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Anti sclerostin antibodies

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https://www.readbyqxmd.com/read/27888056/sclerostin-expression-and-functions-beyond-the-osteocyte
#1
Megan M Weivoda, Stephanie J Youssef, Merry Jo Oursler
Sclerostin, the product of the SOST gene, is a secreted inhibitor of Wnt signaling that is produced by osteocytes to regulate bone formation. While it is often considered an osteocyte-specific protein, SOST expression has been reported in numerous other cell types, including hypertrophic chondrocytes and cementocytes. Of interest, SOST/sclerostin expression is altered in certain pathogenic conditions, including osteoarthritis and rheumatic joint disease, and it is unclear whether sclerostin plays a protective role or whether sclerostin may mediate disease pathogenesis...
November 23, 2016: Bone
https://www.readbyqxmd.com/read/27837171/preventing-painful-age-related-bone-fractures-anti-sclerostin-therapy-builds-cortical-bone-and-increases-the-proliferation-of-osteogenic-cells-in-the-periosteum-of-the-geriatric-mouse-femur
#2
Michelle L Thompson, Stephane R Chartier, Stefanie A Mitchell, Patrick W Mantyh
Age-related bone fractures are usually painful and have highly negative effects on a geriatric patient's functional status, quality of life, and survival. Currently, there are few analgesic therapies that fully control bone fracture pain in the elderly without significant unwanted side effects. However, another way of controlling age-related fracture pain would be to preemptively administer an osteo-anabolic agent to geriatric patients with high risk of fracture, so as to build new cortical bone and prevent the fracture from occurring...
2016: Molecular Pain
https://www.readbyqxmd.com/read/27780792/application-of-anti-sclerostin-therapy-in-non-osteoporosis-disease-models
#3
Christina M Jacobsen
Sclerostin, a known inhibitor of the low density lipoprotein related protein 5 and 6 (LRP5 and LRP6) cell surface signaling receptors, is integral in the maintenance of normal bone mass and strength. Patients with loss of function mutations in SOST or missense mutations in LRP5 that prevent Sclerostin from binding and inhibiting the receptor, have significantly increased bone mass. This observation leads to the development of Sclerostin neutralizing therapies to increase bone mass and strength. Anti-Sclerostin therapy has been shown to be effective at increasing bone density and strength in animal models and patients with osteoporosis...
October 22, 2016: Bone
https://www.readbyqxmd.com/read/27742499/sclerostin-s-role-in-bone-s-adaptive-response-to-mechanical-loading
#4
Gabriel L Galea, Lance E Lanyon, Joanna S Price
Mechanical loading is the primary functional determinant of bone mass and architecture, and osteocytes play a key role in translating mechanical signals into (re)modelling responses. Although the precise mechanisms remain unclear, Wnt signalling pathway components, and the anti-osteogenic canonical Wnt inhibitor Sost/sclerostin in particular, play an important role in regulating bone's adaptive response to loading. Increases in loading-engendered strains down-regulate osteocyte sclerostin expression, whereas reduced strains, as in disuse, are associated with increased sclerostin production and bone loss...
October 12, 2016: Bone
https://www.readbyqxmd.com/read/27742498/role-and-mechanism-of-action-of-sclerostin-in-bone
#5
Jesus Delgado-Calle, Amy Y Sato, Teresita Bellido
After discovering that lack of Sost/sclerostin expression is the cause of the high bone mass human syndromes Van Buchem disease and sclerosteosis, extensive animal experimentation and clinical studies demonstrated that sclerostin plays a critical role in bone homeostasis and that its deficiency or pharmacological neutralization increases bone formation. Dysregulation of sclerostin expression also underlies the pathophysiology of skeletal disorders characterized by loss of bone mass, as well as the damaging effects of some cancers in bone...
October 12, 2016: Bone
https://www.readbyqxmd.com/read/27641475/single-dose-of-bisphosphonate-preserves-gains-in-bone-mass-following-cessation-of-sclerostin-antibody-in-brtl-osteogenesis-imperfecta-model
#6
Joseph E Perosky, Basma M Khoury, Terese N Jenks, Ferrous S Ward, Kai Cortright, Bethany Meyer, David K Barton, Benjamin P Sinder, Joan C Marini, Michelle S Caird, Kenneth M Kozloff
Sclerostin antibody has demonstrated a bone-forming effect in pre-clinical models of osteogenesis imperfecta, where mutations in collagen or collagen-associated proteins often result in high bone fragility in pediatric patients. Cessation studies in osteoporotic patients have demonstrated that sclerostin antibody, like intermittent PTH treatment, requires sequential anti-resorptive therapy to preserve the anabolic effects in adult populations. However, the persistence of anabolic gains from either drug has not been explored clinically in OI, or in any animal model...
December 2016: Bone
https://www.readbyqxmd.com/read/27558933/the-sclerostin-neutralizing-antibody-abd09097-recognizes-an-epitope-adjacent-to-sclerostin-s-binding-site-for-the-wnt-co-receptor-lrp6
#7
V Boschert, C Frisch, J W Back, K van Pee, S E Weidauer, E-M Muth, P Schmieder, M Beerbaum, A Knappik, P Timmerman, T D Mueller
The glycoprotein sclerostin has been identified as a negative regulator of bone growth. It exerts its function by interacting with the Wnt co-receptor LRP5/6, blocks the binding of Wnt factors and thereby inhibits Wnt signalling. Neutralizing anti-sclerostin antibodies are able to restore Wnt activity and enhance bone growth thereby presenting a new osteoanabolic therapy approach for diseases such as osteoporosis. We have generated various Fab antibodies against human and murine sclerostin using a phage display set-up...
August 2016: Open Biology
https://www.readbyqxmd.com/read/27525578/osteoporosis-treatment-bisphosphonates-reign-to-continue-for-a-few-more-years-at-least
#8
Michael Pazianas, Bo Abrahamsen
The findings of the Women's Health Initiative study in 2002 marginalized the use of hormone replacement therapy and established bisphosphonates as the first line of treatment for osteoporosis.  Denosumab could be used in selected patients. Although bisphosphonates only maintain the structure of bone complete with any accumulated structural or material faults, their bone selectivity and effectiveness in reducing the risk of fractures, together with their low cost, have left little room for improvement for new antiresorptives...
July 2016: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/27281399/amgen-ucb-build-on-bone-franchise-with-anti-sclerostin-antibody
#9
Suzanne Elvidge
No abstract text is available yet for this article.
June 9, 2016: Nature Biotechnology
https://www.readbyqxmd.com/read/27089204/sclerostin-inhibition-promotes-tnf-dependent-inflammatory-joint-destruction
#10
Corinna Wehmeyer, Svetlana Frank, Denise Beckmann, Martin Böttcher, Christoph Cromme, Ulrich König, Michelle Fennen, Annelena Held, Peter Paruzel, Christine Hartmann, Athanasios Stratis, Adelheid Korb-Pap, Thomas Kamradt, Ina Kramer, Wim van den Berg, Michaela Kneissel, Thomas Pap, Berno Dankbar
Sclerostin, an inhibitor of the Wnt/β-catenin pathway, has anti-anabolic effects on bone formation by negatively regulating osteoblast differentiation. Mutations in the human sclerostin gene (SOST) lead to sclerosteosis with progressive skeletal overgrowth, whereas sclerostin-deficient (Sost(-/-)) mice exhibit increased bone mass and strength. Therefore, antibody-mediated inhibition of sclerostin is currently being clinically evaluated for the treatment of postmenopausal osteoporosis in humans. We report that in chronic TNFα (tumor necrosis factor α)-dependent arthritis, fibroblast-like synoviocytes constitute a major source of sclerostin and that either the lack of sclerostin or its antibody-mediated inhibition leads to an acceleration of rheumatoid arthritis (RA)-like disease in human TNFα transgenic (hTNFtg) mice with enhanced pannus formation and joint destruction...
March 16, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27075747/anti-il-20-monoclonal-antibody-promotes-bone-fracture-healing-through-regulating-il-20-mediated-osteoblastogenesis
#11
Yu-Hsiang Hsu, Yi-Shu Chiu, Wei-Yu Chen, Kuo-Yuan Huang, I-Ming Jou, Po-Tin Wu, Chih-Hsing Wu, Ming-Shi Chang
Bone loss and skeletal fragility in bone fracture are caused by an imbalance in bone remodeling. The current challenge in bone fracture healing is to promote osteoblastogenesis and bone formation. We aimed to explore the role of IL-20 in osteoblastogenesis, osteoblast differentiation and bone fracture. Serum IL-20 was significantly correlated with serum sclerostin in patients with bone fracture. In a mouse model, anti-IL-20 monoclonal antibody (mAb) 7E increased bone formation during fracture healing. In vitro, IL-20 inhibited osteoblastogenesis by upregulating sclerostin, and downregulating osterix (OSX), RUNX2, and osteoprotegerin (OPG)...
2016: Scientific Reports
https://www.readbyqxmd.com/read/26940053/bone-pain-current-and-future-treatments
#12
REVIEW
Charlotte Ørsted Frost, Rikke Rie Hansen, Anne-Marie Heegaard
Skeletal conditions are common causes of chronic pain and there is an unmet medical need for improved treatment options. Bone pain is currently managed with disease modifying agents and/or analgesics depending on the condition. Disease modifying agents affect the underlying pathophysiology of the disease and reduce as a secondary effect bone pain. Antiresorptive and anabolic agents, such as bisphosphonates and intermittent parathyroid hormone (1-34), respectively, have proven effective as pain relieving agents...
June 2016: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/26938853/investigational-drugs-for-fracture-healing-preclinical-clinical-data
#13
Michail E Klontzas, Eustathios I Kenanidis, Robert J MacFarlane, Theodoros Michail, Michael E Potoupnis, Manolis Heliotis, Athanasios Mantalaris, Eleftherios Tsiridis
INTRODUCTION: The need for fracture healing enhancement for the management of fracture complications such as non-union and for the achievement of early function in fracture patients is constantly increasing. Therefore, the development and evaluation of novel pharmaceutical agents is mandatory in order to accelerate the process and increase bone union rates. AREAS COVERED: This review summarizes the most recent knowledge on the pharmacological enhancement of fracture repair...
2016: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/26845353/the-systemic-effects-of-sclerostin-overexpression-using-%C3%AE-c31-integrase-in-mice
#14
Dongdong Zhang, Bo Mi Park, Myengmo Kang, HeeJin Nam, Eun Jin Kim, ChuHyun Bae, Sung Kil Lim
Sclerostin, encoded by the Sost gene, is mainly produced by osteocytes in bone and antagonizes the Wnt/β-catenin signaling pathway, which is a requisite for bone formation. Currently, human anti-sclerostin antibodies are being tested in phase III clinical trials. In addition, serum sclerostin levels are reported to be associated with bone mineral density and fracture risk in normal individuals; however, the correlation between serum sclerostin and bone mass remains controversial. To study the effects of the continuous exposure of exogenous sclerostin on bone, a ΦC31 integrase system, which has the characteristics of site-specificity and efficiency, was applied for the delivery of the Sost gene in this study...
April 8, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/26785768/increased-dickkopf-1-in-recent-onset-rheumatoid-arthritis-is-a-new-biomarker-of-structural-severity-data-from-the-espoir-cohort
#15
Raphaèle Seror, Saida Boudaoud, Stephan Pavy, Gaetane Nocturne, Thierry Schaeverbeke, Alain Saraux, Philippe Chanson, Jacques-Eric Gottenberg, Valérie Devauchelle-Pensec, Gabriel J Tobón, Xavier Mariette, Corinne Miceli-Richard
Rheumatoid arthritis (RA) is the most common chronic inflammatory rheumatic condition over the world. RA is potentially disabling because chronic inflammation of the joints leads to joint destruction. To date, the best predictor of radiographic progression for patients with early RA is the presence of radiographic erosions at baseline, but a limited number of predictive biomarkers of structural progression are currently used in daily practice. Here, we investigated Dickkopf-1 (DKK-1) and sclerostin (SOST) serum levels in patients with recent inflammatory arthritis from the ESPOIR cohort...
January 20, 2016: Scientific Reports
https://www.readbyqxmd.com/read/26780446/rictor-is-required-for-optimal-bone-accrual-in-response-to-anti-sclerostin-therapy-in-the-mouse
#16
Weiwei Sun, Yu Shi, Wen-Chih Lee, Seung-Yon Lee, Fanxin Long
Wnt signaling has emerged as a major target pathway for the development of novel bone anabolic therapies. Neutralizing antibodies against the secreted Wnt antagonist sclerostin (Scl-Ab) increase bone mass in both animal models and humans. Because we have previously shown that Rictor-dependent mTORC2 activity contributes to Wnt signaling, we test here whether Rictor is required for Scl-Ab to promote bone anabolism. Mice with Rictor deleted in the early embryonic limb mesenchyme (Prx1-Cre;Rictor(f/f), hereafter RiCKO) were subjected to Scl-Ab treatment for 5weeks starting at 4months of age...
April 2016: Bone
https://www.readbyqxmd.com/read/26769006/effect-of-anti-sclerostin-therapy-and-osteogenesis-imperfecta-on-tissue-level-properties-in-growing-and-adult-mice-while-controlling-for-tissue-age
#17
Benjamin P Sinder, William R Lloyd, Joseph D Salemi, Joan C Marini, Michelle S Caird, Michael D Morris, Kenneth M Kozloff
Bone composition and biomechanics at the tissue-level are important contributors to whole bone strength. Sclerostin antibody (Scl-Ab) is a candidate anabolic therapy for the treatment of osteoporosis that increases bone formation, bone mass, and bone strength in animal studies, but its effect on bone quality at the tissue-level has received little attention. Pre-clinical studies of Scl-Ab have recently expanded to include diseases with altered collagen and material properties such as osteogenesis imperfecta (OI)...
March 2016: Bone
https://www.readbyqxmd.com/read/26768288/anti-sclerostin-is-there-an-indication
#18
Sune Larsson
Several decades ago, a clinical condition that included severe bone overgrowth was described in a few patients in South Africa. The autosomal-recessive disease that later was named sclerosteosis was found to be caused by a mutation in the SOTS gene causing a lack of the protein sclerostin. This protein is produced by osteocytes and exerts its effect as an inhibitor of bone formation by blocking the Wnt signaling pathway. By the use of a monoclonal antibody that can block sclerostin a novel therapeutic pathway for rebuilding bone has been described...
January 2016: Injury
https://www.readbyqxmd.com/read/26763740/regulation-of-sclerostin-expression-in-multiple-myeloma-by-dkk-1-a-potential-therapeutic-strategy-for-myeloma-bone-disease
#19
Homare Eda, Loredana Santo, Marc N Wein, Dorothy Z Hu, Diana D Cirstea, Neeharika Nemani, Yu-Tzu Tai, Sarah E Raines, Stuart Allen Kuhstoss, Nikhil C Munshi, Henry M Kronenberg, Noopur S Raje
Sclerostin is a potent inhibitor of osteoblastogenesis. Interestingly, newly diagnosed multiple myeloma (MM) patients have high levels of circulating sclerostin that correlate with disease stage and fractures. However, the source and impact of sclerostin in MM remains to be defined. Our goal was to determine the role of sclerostin in the biology of MM and its bone microenvironment as well as investigate the effect of targeting sclerostin with a neutralizing antibody (scl-Ab) in MM bone disease. Here we confirm increased sclerostin levels in MM compared with precursor disease states like monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM...
June 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/26728536/-newly-developed-drugs-to-improve-bone-strength
#20
REVIEW
Hiroshi Hagino
Drugs for the treatment of osteoporosis improve bone strength by inhibiting bone resorption or stimulating bone formation. New drugs already using some action mechanism such as bisphosphonate or parathyroid hormone-related peptide analog are being developed in Japan. In addition, new drugs with new action mechanisms such as cathepsin K inhibitor or anti-sclerostin antibody are also being developed and it has been reported that they have good potential to increase bone mineral density.
January 2016: Clinical Calcium
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