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C Tsentidis, D Gourgiotis, L Kossiva, A Marmarinos, A Doulgeraki, K Karavanaki
: Higher levels of Dickkopf-1, which is an inhibitor of Wnt/β-catenin bone metabolic pathway, could be indicative of downregulated Wnt system, with possible lower osteoblast activation and higher osteoclast signaling in type 1 diabetes mellitus children and adolescents. Dickkopf-1 could significantly contribute to diabetes osteopathy. INTRODUCTION: Increased fracture risk and elevated Dickkopf-1 levels, which is an inhibitor of Wnt/β-catenin bone metabolic pathway, have been documented in adult patients with type 2 diabetes mellitus (T2D), while no relevant data exist on childhood type 1 diabetes (T1D)...
October 20, 2016: Osteoporosis International
Marc N Wein, Yanke Liang, Olga Goransson, Thomas B Sundberg, Jinhua Wang, Elizabeth A Williams, Maureen J O'Meara, Nicolas Govea, Belinda Beqo, Shigeki Nishimori, Kenichi Nagano, Daniel J Brooks, Janaina S Martins, Braden Corbin, Anthony Anselmo, Ruslan Sadreyev, Joy Y Wu, Kei Sakamoto, Marc Foretz, Ramnik J Xavier, Roland Baron, Mary L Bouxsein, Thomas J Gardella, Paola Divieti-Pajevic, Nathanael S Gray, Henry M Kronenberg
Parathyroid hormone (PTH) activates receptors on osteocytes to orchestrate bone formation and resorption. Here we show that PTH inhibition of SOST (sclerostin), a WNT antagonist, requires HDAC4 and HDAC5, whereas PTH stimulation of RANKL, a stimulator of bone resorption, requires CRTC2. Salt inducible kinases (SIKs) control subcellular localization of HDAC4/5 and CRTC2. PTH regulates both HDAC4/5 and CRTC2 localization via phosphorylation and inhibition of SIK2. Like PTH, new small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation of HDAC4/5 and CRTC2...
October 19, 2016: Nature Communications
Ibrahim El Deeb Zakhary, Karl Wenger, Mohammed Elsalanty, James Cray, Mohamed Sharawy, Regina Messer
OBJECTIVE: The mandible is continuously undergoing remodeling as a result of mechanobiologic factors, such as chewing forces, tooth loss, orthodontic forces, and periodontitis. The effects of mechanical stress and biologic signals in bone homeostasis have been the focus of many investigations. However, much of this research utilized osteocytes derived from long bones, but little is known about the mandible-derived osteocytes. This study tests a protocol to isolate and grow osteocytes from rat mandible...
September 9, 2016: Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Pamela S Hinton, Peggy Nigh, John Thyfault
PURPOSE: We previously reported that 12months of resistance training (RT, 2×/wk, N=19) or jump training (JUMP, 3×/wk, N=19) increased whole body and lumbar spine BMD and increased serum bone formation markers relative to resorption in physically active (≥4h/wk) men (mean age: 44±2y; median: 44y) with osteopenia of the hip or spine. The purpose of this secondary analysis was to examine the effects of the RT or JUMP intervention on potential endocrine mediators of the exercise effects on bone, specifically IGF-I, PTH and sclerostin...
October 12, 2016: Bone
Aline G Costa, Serge Cremers, John P Bilezikian
Sclerostin a potent regulator of bone formation, is an antagonist of the Wnt-signaling pathway. The advent of assays to measure circulating sclerostin has enabled research to be performed with the aim to understand the potential role of circulating sclerostin as a pathophysiological marker in a variety of clinical settings. At this time, however, assays to measure circulating sclerostin are still relatively new and have not demonstrated consistent internal agreement in addition to which there are differences between serum and plasma levels...
October 11, 2016: Bone
Antoon H van Lierop, Natasha M Appelman-Dijkstra, Socrates E Papapoulos
Sclerosteosis and van Buchem disease are two rare bone sclerosing dysplasia caused by genetic defects in the synthesis of sclerostin. In this article we review the demographic, clinical, biochemical, radiological, and histological characteristics of patients with sclerosteosis and van Buchem disease that led to a better understanding of the role of sclerostin in bone metabolism in humans and we discuss the relevance of these findings for the development of new therapeutics for the treatment of patients with osteoporosis...
October 11, 2016: Bone
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
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 11, 2016: Bone
Hanna Taipaleenmäki, Nicholas H Farina, Andre J van Wijnen, Janet L Stein, Eric Hesse, Gary S Stein, Jane B Lian
Wnt signaling is implicated in bone formation and activated in breast cancer cells promoting primary and metastatic tumor growth. A compelling question is whether osteogenic miRNAs that increase Wnt activity for bone formation are aberrantly expressed in breast tumor cells to support metastatic bone disease. Here we report that miR-218-5p is highly expressed in bone metastases from breast cancer patients, but is not detected in normal mammary epithelial cells. Furthermore, inhibition of miR-218-5p impaired the growth of bone metastatic MDA-MB-231 cells in the bone microenvironment in vivo...
October 12, 2016: Oncotarget
Maria Felicia Faienza, Annamaria Ventura, Maurizio Delvecchio, Anna Fusillo, Laura Piacente, Gabriella Aceto, Graziana Colaianni, Silvia Colucci, Luciano Cavallo, Maria Grano, Giacomina Brunetti
CONTEXT: Childhood type 1 diabetes (T1DM) is associated with decreased bone mass. Sclerostin and dickkopf-1 (DKK-1) are Wnt inhibitors which regulate bone formation. OBJECTIVE: To evaluate sclerostin and DKK-1 levels in TD1M children and to analyze the influence of the glycaemic control on bone health. DESIGN AND SETTING: Cross-sectional study conducted at a clinical research center. Partecipants: One hundred and six T1DM subjects (12.2 ± 4 years), 66 on multiple daily injections (MDI) and 40 on continuous subcutaneous infusion of insulin (CSII), and 80 controls...
October 12, 2016: Journal of Clinical Endocrinology and Metabolism
Ashish S Shriwastav, Lubna Zafar, Anjum Anjum, S S Siddiqi
No abstract text is available yet for this article.
January 2016: Journal of the Association of Physicians of India
Hailin Yang, Jinbo Dong, Wei Xiong, Zhong Fang, Hanfeng Guan, Feng Li
Sclerostin/SOST is a robust negative regulator of bone formation. Loss-of-function mutations of the sclerostin gene (SOST) cause sclerosteosis and Van Buchem disease characterized by bone overgrowth. Mediated by myocyte enhancer factor 2 (MEF2) transcription factors, parathyroid hormone (PTH) suppresses SOST expression through formation of complexes of parathyroid hormone-parathyroid hormone-related peptide receptor 1 (PTH1R) and lipoprotein receptor-related protein 6 (LRP6). N-cadherin has been shown to negatively regulate Wnt/β-catenin and PTH induced, protein kinase-dependent β-catenin signaling...
October 10, 2016: Annals of the New York Academy of Sciences
Mildred C Embree, Mo Chen, Serhiy Pylawka, Danielle Kong, George M Iwaoka, Ivo Kalajzic, Hai Yao, Chancheng Shi, Dongming Sun, Tzong-Jen Sheu, David A Koslovsky, Alia Koch, Jeremy J Mao
Tissue regeneration using stem cell-based transplantation faces many hurdles. Alternatively, therapeutically exploiting endogenous stem cells to regenerate injured or diseased tissue may circumvent these challenges. Here we show resident fibrocartilage stem cells (FCSCs) can be used to regenerate and repair cartilage. We identify FCSCs residing within the superficial zone niche in the temporomandibular joint (TMJ) condyle. A single FCSC spontaneously generates a cartilage anlage, remodels into bone and organizes a haematopoietic microenvironment...
October 10, 2016: Nature Communications
J Delgado-Calle, X Tu, R Pacheco-Costa, K McAndrews, R Edwards, G Pellegrini, K Kuhlenschmidt, N Olivos, A Robling, M Peacock, L I Plotkin, T Bellido
Osteocytes integrate the responses of bone to mechanical and hormonal stimuli by mechanisms poorly understood. We report here that mice with conditional deletion of the parathyroid hormone (PTH) receptor 1 (Pth1r) in DMP1-8kb-expressing cells (cKO) exhibit a modest decrease in bone resorption leading to a mild increase in cancellous bone without changes in cortical bone. However, bone resorption in response to endogenous chronic elevation of PTH in growing or adult cKO mice induced by a low calcium diet remained intact, as the increased bone remodeling and bone loss was indistinguishable from that exhibited by control littermates...
October 5, 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Evangelia Kalaitzoglou, Iuliana Popescu, R Clay Bunn, John L Fowlkes, Kathryn M Thrailkill
PURPOSE OF REVIEW: To describe the effects of type 1 diabetes on bone cells. RECENT FINDINGS: Type 1 diabetes (T1D) is associated with low bone mineral density, increased risk of fractures, and poor fracture healing. Its effects on the skeleton were primarily attributed to impaired bone formation, but recent data suggests that bone remodeling and resorption are also compromised. The hyperglycemic and inflammatory environment associated with T1D impacts osteoblasts, osteocytes, and osteoclasts...
October 4, 2016: Current Osteoporosis Reports
Marta Maycas, Kevin A McAndrews, Amy Y Sato, Gretel G Pellegrini, Drew M Brown, Matthew R Allen, Lilian I Plotkin, Arancha R Gortazar, Pedro Esbrit, Teresita Bellido
There is an unmet need to understand the mechanisms underlying skeletal deterioration in diabetes mellitus (DM) and to develop therapeutic approaches to treat bone fragility in diabetic patients. We demonstrate herein that mice with type 1 DM induced by streptozotocin exhibited low bone mass, inferior mechanical and material properties, increased bone resorption, decreased bone formation, increased apoptosis of osteocytes, and increased expression of the osteocyte-derived bone formation inhibitor Sost/sclerostin...
September 28, 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
M Atteritano, E Di Mauro, V Canale, A M Bruzzese, C A Ricciardi, V Cernaro, A Lacquaniti, M Buemi, D Santoro
: In hemodialysis patients, vertebral fractures were associated with elevated sclerostin levels, suggesting that sclerostin could reflect bone fragility in these patients. INTRODUCTION: Fragility fractures are common in hemodialysis patients. The aims of our study were to determine the prevalence of vertebral fracture and analyze associations between sclerostin serum levels and vertebral fractures in hemodialysis patients. METHODS: Ninety-two hemodialysis patients and 100 controls matched for age and sex were studied...
September 28, 2016: Osteoporosis International
C Wibmer, K Amrein, A Fahrleitner-Pammer, M M Gilg, A Berghold, G C Hutterer, W Maurer-Ertl, A Gerger, A Leithner, M Pichler, J Szkandera
Sclerostin has been proposed as a potent inhibitor of bone formation. Sclerostin antibodies are under clinical development to treat osteoporosis and metastatic bone disease. Serum sclerostin level is elevated in multiple myeloma, an osteolytic malignancy, where it might serve as predictive marker for the use of sclerostin-directed antibodies. As renal cell carcinoma (RCC) patients often present with osteolytic metastases, we aimed to investigate serum sclerostin levels in RCC patients. Our study included 53 RCC patients (19 with bone metastases, 25 with visceral metastases and 9 with localized disease) and 53 age- and gender-matched non-osteoporotic controls...
September 26, 2016: Scientific Reports
Long Wu, Haohui Guo, Kening Sun, Xin Zhao, Tao Ma, Qunhua Jin
The aim of this study was to assess the expression of β-catenin, transcription factor-4 (TCF-4) and sclerostin in the subchondral bone of patients with primary knee osteoarthritis (OA). Tibial plateau specimens from patients with OA who underwent total knee arthroplasty were classified into the early stage (n=15), intermediate stage (n=13) and late stage (n=17) groups using the Mankin score. Structural parameters, including total articular cartilage (TAC), subchondral bone plate (SCP) thickness and trabecular bone volume (BV/TV), were assessed using Image-Pro Plus 6...
September 19, 2016: International Journal of Molecular Medicine
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...
September 15, 2016: Bone
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