental
https://www.readbyqxmd.com/read/29069393/sclerostin-antibody-reverses-bone-loss-by-increasing-bone-formation-and-decreasing-bone-resorption-in-a-rat-model-of-male-osteoporosis
#17
Xiaodong Li, Michael S Ominsky, Kelly S Villasenor, Qing-Tian Niu, Frank J Asuncion, Xuechun Xia, Mario Grisanti, Thomas J Wronski, W Scott Simonet, Hua Zhu Ke
Sclerostin antibody (Scl-Ab) restored bone mass and strength in the ovariectomized rat model of postmenopausal osteoporosis. Increased bone mineral density (BMD) and decreased skeletal fragility fracture risk have been reported in postmenopausal osteoporotic women receiving Scl-Ab. In males, loss of androgen leads to rapid decreases in BMD and increased risk for fragility fractures. We hypothesized that Scl-Ab could reverse the loss of bone mass and strength caused by androgen ablation in the orchiectomized (ORX) rat model of male osteoporosis...
October 20, 2017: Endocrinology
https://www.readbyqxmd.com/read/29059259/sclerostin-and-bone-metabolism-markers-in-hyperthyroidism-before-treatment-and-interrelations-between-them
#18
İlker Sarıtekin, Şerefden Açıkgöz, Taner Bayraktaroğlu, Fatih Kuzu, Murat Can, Berrak Güven, Görkem Mungan, Çağatay Büyükuysal, Selda Sarıkaya
Sclerostin, which is a glycoprotein produced by osteocytes, reduces the formation of bones by inhibiting the Wnt signal pathway. Thyroid hormones are related with Wnt signal pathway and it has been reported that increased thyroid hormones in hyperthyroidism fasten epiphysis maturation in childhood, and increase the risk of bone fractures by stimulating the bone loss in adults. The aim of this study was to examine the sclerostin serum levels, the relation between sclerostin and thyroid hormones as well as the biochemical markers of the bone metabolism in patients with hyperthyroidism (including multinodular goiter and Graves' disease), whose treatments have not started yet...
October 25, 2017: Acta Biochimica Polonica
https://www.readbyqxmd.com/read/29050900/bone-and-mineral-disorders-in-chronic-kidney-disease-implications-for-cardiovascular-health-and-ageing-in-the-general-population
#19
REVIEW
Adrian Covic, Marc Vervloet, Ziad A Massy, Pablo Ureña Torres, David Goldsmith, Vincent Brandenburg, Sandro Mazzaferro, Pieter Evenepoel, Jordi Bover, Mugurel Apetrii, Mario Cozzolino
The patient with chronic kidney disease (CKD) represents an extreme model for arteriosclerosis, vascular calcification, and bone disorders, all of which are also associated with ageing in the general population. These pathological features are also relevant to other common chronic health disorders such as diabetes, and chronic inflammatory and cardiovascular diseases. Although management and interventions for these major risk factors are now incorporated into most public health guidelines (eg, smoking cessation and control of bodyweight and blood pressure, as well as glucose and cholesterol concentrations), some residual cardiovascular risk is not reduced by implementation of these interventions...
October 16, 2017: Lancet Diabetes & Endocrinology
https://www.readbyqxmd.com/read/29048521/sclerostin-and-chronic-kidney-disease-the-assay-impacts-what-we-thought-to-know
#20
Pierre Delanaye, François Paquot, Antoine Bouquegneau, Frank Blocki, Jean-Marie Krzesinski, Pieter Evenepoel, Hans Pottel, Etienne Cavalier
Background: Sclerostin, a 22-kDa protein secreted by osteocytes, acts as a potent inhibitor of osteoblast activity. In chronic kidney disease (CKD), sclerostin is a putative driver of the bone-vascular axis. However, large discrepancies between sclerostin assays have been described. Methods: We compared four different assays [Biomedica (BM), TecoMedical (TE), R&D (RD) and MesoScaleDiscovery (MSD)] in an analytical study and addressed the question whether bioassay choice affects the correlation between circulating sclerostin and clinical and biochemical determinants...
October 18, 2017: Nephrology, Dialysis, Transplantation
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