43 results on '"John G. Logan"'
Search Results
2. Accelerating functional gene discovery in osteoarthritis
- Author
-
Natalie C. Butterfield, Katherine F. Curry, Julia Steinberg, Hannah Dewhurst, Davide Komla-Ebri, Naila S. Mannan, Anne-Tounsia Adoum, Victoria D. Leitch, John G. Logan, Julian A. Waung, Elena Ghirardello, Lorraine Southam, Scott E. Youlten, J. Mark Wilkinson, Elizabeth A. McAninch, Valerie E. Vancollie, Fiona Kussy, Jacqueline K. White, Christopher J. Lelliott, David J. Adams, Richard Jacques, Antonio C. Bianco, Alan Boyde, Eleftheria Zeggini, Peter I. Croucher, Graham R. Williams, and J. H. Duncan Bassett
- Subjects
Science - Abstract
Osteoarthritis is a chronic, heritable disease with no available treatment. Here, the authors show that a validated, rapid-throughput joint phenotyping pipeline detects osteoarthritis in the mouse knee following surgical provocation, in aging and after single gene deletion or point mutation.
- Published
- 2021
- Full Text
- View/download PDF
3. Mitoguardin-2 deficiency results in severe osteoporosis
- Author
-
Davide Komla-Ebri, Andrea S. Pollard, Penny C. Sparkes, Elena J. Ghirardello, Apostolos Gogakos, John G. Logan, Graham R. Williams, and J.H. Duncan Bassett
- Subjects
Diseases of the musculoskeletal system ,RC925-935 - Published
- 2020
- Full Text
- View/download PDF
4. Slc38a10 is a novel regulator of osteoblastic bone formation
- Author
-
Andrea S. Pollard, Davide Komla Ebri, Penny Sparkes, Apostolos Gogakos, John G. Logan, Natalie C. Butterfield, Victoria Leitch, J.H. Duncan Bassett, and Graham R. Williams
- Subjects
Diseases of the musculoskeletal system ,RC925-935 - Published
- 2020
- Full Text
- View/download PDF
5. Publisher Correction: Accelerating functional gene discovery in osteoarthritis
- Author
-
Natalie C. Butterfield, Katherine F. Curry, Julia Steinberg, Hannah Dewhurst, Davide Komla-Ebri, Naila S. Mannan, Anne-Tounsia Adoum, Victoria D. Leitch, John G. Logan, Julian A. Waung, Elena Ghirardello, Lorraine Southam, Scott E. Youlten, J. Mark Wilkinson, Elizabeth A. McAninch, Valerie E. Vancollie, Fiona Kussy, Jacqueline K. White, Christopher J. Lelliott, David J. Adams, Richard Jacques, Antonio C. Bianco, Alan Boyde, Eleftheria Zeggini, Peter I. Croucher, Graham R. Williams, and J. H. Duncan Bassett
- Subjects
Science - Published
- 2021
- Full Text
- View/download PDF
6. Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density.
- Author
-
Anna L Swan, Christine Schütt, Jan Rozman, Maria Del Mar Muñiz Moreno, Stefan Brandmaier, Michelle Simon, Stefanie Leuchtenberger, Mark Griffiths, Robert Brommage, Piia Keskivali-Bond, Harald Grallert, Thomas Werner, Raffaele Teperino, Lore Becker, Gregor Miller, Ala Moshiri, John R Seavitt, Derek D Cissell, Terrence F Meehan, Elif F Acar, Christopher J Lelliott, Ann M Flenniken, Marie-France Champy, Tania Sorg, Abdel Ayadi, Robert E Braun, Heather Cater, Mary E Dickinson, Paul Flicek, Juan Gallegos, Elena J Ghirardello, Jason D Heaney, Sylvie Jacquot, Connor Lally, John G Logan, Lydia Teboul, Jeremy Mason, Nadine Spielmann, Colin McKerlie, Stephen A Murray, Lauryl M J Nutter, Kristian F Odfalk, Helen Parkinson, Jan Prochazka, Corey L Reynolds, Mohammed Selloum, Frantisek Spoutil, Karen L Svenson, Taylor S Vales, Sara E Wells, Jacqueline K White, Radislav Sedlacek, Wolfgang Wurst, K C Kent Lloyd, Peter I Croucher, Helmut Fuchs, Graham R Williams, J H Duncan Bassett, Valerie Gailus-Durner, Yann Herault, Ann-Marie Mallon, Steve D M Brown, Philipp Mayer-Kuckuk, Martin Hrabe de Angelis, and IMPC Consortium
- Subjects
Genetics ,QH426-470 - Abstract
The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.
- Published
- 2020
- Full Text
- View/download PDF
7. Pharmacological Inhibition of NFκB Reduces Prostate Cancer Related Osteoclastogenesis In Vitro and Osteolysis Ex Vivo
- Author
-
Silvia Marino, Giovana Carrasco, Aymen I. Idris, Ryan T. Bishop, John G. Logan, and Boya Li
- Subjects
Male ,musculoskeletal diseases ,0301 basic medicine ,Osteolysis ,Cell Survival ,Endocrinology, Diabetes and Metabolism ,Osteoclasts ,Apoptosis ,030209 endocrinology & metabolism ,DNA Fragmentation ,Mice ,03 medical and health sciences ,Prostate cancer ,Organ Culture Techniques ,0302 clinical medicine ,Endocrinology ,Osteogenesis ,Osteoclast ,Cell Line, Tumor ,Bone cell ,Cell Adhesion ,medicine ,Animals ,Humans ,Orthopedics and Sports Medicine ,Neoplasm Metastasis ,Osteoblasts ,biology ,Chemistry ,NF-kappa B p50 Subunit ,Prostatic Neoplasms ,Cancer ,Osteoblast ,X-Ray Microtomography ,medicine.disease ,Coculture Techniques ,Rats ,Mice, Inbred C57BL ,medicine.anatomical_structure ,RANKL ,Cancer cell ,Cancer research ,biology.protein ,030101 anatomy & morphology ,Sesquiterpenes ,Signal Transduction - Abstract
NFκB is implicated in cancer and bone remodelling, and we have recently reported that the verified NFκB inhibitor Parthenolide (PTN) reduced osteolysis and skeletal tumour growth in models of metastatic breast cancer. Here, we took advantage of in vitro and ex vivo bone cell and organ cultures to study the effects of PTN on the ability of prostate cancer cells and their derived factors to regulate bone cell activity and osteolysis. PTN inhibited the in vitro growth of a panel of human, mouse and rat prostate cancer cells in a concentration-dependent manner with a varying degree of potency. In prostate cancer cell-osteoclast co-cultures, the rat Mat-Ly-Lu, but not human PC3 or mouse RM1-BT, enhanced RANKL stimulated osteoclast formation and PTN reduced these effects without affecting prostate cancer cell viability. In the absence of cancer cells, PTN reduced the support of Mat-Ly-Lu conditioned medium for the adhesion and spreading of osteoclast precursors, and survival of mature osteoclasts. Pre-exposure of osteoblasts to PTN prior to the addition of conditioned medium from Mat-Ly-Lu cells suppressed their ability to support the formation of osteoclasts by inhibition of RANKL/OPG ratio. PTN enhanced the ability of Mat-Ly-Lu derived factors to increase calvarial osteoblast differentiation and growth. Ex vivo, PTN enhanced bone volume in calvaria organ-Mat-Ly-Lu cell co-culture, without affecting Mat-Ly-Lu viability or apoptosis. Mechanistic studies in osteoclasts and osteoblasts confirmed that PTN inhibit NFκB activation related to derived factors from Mat-Ly-Lu cells. Collectively, these findings suggest that pharmacological inhibition of the skeletal NFκB signalling pathway reduces prostate cancer related osteolysis, but further studies in the therapeutic implications of NFκB inhibition in cells of the osteoblastic lineage are needed.
- Published
- 2019
8. Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density
- Author
-
Paul Flicek, Raffaele Teperino, Lydia Teboul, Thomas Werner, Marie-France Champy, Christopher J. Lelliott, Graham R. Williams, Jacqueline K. White, Gregor Miller, Mary E. Dickinson, Ann M Flenniken, Radislav Sedlacek, Martin Hrabé de Angelis, John R. Seavitt, Peter I. Croucher, Maria del Mar Muniz Moreno, Sara Wells, Jan Rozman, Terrence F. Meehan, Kristian F Odfalk, Juan Gallegos, J. H. Duncan Bassett, Mohammed Selloum, John G. Logan, Sylvie Jacquot, Elena J. Ghirardello, Robert Braun, Frantisek Spoutil, Kevin C K Lloyd, Lore Becker, Stephen A. Murray, Jan Prochazka, Elif F. Acar, Taylor S Vales, Michelle Simon, Helmut Fuchs, Nadine Spielmann, Mark Griffiths, Piia Keskivali-Bond, Valerie Gailus-Durner, Tania Sorg, Christine Schütt, Jeremy Mason, Helen Parkinson, Karen L. Svenson, Abdel Ayadi, Anna L Swan, Jason D. Heaney, Colin McKerlie, Wolfgang Wurst, Ann-Marie Mallon, Heather Cater, Stefanie Leuchtenberger, Harald Grallert, Steve D.M. Brown, Stefan Brandmaier, Yann Herault, Philipp Mayer-Kuckuk, Corey L. Reynolds, Ala Moshiri, Robert Brommage, Derek D. Cissell, Lauryl M J Nutter, Connor Lally, MRC Harwell Institute [UK], German Research Center for Environmental Health - Helmholtz Center München (GmbH), German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), Institute of Molecular Genetics of the Czech Academy of Sciences (IMG / CAS), Czech Academy of Sciences [Prague] (CAS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Helmholtz-Zentrum München (HZM), The Wellcome Trust Sanger Institute [Cambridge], University of Michigan [Ann Arbor], University of Michigan System, University of California [Davis] (UC Davis), University of California, Baylor College of Medicine (BCM), Baylor University, European Molecular Biology Laboratory [Hinxton], University of Toronto, University of Manitoba [Winnipeg], Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], French National Infrastructure for Mouse Phenogenomics (PHENOMIN), The Jackson Laboratory [Bar Harbor] (JAX), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Imperial College London, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Deutsches Zentrum für Neurodegenerative Erkrankungen [Ulm] (DZNE), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Garvan Institute of Medical Research [Sydney, Australia], St. Vincent’s Clinical School [Sydney, Australia], UNSW Faculty of Medicine [Sydney], University of New South Wales [Sydney] (UNSW)-University of New South Wales [Sydney] (UNSW), Université de Nouvelle-Galles du Sud - UNSW [Sydney, Australia], Mundlos, Stefan, Wellcome Trust, Commission of the European Communities, European Commission, Herault, Yann, Helmholtz Zentrum München = German Research Center for Environmental Health, University of California (UC), Garvan Institute of medical research, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Technische Universität München [München] (TUM), Technische Universität München [München] (TUM)-Ludwig-Maximilians-Universität München (LMU), Swan, Anna L [0000-0003-1810-3756], Rozman, Jan [0000-0002-8035-8904], Del Mar Muñiz Moreno, Maria [0000-0002-2662-890X], Leuchtenberger, Stefanie [0000-0003-2475-0810], Brommage, Robert [0000-0002-9947-3822], Grallert, Harald [0000-0002-6876-9655], Werner, Thomas [0000-0003-0402-4539], Teperino, Raffaele [0000-0001-8815-1409], Becker, Lore [0000-0002-6890-4984], Miller, Gregor [0000-0002-4281-4905], Seavitt, John R [0000-0003-3209-3187], Cissell, Derek D [0000-0002-6450-422X], Acar, Elif F [0000-0003-2908-7691], Lelliott, Christopher J [0000-0001-8087-4530], Braun, Robert E [0000-0003-3856-9465], Cater, Heather [0000-0002-8696-6070], Flicek, Paul [0000-0002-3897-7955], Ghirardello, Elena J [0000-0002-1100-9217], Heaney, Jason D [0000-0001-8475-8828], Lally, Connor [0000-0002-3801-1966], Logan, John G [0000-0003-2801-700X], Mason, Jeremy [0000-0002-2796-5123], Nutter, Lauryl MJ [0000-0001-9619-146X], Odfalk, Kristian F [0000-0003-4152-4583], Prochazka, Jan [0000-0003-4675-8995], Selloum, Mohammed [0000-0003-4057-3519], Spoutil, Frantisek [0000-0002-7310-3487], Svenson, Karen L [0000-0002-7928-1911], Vales, Taylor S [0000-0001-9751-5681], Wells, Sara E [0000-0002-0572-0600], White, Jacqueline K [0000-0001-6268-2826], Sedlacek, Radislav [0000-0002-3352-392X], Wurst, Wolfgang [0000-0003-4422-7410], Lloyd, KC Kent [0000-0002-5318-4144], Williams, Graham R [0000-0002-8555-8219], Herault, Yann [0000-0001-7049-6900], Brown, Steve DM [0000-0002-0617-4824], Hrabe de Angelis, Martin [0000-0002-7898-2353], and Apollo - University of Cambridge Repository
- Subjects
Male ,Osteoporosis ,genetics [Gene Expression Regulation] ,Transgenic ,Transcriptome ,Mice ,0302 clinical medicine ,Animal Cells ,Aetiology ,Musculoskeletal System ,Connective Tissue Cells ,Genetics & Heredity ,0303 health sciences ,Genomics ,3. Good health ,Cellular Types ,musculoskeletal diseases ,Genotype ,In silico ,1.1 Normal biological development and functioning ,03 medical and health sciences ,genetics [Osteoporosis] ,Rheumatology ,pathology [Osteoblasts] ,Genetic ,Genome-Wide Association Studies ,Genetics ,GENOME-WIDE ASSOCIATION ,Molecular Biology ,Skeleton ,Ecology, Evolution, Behavior and Systematics ,METAANALYSIS ,metabolism [Osteoblasts] ,0604 Genetics ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Science & Technology ,Osteoblasts ,IDENTIFICATION ,Biology and Life Sciences ,Computational Biology ,medicine.disease ,COLLAGEN ,Biological Tissue ,OSTEOGENESIS IMPERFECTA ,DISCOVERY ,IMPC Consortium ,Mutation ,Animal Studies ,Developmental Biology ,Candidate gene ,Cancer Research ,Bone density ,Gene Expression ,Osteoclasts ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,QH426-470 ,Bone remodeling ,Bone Density ,Medicine and Health Sciences ,2.1 Biological and endogenous factors ,Protein Interaction Maps ,Connective Tissue Diseases ,Promoter Regions, Genetic ,Genetics (clinical) ,Bone mineral ,Sex Characteristics ,genetics [Bone Density] ,metabolism [Osteoclasts] ,Genetic Pleiotropy ,Animal Models ,pathology [Osteoclasts] ,Phenotype ,DIFFERENTIATION ,Experimental Organism Systems ,ANIMAL-MODELS ,Connective Tissue ,SEX ,Female ,Anatomy ,Technology Platforms ,Life Sciences & Biomedicine ,Research Article ,metabolism [Osteoporosis] ,Mouse Models ,030209 endocrinology & metabolism ,Mice, Transgenic ,Biology ,Research and Analysis Methods ,Promoter Regions ,Model Organisms ,Underpinning research ,medicine ,Animals ,ddc:610 ,Bone ,030304 developmental biology ,Human Genetics ,Cell Biology ,Genome Analysis ,Gene Ontology ,Gene Expression Regulation ,Musculoskeletal ,Genome-Wide Association Study - Abstract
The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease., Author summary Patients affected by osteoporosis frequently present with decreased BMD and increased fracture risk. Genes are known to control the onset and progression of bone diseases such as osteoporosis. Therefore, we aimed to identify osteoporosis-related genes using BMD measures obtained from a large pool of mutant mice genetically modified for deletion of individual genes (knockout mice). In a collaborative endeavor involving several research sites world-wide, we generated and phenotyped 3,823 knockout mice and identified 200 genes which regulated BMD. Of the 200 BMD genes, 141 genes were previously not known to affect BMD. The discovery and study of novel BMD genes will help to better understand the causes and therapeutic options for patients with low BMD. In the long run, this will improve the clinical management of osteoporosis.
- Published
- 2021
- Full Text
- View/download PDF
9. Slc38a10 is a novel regulator of osteoblastic bone formation
- Author
-
Graham R. Williams, Davide Komla Ebri, Andrea S. Pollard, Victoria D. Leitch, J. H. Duncan Bassett, John G. Logan, Penny C. Sparkes, Apostolos Gogakos, and Natalie C. Butterfield
- Subjects
lcsh:Diseases of the musculoskeletal system ,Chemistry ,Endocrinology, Diabetes and Metabolism ,Regulator ,Orthopedics and Sports Medicine ,Bone formation ,lcsh:RC925-935 ,Cell biology - Published
- 2020
10. Functional validation of the osteoporosis GWAS candidate FUBP3 in knockout mice
- Author
-
Natalie C. Butterfield, Bernard Freudenthal, Davide Komla-Ebri, Naila S. Mannan, J. H. Duncan Bassett, Graham R. Williams, Andrea S. Pollard, John G. Logan, Laura Watts, and Victoria D. Leitch
- Subjects
Functional validation ,lcsh:Diseases of the musculoskeletal system ,business.industry ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,Knockout mouse ,medicine ,Orthopedics and Sports Medicine ,Genome-wide association study ,lcsh:RC925-935 ,medicine.disease ,Bioinformatics ,business - Published
- 2020
11. Author response: A trans-eQTL network regulates osteoclast multinucleation and bone mass
- Author
-
John G. Logan, Hayley Protheroe, Jeong-Hun Ko, Kee-Beom Kim, Graham R. Williams, Kwon-Sik Park, Jacques Behmoaras, Peter I. Croucher, J. H. Duncan Bassett, Enrico Petretto, Marie Pereira, Maxime Rotival, and Amelia Li Min Tan
- Subjects
medicine.anatomical_structure ,Osteoclast ,Chemistry ,Expression quantitative trait loci ,medicine ,Cell biology ,Bone mass - Published
- 2020
12. IGSF1 deficiency results in human and murine somatotrope neurosecretory hyperfunction
- Author
-
Graham R. Williams, Frederik J. Steyn, Robert P Kosilek, Pierre Fontanaud, Marc-Olivier Turgeon, J. H. Duncan Bassett, Herman M. Kroon, Mark Gurnell, Daniel J. Bernard, Nadia Schoenmakers, John G. Logan, Emilie Brûlé, Chirine Toufaily, Xiang Zhou, Wilma Oostdijk, Jan M. Wit, Beata Bak, Ferdinand Roelfsema, Alberto M. Pereira, A S Paul van Trotsenburg, Harald Jörn Schneider, Paul Le Tissier, Sjoerd D. Joustra, Natalie C. Butterfield, Olympia Koulouri, Nienke R. Biermasz, Gurnell, Mark [0000-0001-5745-6832], Schoenmakers, Nadia [0000-0002-0847-2884], Apollo - University of Cambridge Repository, Paediatric Endocrinology, AGEM - Endocrinology, metabolism and nutrition, and ANS - Cellular & Molecular Mechanisms
- Subjects
Male ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Biochemistry ,pituitary ,Basal (phylogenetics) ,Mice ,Endocrinology ,0302 clinical medicine ,Insulin-Like Growth Factor I ,Aged, 80 and over ,Intercellular Signaling Peptides and Proteins/deficiency ,0303 health sciences ,Neurosecretion ,Middle Aged ,Growth hormone secretion ,Hypoprolactinemia ,3. Good health ,Online Only ,Hypothalamus ,Intercellular Signaling Peptides and Proteins ,AcademicSubjects/MED00250 ,Adult ,medicine.medical_specialty ,Insulin-Like Growth Factor I/analysis ,Membrane Proteins/deficiency ,Somatotropic cell ,Immunoglobulins ,030209 endocrinology & metabolism ,Biology ,03 medical and health sciences ,Internal medicine ,Central hypothyroidism ,medicine ,Animals ,Humans ,Somatotrophs/physiology ,Clinical Research Articles ,congenital hypopituitarism ,030304 developmental biology ,Aged ,Neurosecretion/physiology ,IGSF1 ,Macroorchidism ,Biochemistry (medical) ,Membrane Proteins ,Hyperfunction ,medicine.disease ,Somatotrophs ,growth hormone ,Immunoglobulins/deficiency ,Growth Hormone/biosynthesis - Abstract
Context The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition. Objective We aimed to evaluate the role of IGSF1 in human and murine somatotrope function. Patients, Design, and Setting We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting. Main Outcome Measures We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates. Results IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels. Conclusions We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure.
- Published
- 2020
13. A trans-eQTL network regulates osteoclast multinucleation and bone mass
- Author
-
John G. Logan, Jeong-Hun Ko, J. H. Duncan Bassett, Hayley Protheroe, Kee-Beom Kim, Graham R. Williams, Enrico Petretto, Jacques Behmoaras, Kwon-Sik Park, Marie Pereira, Maxime Rotival, and Amelia Li Min Tan
- Subjects
0303 health sciences ,Gene regulatory network ,Genome-wide association study ,Biology ,Osteoclast fusion ,Phenotype ,Resorption ,Cell biology ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Osteoclast ,030220 oncology & carcinogenesis ,Knockout mouse ,medicine ,Gene ,030304 developmental biology - Abstract
Functional characterisation of cell-type specific regulatory networks is key to establish a causal link between genetic variation and phenotype. The osteoclast offers a unique model for interrogating the contribution of co-regulated genes to in vivo phenotype as its multinucleation and resorption activities determine quantifiable skeletal traits. Here we took advantage of a trans-regulated gene network (MMnet, macrophage multinucleation network) which we found to be significantly enriched for GWAS variants associated with bone-related phenotypes. We found that the network hub gene Bcat1 and seven other co-regulated MMnet genes out of 13, regulate bone function. Specifically, global (Pik3cb−/−, Atp8b2+/−, Igsf8−/−, Eml1−/−, Appl2−/−, Deptor−/−) and myeloid-specific Slc40a1ΔLysMCre knockout mice displayed abnormal bone phenotypes. We report antagonizing effects of MMnet genes on bone mass in mice and osteoclast multinucleation/resorption in humans with strong correlation between the two. These results identify MMnet as a functionally conserved network that regulates osteoclast fusion and bone mass.Impact statementWe took advantage of the osteoclast whose multinucleation properties correlate with bone mass. We show that a trans-regulated gene network (MMnet) controls skeletal homeostasis through osteoclast multinucleation and function.
- Published
- 2020
14. A trans-eQTL network regulates osteoclast multinucleation and bone mass
- Author
-
Jacques Behmoaras, Marie Pereira, Enrico Petretto, Peter I. Croucher, Amelia Li Min Tan, Kwon-Sik Park, Graham R. Williams, J. H. Duncan Bassett, Maxime Rotival, Jeong-Hun Ko, Hayley Protheroe, Kee-Beom Kim, John G. Logan, Imperial College London, Hammersmith Hospital NHS Imperial College Healthcare, University of Virginia, Duke-NUS Medical School [Singapore], University of New South Wales [Sydney] (UNSW), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Medical Research Council ‘Control of Macrophage Multinucleation in Health and Disease’ (MR/N01121X/1 to JB, GRW, JHDB), a Wellcome Trust Strategic Award (Grant Number 101123 to GRW and JHDB) and National Institutes of Health/ National Cancer Institute (NIH/NCI U01CA224293)., and Medical Research Council (MRC)
- Subjects
0301 basic medicine ,Life Sciences & Biomedicine - Other Topics ,Male ,Network - organization ,Rat and human model ,Gene regulatory network ,Cell biology and structure ,Osteoclasts ,Genome-wide association study ,DETERMINANTS ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,0601 Biochemistry and Cell Biology ,Rats, Inbred WKY ,bone ,Mice ,0302 clinical medicine ,Bone Density ,genetics ,Gene Regulatory Networks ,rat ,Biology (General) ,MACROPHAGES ,Genomics and evolution ,RISK ,Mice, Knockout ,General Neuroscience ,General Medicine ,Phenotype ,Cell biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Knockout mouse ,osteoclast ,Genetics Humans ,Medicine ,PHOSPHATIDYLINOSITOL 3-KINASE ,Bone Biology ,Female ,Human - human interaction ,Life Sciences & Biomedicine ,Research Article ,Human ,Osteoclast gene ,QH301-705.5 ,Science ,Quantitative Trait Loci ,Quantitative trait locus ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Bone resorption ,03 medical and health sciences ,Osteoclast ,medicine ,genomics ,Animals ,GENOME-WIDE ASSOCIATION ,DC-STAMP ,Bone Resorption ,Gene ,METAANALYSIS ,mouse ,Science & Technology ,General Immunology and Microbiology ,COMPLEX TRAITS ,Genetics and Genomics ,Cell Biology ,Rats ,030104 developmental biology ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Rats, Inbred Lew ,network ,SYSTEMS GENETICS ,MINERAL DENSITY ,Genome-Wide Association Study - Abstract
International audience; Functional characterisation of cell-type-specific regulatory networks is key to establish a causal link between genetic variation and phenotype. The osteoclast offers a unique model for interrogating the contribution of co-regulated genes to in vivo phenotype as its multinucleation and resorption activities determine quantifiable skeletal traits. Here we took advantage of a trans-regulated gene network (MMnet, macrophage multinucleation network) which we found to be significantly enriched for GWAS variants associated with bone-related phenotypes. We found that the network hub gene Bcat1 and seven other co-regulated MMnet genes out of 13, regulate bone function. Specifically, global (Pik3cb-/-, Atp8b2+/-, Igsf8-/-, Eml1-/-, Appl2-/-, Deptor-/-) and myeloid-specific Slc40a1 knockout mice displayed abnormal bone phenotypes. We report opposing effects of MMnet genes on bone mass in mice and osteoclast multinucleation/resorption in humans with strong correlation between the two. These results identify MMnet as a functionally conserved network that regulates osteoclast multinucleation and bone mass.
- Published
- 2020
15. Accelerating functional gene discovery in osteoarthritis
- Author
-
Hannah F. Dewhurst, Peter I. Croucher, Julian A. Waung, Elena J. Ghirardello, Jacqueline K. White, Julia Steinberg, Anne-Tounsia Adoum, J. Mark Wilkinson, Graham R. Williams, Alan Boyde, John G. Logan, Valerie E. Vancollie, Naila S. Mannan, J. H. Duncan Bassett, Fiona Kussy, Natalie C. Butterfield, Davide Komla-Ebri, Lorraine Southam, Antonio C. Bianco, Scott E. Youlten, Victoria D. Leitch, Katherine F. Curry, Christopher J. Lelliott, David J. Adams, Elizabeth A. McAninch, Eleftheria Zeggini, Richard Jacques, Wellcome Trust, Commission of the European Communities, European Commission, Butterfield, Natalie C [0000-0002-5209-7508], Steinberg, Julia [0000-0002-0585-2312], Komla-Ebri, Davide [0000-0002-8381-5381], Leitch, Victoria D [0000-0001-5760-2887], Youlten, Scott E [0000-0001-9314-2945], Wilkinson, J Mark [0000-0001-5577-3674], McAninch, Elizabeth A [0000-0003-3993-4663], Vancollie, Valerie E [0000-0003-1547-1975], Lelliott, Christopher J [0000-0001-8087-4530], Adams, David J [0000-0001-9490-0306], Jacques, Richard [0000-0001-6710-5403], Boyde, Alan [0000-0002-9871-5498], Zeggini, Eleftheria [0000-0003-4238-659X], Croucher, Peter I [0000-0002-7102-2413], Williams, Graham R [0000-0002-8555-8219], Bassett, JH Duncan [0000-0003-0817-0082], and Apollo - University of Cambridge Repository
- Subjects
musculoskeletal diseases ,0301 basic medicine ,Science ,Mutant ,General Physics and Astronomy ,Osteoarthritis ,Bioinformatics ,Iodide Peroxidase ,Bone and Bones ,General Biochemistry, Genetics and Molecular Biology ,Article ,Gonadotropin-Releasing Hormone ,International Knockout Mouse Consortium ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Genome editing ,Drug Discovery ,medicine ,Animals ,Paired Box Transcription Factors ,CRISPR ,Clustered Regularly Interspaced Short Palindromic Repeats ,Genetic Predisposition to Disease ,Bone ,Gene ,Genetic Association Studies ,030304 developmental biology ,Gene Editing ,Mice, Knockout ,030203 arthritis & rheumatology ,0303 health sciences ,Multidisciplinary ,Drug discovery ,Cas9 ,business.industry ,General Chemistry ,medicine.disease ,Publisher Correction ,Phenotype ,3. Good health ,Disease Models, Animal ,030104 developmental biology ,Cartilage ,CRISPR-Cas Systems ,business - Abstract
Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease., Osteoarthritis is a chronic, heritable disease with no available treatment. Here, the authors show that a validated, rapid-throughput joint phenotyping pipeline detects osteoarthritis in the mouse knee following surgical provocation, in aging and after single gene deletion or point mutation.
- Published
- 2019
16. Regulation of breast cancer induced bone disease by cancer-specific IKKβ
- Author
-
Andrew H. Sims, Mattia Capulli, Luca Ventura, Stuart H. Ralston, Aymen I. Idris, Ryan T. Bishop, Antonia Sophocleous, Silvia Marino, Barbara Mognetti, Nadia Rucci, John G. Logan, and Patrick Mollat
- Subjects
Bone metastasis ,Breast cancer ,IKKβ ,NFκB ,Osteolysis ,Oncology ,0301 basic medicine ,Bone disease ,03 medical and health sciences ,breast cancer ,Osteoclast ,medicine ,skin and connective tissue diseases ,bone metastasis ,business.industry ,Cancer ,Osteoblast ,medicine.disease ,NFKB ,Vascular endothelial growth factor A ,030104 developmental biology ,medicine.anatomical_structure ,osteoclast ,osteoblast ,Cancer research ,osteolysis ,business ,Research Paper - Abstract
NFκB is implicated in breast cancer bone metastasis and skeletal remodelling. However, the role of IKKβ, a key component of the canonical NFκB pathway, in the regulation of breast cancer osteolytic metastasis has not been investigated. Here, we describe the cancer-specific contribution of IKKβ to bone metastasis, skeletal tumour growth and osteolysis associated with breast cancer. IKKβ is highly expressed in invasive breast tumours and its level of expression was higher in patients with bone metastasis. IKKβ overexpression in parental MDA-MD-231 breast cancer cells, promoted mammary tumour growth but failed to convey osteolytic potential to these cells in mice. In contrast, IKKβ overexpression in osteotropic sub-clones of MDA-MB-231 cells with differing osteolytic phenotypes increased incidence of bone metastasis, exacerbated osteolysis and enhanced skeletal tumour growth, whereas its knockdown was inhibitory. Functional and mechanistic studies revealed that IKKβ enhanced the ability of osteotropic MDA-MB-231 cells to migrate, increase osteoclastogenesis, and to inhibit osteoblast differentiation via a mechanism mediated, at least in part, by cytoplasmic sequestering of FoxO3a and VEGFA production. Thus, tumour-selective manipulation of IKKβ and its interaction with FoxO3a may represent a novel strategy to reduce the development of secondary breast cancer in the skeleton.
- Published
- 2018
17. PYY is a negative regulator of bone mass and strength
- Author
-
Victoria D, Leitch, Mary Jane, Brassill, Sofia, Rahman, Natalie C, Butterfield, Pattara, Ma, John G, Logan, Alan, Boyde, Holly, Evans, Peter I, Croucher, Rachel L, Batterham, Graham R, Williams, and J H Duncan, Bassett
- Subjects
Male ,Mice, Knockout ,Bone Development ,PYY ,Osteoblast ,digestive, oral, and skin physiology ,Osteoclasts ,Organ Size ,Bone and Bones ,Article ,Mice, Inbred C57BL ,Calcification, Physiologic ,Fracture ,Bone Density ,Cortical Bone ,Bone mineral density ,Animals ,Osteoporosis ,Female ,Peptide YY ,Femur ,Bone Resorption ,Porosity ,hormones, hormone substitutes, and hormone antagonists - Abstract
Objective Bone loss in anorexia nervosa and following bariatric surgery is associated with an elevated circulating concentration of the gastrointestinal, anorexigenic hormone, peptide YY (PYY). Selective deletion of the PYY receptor Y1R in osteoblasts or Y2R in the hypothalamus results in high bone mass, but deletion of PYY in mice has resulted in conflicting skeletal phenotypes leading to uncertainty regarding its role in the regulation of bone mass. As PYY analogs are under development for treatment of obesity, we aimed to clarify the relationship between PYY and bone mass. Methods The skeletal phenotype of Pyy knockout (KO) mice was investigated during growth (postnatal day P14) and adulthood (P70 and P186) using X-ray microradiography, micro-CT, back-scattered electron scanning electron microscopy (BSE-SEM), histomorphometry and biomechanical testing. Results Bones from juvenile and Pyy KO mice were longer (P, Highlights • Juvenile Pyy KO mice have accelerated growth and reduced bone mass. • Adult Pyy KO mice have increased bone mass and mineralisation. • Adult Pyy KO mice have increased osteoblastic bone formation and mineral apposition. • Adult Pyy KO mice have increased bone strength despite increased porosity. • Elevated PYY implicated in the pathogenesis of weight loss related osteoporosis.
- Published
- 2019
18. Quantitative X-Ray Imaging of Mouse Bone by Faxitron
- Author
-
Natalie C, Butterfield, John G, Logan, Julian, Waung, Graham R, Williams, and J H Duncan, Bassett
- Subjects
Mice ,Bone Density ,Models, Animal ,Image Processing, Computer-Assisted ,Animals ,Microradiography ,Bone and Bones ,Software - Abstract
This chapter describes the use of point projection digital microradiography for rapid imaging and quantitation of bone mineral content in mice.
- Published
- 2019
19. Mitoguardin-2 deficiency results in severe osteoporosis
- Author
-
Graham R. Williams, Andrea S. Pollard, J. H. Duncan Bassett, Apostolos Gogakos, Davide Komla-Ebri, Penny C. Sparkes, Elena J. Ghirardello, and John G. Logan
- Subjects
Pediatrics ,medicine.medical_specialty ,lcsh:Diseases of the musculoskeletal system ,business.industry ,Endocrinology, Diabetes and Metabolism ,medicine ,Severe osteoporosis ,Orthopedics and Sports Medicine ,lcsh:RC925-935 ,business - Published
- 2020
20. An Atlas of Human and Murine Genetic Influences on Osteoporosis
- Author
-
Laetitia Laurent, Naila S. Mannan, Stephen Kaptoge, John A. Morris, Carolina Medina-Gomez, David Karasik, Cyrus Cooper, Cheryl L. Ackert-Bicknell, Anne-Tounsia Adoum, Jonathan H Tobias, Victoria D. Leitch, David A. Hinds, Katharine F. Curry, David J. Adams, Penny C. Sparkes, Scott E. Youlten, Aimee Lee Luco, Thomas A D Hassall, Marie-Michelle Simon, Elena J. Ghirardello, Celia L Gregson, Paul A. Baldock, Andrea S. Pollard, Suzanne M. Vaillancourt, Matthew T. Maurano, Albena Pramatarova, Graham R. Williams, Katerina Trajanoska, Nicholas A. Vulpescu, Nicholas C. Harvey, Loan Nguyen-Yamamoto, C. Marcelo Sergio, Fernando Rivadeneira, David Goltzman, Douglas J. Adams, John P. Kemp, Evangelia E. Ntzani, Hannah F. Dewhurst, David M. Evans, Vincenzo Forgetta, Davide Komla-Ebri, Sindhu T. Mohanty, Aaron Kleinman, Julian M.W. Quinn, Evangelos Evangelou, J. H. Duncan Bassett, Christopher J. Lelliott, Douglas P. Kiel, Jinchu Vijay, Peter I. Croucher, Elin Grundberg, Yi-Hsiang Hsu, Natalie C. Butterfield, Jonathan Reeve, Michael-John G. Beltejar, Ryan C. Chai, Claes Ohlsson, J. Brent Richards, and John G. Logan
- Subjects
Bone mineral ,0303 health sciences ,medicine.medical_specialty ,Bone density ,Osteoporosis ,Bone fracture ,Odds ratio ,Biology ,medicine.disease ,Phenotype ,3. Good health ,Chromatin ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,Gene ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Osteoporosis is a common debilitating chronic disease diagnosed primarily using bone mineral density (BMD). We undertook a comprehensive assessment of human genetic determinants of bone density in 426,824 individuals, identifying a total of 518 genome-wide significant loci, (301 novel), explaining 20% of the total variance in BMD—as estimated by heel quantitative ultrasound (eBMD). Next, meta-analysis identified 13 bone fracture loci in ~1.2M individuals, which were also associated with BMD. We then identified target genes from cell-specific genomic landscape features, including chromatin conformation and accessible chromatin sites, that were strongly enriched for genes known to influence bone density and strength (maximum odds ratio = 58, P = 10−75). We next performed rapid throughput skeletal phenotyping of 126 knockout mice lacking eBMD Target Genes and showed that these mice had an increased frequency of abnormal skeletal phenotypes compared to 526 unselected lines (P < 0.0001). In-depth analysis of one such Target Gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This comprehensive human and murine genetic atlas provides empirical evidence testing how to link associated SNPs to causal genes, offers new insights into osteoporosis pathophysiology and highlights opportunities for drug development.
- Published
- 2018
- Full Text
- View/download PDF
21. Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects
- Author
-
Hans Bisgaard, Leon Eyrich Jessen, John G. Logan, Gudmar Porleifsson, Hou-Feng Zheng, Annelies C. Ham, Tarunveer S. Ahluwalia, Struan F.A. Grant, Yongmei Liu, M. Carola Zillikens, Ivana Nedeljkovic, Mattias Lorentzon, Daniel S. Evans, Kari Stefansson, Jing Hua Zhao, Gunnar Sigurdsson, Fiona E. McGuigan, Rebecca D. Jackson, Douglas P. Kiel, M. Arfan Ikram, David Karasik, J. Brent Richards, Scott Wilson, Tamara B. Harris, Najaf Amin, James F. Wilson, Peter I. Croucher, John A Robbins, Carolina Medina-Gomez, Raimo Joro, Frances M K Williams, Stuart H. Ralston, Unnur Styrkarsdottir, Timo A. Lakka, Jian'an Luan, Cheryl L. Ackert-Bicknell, John P. Walsh, Benjamin H. Mullin, Fernando Pires Hartwig, Bruce M. Psaty, Robert A. Scott, Claes Ohlsson, Janine F. Felix, Bram C. J. van der Eerden, Jonathan H Tobias, Mike A. Nalls, Christian J. Carlsson, Cindy G. Boer, Kun Zhu, Tim D. Spector, Linda Broer, Babette S. Zemel, Martin den Heijer, Mustafa Atalay, Eric S. Orwoll, David M. Evans, Ruifang Li-Gao, John P. Kemp, Katharina E. Schraut, Dennis O. Mook-Kanamori, Kristina Åkesson, Katerina Trajanoska, Maria Nethander, Evangelia E. Ntzani, Cornelia M. van Duijn, Craig E. Pennell, Yanhua Zhou, Ching-Ti Liu, Vincenzo Forgetta, Claudia Langenberg, Fernando Rivadeneira, Vincent W. V. Jaddoe, Nathalie van der Velde, J. H. Duncan Bassett, Bernardo L. Horta, Jeroen van de Peppel, Samuel K. Handelman, Evangelos Evangelou, Klaus Bønnelykke, Renée de Mutsert, Denise H. M. Heppe, Nicholas J. Wareham, Graham R. Williams, Bo L. Chawes, Andre J. van Wijnen, Carol A. Wang, Mohsen Ghanbari, Alessandra Chesi, André G. Uitterlinden, Epidemiology, Erasmus MC other, Internal Medicine, Clinical Genetics, Pediatrics, Luan, Jian'an [0000-0003-3137-6337], Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Zhao, Jing Hua [0000-0003-4930-3582], Apollo - University of Cambridge Repository, Geriatrics, APH - Aging & Later Life, AMS - Ageing & Morbidty, AMS - Amsterdam Movement Sciences, Wellcome Trust, Pediatric surgery, General practice, Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, and IOO
- Subjects
0301 basic medicine ,Aging ,Bone density ,Osteoporosis ,Genome-wide association study ,Bioinformatics ,Medical and Health Sciences ,total-body DXA ,CREB3L1 ,Mice ,0302 clinical medicine ,Bone Density ,GWASs ,2.1 Biological and endogenous factors ,Aetiology ,Child ,Genetics (clinical) ,Bone mineral ,Genetics & Heredity ,Mice, Knockout ,ESR1 ,RANKL ,Age Factors ,11 Medical And Health Sciences ,Single Nucleotide ,Biological Sciences ,Polymorphism, Single Nucleotide/genetics ,genetic correlation ,medicine.anatomical_structure ,Meta-analysis ,Child, Preschool ,Regression Analysis ,musculoskeletal diseases ,Adolescent ,Knockout ,030209 endocrinology & metabolism ,Biology ,Genetic correlation ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Quantitative Trait ,Rare Diseases ,Quantitative Trait, Heritable ,Bone Density/genetics ,Clinical Research ,BMD ,meta-regression ,medicine ,Genetics ,Journal Article ,Animals ,Humans ,Polymorphism ,Preschool ,Heritable ,Genetic association ,Femoral neck ,age-dependent effects ,Human Genome ,Infant, Newborn ,Infant ,06 Biological Sciences ,medicine.disease ,Newborn ,030104 developmental biology ,Good Health and Well Being ,fracture ,Genetic Loci ,Musculoskeletal ,genome-wide association studies ,bone mineral density ,Genome-Wide Association Study - Abstract
Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.
- Published
- 2018
22. Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo
- Author
-
Lars C. Moeller, Sören Latteyer, Janina Gassen, Lars Grøntved, Xiao Hui Liao, David L. Armstrong, Martin Hrabé de Angelis, Graham R. Williams, Eddy Rijntjes, Majken S. Siersbæk, J. H. Duncan Bassett, Karl Heinz Strucksberg, Helena Rakov, Dagmar Führer, Petra Kleinbongard, Kathrin Engels, John G. Logan, Eugenie Werbenko, Josef Köhrle, Jan Rozman, Andrea S. Pollard, Samuel Refetoff, Ludger Klein-Hitpass, Denise Zwanziger, Valerie Gailus-Durner, G. Sebastian Hönes, Helmut Fuchs, Stine M. Præstholm, and Wellcome Trust
- Subjects
0301 basic medicine ,thyroid hormone receptor ,noncanonical signaling ,thyroid hormone action ,skeleton ,cardiometabolic effects ,Medizin ,Pituitary-Adrenal System ,medicine.disease_cause ,ACTIVATION ,Mice ,0302 clinical medicine ,Gene expression ,Gene Knock-In Techniques ,Receptor ,Thyroid hormone receptor ,GENE-EXPRESSION ,Mice, Knockout ,Mutation ,Multidisciplinary ,Receptors, Thyroid Hormone ,Thyroid ,Cell biology ,Multidisciplinary Sciences ,medicine.anatomical_structure ,PNAS Plus ,Regulatory sequence ,Science & Technology - Other Topics ,SERUM-LIPIDS ,Signal transduction ,Thyroid hormone action ,Signal Transduction ,RECEPTOR DNA-BINDING ,medicine.medical_specialty ,Hypothalamo-Hypophyseal System ,Thyroid Hormones ,030209 endocrinology & metabolism ,Biology ,03 medical and health sciences ,TR-BETA ,In vivo ,Internal medicine ,medicine ,Animals ,Hormone signaling ,Gene ,Skeleton ,Science & Technology ,THYROTROPIN ,business.industry ,Myocardium ,Cardiometabolic effects ,L-THYROXINE ,030104 developmental biology ,Endocrinology ,PLASMA-MEMBRANE ,Noncanonical signaling ,business ,RESISTANCE ,Hormone - Abstract
Thyroid hormone (TH) and TH receptors (TRs) α and β act by binding to TH response elements (TREs) in regulatory regions of target genes. This nuclear signaling is established as the canonical or type 1 pathway for TH action. Nevertheless, TRs also rapidly activate intracellular second-messenger signaling pathways independently of gene expression (noncanonical or type 3 TR signaling). To test the physiological relevance of noncanonical TR signaling, we generated knockin mice with a mutation in the TR DNA-binding domain that abrogates binding to DNA and leads to complete loss of canonical TH action. We show that several important physiological TH effects are preserved despite the disruption of DNA binding of TRα and TRβ, most notably heart rate, body temperature, blood glucose, and triglyceride concentration, all of which were regulated by noncanonical TR signaling. Additionally, we confirm that TRE-binding–defective TRβ leads to disruption of the hypothalamic–pituitary–thyroid axis with resistance to TH, while mutation of TRα causes a severe delay in skeletal development, thus demonstrating tissue- and TR isoform-specific canonical signaling. These findings provide in vivo evidence that noncanonical TR signaling exerts physiologically important cardiometabolic effects that are distinct from canonical actions. These data challenge the current paradigm that in vivo physiological TH action is mediated exclusively via regulation of gene transcription at the nuclear level.
- Published
- 2017
23. Bone Cell-autonomous Contribution of Type 2 Cannabinoid Receptor to Breast Cancer-induced Osteolysis
- Author
-
John G. Logan, Stuart H. Ralston, Antonia Sophocleous, Aymen I. Idris, Patrick Mollat, and Silvia Marino
- Subjects
medicine.medical_specialty ,Osteolysis ,Blotting, Western ,Osteoclasts ,Parathyroid hormone ,Bone Marrow Cells ,Breast Neoplasms ,Biochemistry ,Bone remodeling ,Receptor, Cannabinoid, CB2 ,Phosphatidylinositol 3-Kinases ,Osteogenesis ,Osteoclast ,Cell Line, Tumor ,Internal medicine ,Bone cell ,medicine ,Cannabinoid receptor type 2 ,Animals ,Humans ,Molecular Biology ,Cells, Cultured ,Cell Proliferation ,Mice, Knockout ,Osteoblasts ,biology ,Cannabinoids ,Chemistry ,RANK Ligand ,Osteoblast ,Cell Biology ,medicine.disease ,Coculture Techniques ,Endocrinology ,medicine.anatomical_structure ,Parathyroid Hormone ,RANKL ,Culture Media, Conditioned ,MCF-7 Cells ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
The cannabinoid type 2 receptor (CB2) has previously been implicated as a regulator of tumor growth, bone remodeling, and bone pain. However, very little is known about the role of the skeletal CB2 receptor in the regulation of osteoblasts and osteoclasts changes associated with breast cancer. Here we found that the CB2-selective agonists HU308 and JWH133 reduced the viability of a variety of parental and bone-tropic human and mouse breast cancer cells at high micromolar concentrations. Under conditions in which these ligands are used at the nanomolar range, HU308 and JWH133 enhanced human and mouse breast cancer cell-induced osteoclastogenesis and exacerbated osteolysis, and these effects were attenuated in cultures obtained from CB2-deficient mice or in the presence of a CB2 receptor blocker. HU308 and JWH133 had no effects on osteoblast growth or differentiation in the presence of conditioned medium from breast cancer cells, but under these circumstances both agents enhanced parathyroid hormone-induced osteoblast differentiation and the ability to support osteoclast formation. Mechanistic studies in osteoclast precursors and osteoblasts showed that JWH133 and HU308 induced PI3K/AKT activity in a CB2-dependent manner, and these effects were enhanced in the presence of osteolytic and osteoblastic factors such as RANKL (receptor activator of NFκB ligand) and parathyroid hormone. When combined with published work, these findings suggest that breast cancer and bone cells exhibit differential responses to treatment with CB2 ligands depending upon cell type and concentration used. We, therefore, conclude that both CB2-selective activation and antagonism have potential efficacy in cancer-associated bone disease, but further studies are warranted and ongoing.
- Published
- 2015
24. Thyrostimulin Regulates Osteoblastic Bone Formation During Early Skeletal Development
- Author
-
J H Duncan, Bassett, Anne, van der Spek, John G, Logan, Apostolos, Gogakos, Jayashree, Bagchi-Chakraborty, Allan J, Williams, Elaine, Murphy, Clementine, van Zeijl, Jenny, Down, Peter I, Croucher, Alan, Boyde, Anita, Boelen, Graham R, Williams, Amsterdam institute for Infection and Immunity, Amsterdam Gastroenterology Endocrinology Metabolism, Graduate School, Laboratory for Endocrinology, and Endocrinology
- Subjects
Male ,musculoskeletal diseases ,medicine.medical_specialty ,Stromal cell ,Osteoclasts ,Thyrotropin ,CHO Cells ,Biology ,Bone and Bones ,Paracrine signalling ,Endocrinology ,Calcification, Physiologic ,Cricetulus ,Osteoclast ,Bone Density ,Osteogenesis ,Internal medicine ,Cricetinae ,Calcium-Regulating Hormones-Bone ,Paracrine Communication ,medicine ,Animals ,Humans ,Receptor ,Protein kinase B ,Glycoproteins ,Original Research ,Mice, Knockout ,Osteoblasts ,Correction ,Osteoblast ,Receptors, Thyrotropin ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Phenotype ,Female ,Bone marrow ,Signal transduction - Abstract
The ancestral glycoprotein hormone thyrostimulin is a heterodimer of unique glycoprotein hormone subunit alpha (GPA)2 and glycoprotein hormone subunit beta (GPB)5 subunits with high affinity for the TSH receptor. Transgenic overexpression of GPB5 in mice results in cranial abnormalities, but the role of thyrostimulin in bone remains unknown. We hypothesized that thyrostimulin exerts paracrine actions in bone and determined: 1) GPA2 and GPB5 expression in osteoblasts and osteoclasts, 2) the skeletal consequences of thyrostimulin deficiency in GPB5 knockout (KO) mice, and 3) osteoblast and osteoclast responses to thyrostimulin treatment. Gpa2 and Gpb5 expression was identified in the newborn skeleton but declined rapidly thereafter. GPA2 and GPB5 mRNAs were also expressed in primary osteoblasts and osteoclasts at varying concentrations. Juvenile thyrostimulin-deficient mice had increased bone volume and mineralization as a result of increased osteoblastic bone formation. However, thyrostimulin failed to induce a canonical cAMP response or activate the noncanonical Akt, ERK, or mitogen-activated protein kinase (P38) signaling pathways in primary calvarial or bone marrow stromal cell-derived osteoblasts. Furthermore, thyrostimulin did not directly inhibit osteoblast proliferation, differentiation or mineralization in vitro. These studies identify thyrostimulin as a negative but indirect regulator of osteoblastic bone formation during skeletal development.
- Published
- 2015
25. Photoperiod-induced central actions of thyroid hormone are essential for medullary bone formation
- Author
-
Justyna Miszkiewicz, Takashi Yoshimura, Natalie C. Butterfield, Victoria Leitch, Graham R. Williams, John G. Logan, and Duncan Bassett
- Subjects
photoperiodism ,medicine.medical_specialty ,medicine.anatomical_structure ,Endocrinology ,Medullary cavity ,Internal medicine ,Thyroid ,medicine ,Biology ,Hormone - Published
- 2017
26. Pharmacological evidence for the bone-autonomous contribution of the NFκB/β-catenin axis to breast cancer related osteolysis
- Author
-
John G. Logan, Silvia Marino, Patrick Mollat, Ryan T. Bishop, and Aymen I. Idris
- Subjects
0301 basic medicine ,musculoskeletal diseases ,Cancer Research ,Time Factors ,Osteolysis ,β-Catenin ,Osteoclasts ,Apoptosis ,Bone Neoplasms ,Breast Neoplasms ,03 medical and health sciences ,chemistry.chemical_compound ,Breast cancer ,Osteogenesis ,Osteoclast ,medicine ,Animals ,Humans ,Parthenolide ,Oncology & Carcinogenesis ,Bone ,beta Catenin ,Cell Proliferation ,Mice, Inbred BALB C ,Osteoblasts ,Dose-Response Relationship, Drug ,Chemistry ,NF-kappa B ,Bone metastasis ,Cell Differentiation ,Osteoblast ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Catenin ,Immunology ,MCF-7 Cells ,Cancer research ,Female ,Sesquiterpenes ,1112 Oncology And Carcinogenesis ,Signal Transduction ,NFκB - Abstract
The NFκB signaling pathway is implicated in breast cancer and bone metastasis. However, the bone-autonomous contribution of NFκB to breast cancer-induced osteolysis is poorly understood. Here, we report that pretreatment of osteoblasts with the sesquiterpene lactone Parthenolide (PTN), a verified NFκB inhibitor, prior to exposure to conditioned medium from human and mouse breast cancer cell lines enhanced osteoblast differentiation and reduced osteoblast ability to stimulate osteoclastogenesis. PTN prevented breast cancer-induced osteoclast formation and reduced the ability of breast cancer cells to prolong osteoclast survival and to inhibit osteoclast apoptosis. In vivo, administration of PTN in immuno-competent mice reduced osteolytic bone loss and skeletal tumour growth following injection of the syngeneic 4T1-BT1 cells and reduced local osteolysis caused by conditioned medium from human and mouse osteotropic breast cancer cell lines. Mechanistic studies revealed that NFκB inhibition by PTN in osteoblasts and osteoclasts was accompanied by a significant increase in β-catenin activation and expression. Collectively, these results raise the possibility that combined targeting of NFκB and β-catenin signalling in the tumour microenvironment may be of value in the treatment of breast cancer related osteolysis.
- Published
- 2017
27. Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis
- Author
-
Katharine F. Curry, Graham R. Williams, Stephen Kaptoge, Celia M. T. Greenwood, J. H. Duncan Bassett, Carolina Medina-Gomez, Nicole M. Warrington, Fernando Rivadeneira, Matthew T. Maurano, David J. Adams, Keelin M Greenlaw, Fiona Kussy, Penny C. Sparkes, Jacqueline K. White, Scott E. Youlten, Peter I. Croucher, Cheryl L. Ackert-Bicknell, Victoria D. Leitch, Cyrus Cooper, ChangJiang Xu, John A. Morris, Natalie C. Butterfield, Rebecca Allen, Anne-Tounsia Adoum, Nicholas C. Harvey, John P. Kemp, Jonathan H Tobias, Davide Komla-Ebri, David M. Evans, John G. Logan, Andrea S. Pollard, Vincenzo Forgetta, J. Brent Richards, Elin Grundberg, Katerina Trajanoska, Elena J. Ghirardello, Celia L Gregson, Jie Zheng, Epidemiology, and Wellcome Trust
- Subjects
0301 basic medicine ,Male ,Bone density ,LD SCORE REGRESSION ,Osteoporosis ,Osteoclasts ,Genome-wide association study ,MOUSE ,Mice ,0302 clinical medicine ,Bone Density ,GWAS ,Femur ,11 Medical and Health Sciences ,Growth Disorders ,Genetics & Heredity ,RISK ,Bone mineral ,Genetics ,Mice, Knockout ,Genome-wide association ,HERITABILITY ,ultrasound ,Phenotype ,Knockout mouse ,MENDELIAN RANDOMIZATION ,Female ,HIGH-TRAUMA FRACTURES ,Life Sciences & Biomedicine ,musculoskeletal diseases ,UK Biobank ,030209 endocrinology & metabolism ,Single-nucleotide polymorphism ,Biology ,Osteochondrodysplasias ,Osteocytes ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Glypicans ,Ultrasound ,medicine ,Bone mineral density ,Animals ,Humans ,Science & Technology ,Osteoblasts ,Gene Expression Profiling ,Molecular Sequence Annotation ,06 Biological Sciences ,medicine.disease ,osteoporosis ,Gene expression profiling ,Calcaneus ,Disease Models, Animal ,030104 developmental biology ,GPC6 ,OLDER WOMEN ,genome-wide association ,QUANTITATIVE ULTRASOUND ,bone mineral density ,Developmental Biology ,Genome-Wide Association Study - Abstract
Osteoporosis is a common disease diagnosed primarily by measurement of bone mineral density (BMD). We undertook a genome-wide association study (GWAS) in 142,487 individuals from the UK Biobank to identify loci associated with BMD as estimated by quantitative ultrasound of the heel. We identified 307 conditionally independent single-nucleotide polymorphisms (SNPs) that attained genome-wide significance at 203 loci, explaining approximately 12% of the phenotypic variance. These included 153 previously unreported loci, and several rare variants with large effect sizes. To investigate the underlying mechanisms, we undertook (1) bioinformatic, functional genomic annotation and human osteoblast expression studies; (2) gene-function prediction; (3) skeletal phenotyping of 120 knockout mice with deletions of genes adjacent to lead independent SNPs; and (4) analysis of gene expression in mouse osteoblasts, osteocytes and osteoclasts. The results implicate GPC6 as a novel determinant of BMD, and also identify abnormal skeletal phenotypes in knockout mice associated with a further 100 prioritized genes.
- Published
- 2017
28. THRA and DIO2 mutations are unlikely to be a common cause of increased bone mineral density in euthyroid post-menopausal women
- Author
-
Christian Roux, Graham R. Williams, Julian A. Waung, David M Reid, Dieter Felsenberg, John G. Logan, Duncan Bassett, Richard Eastell, Apostolos Gogakos, and Claus-Christian Gluer
- Subjects
medicine.medical_specialty ,Genotype ,Endocrinology, Diabetes and Metabolism ,Population ,Osteoporosis ,Thyrotropin ,Parathyroid hormone ,DIO2 ,Iodide Peroxidase ,Bone remodeling ,Cohort Studies ,Absorptiometry, Photon ,Endocrinology ,Bone Density ,Internal medicine ,Humans ,Medicine ,Euthyroid ,Prospective Studies ,Vitamin D ,education ,Aged ,Bone mineral ,education.field_of_study ,business.industry ,Genes, erbA ,Thyroid ,General Medicine ,Middle Aged ,medicine.disease ,Postmenopause ,Thyroxine ,medicine.anatomical_structure ,Parathyroid Hormone ,Mutation ,Triiodothyronine ,Female ,business - Abstract
ObjectiveA new autosomal dominant disorder due to mutation of THRA, which encodes thyroid hormone receptor α, is characterised by severely delayed skeletal development but only slightly abnormal thyroid status. Adult mice with disrupted thyroid hormone action in bone due to a mutation of Thra or deletion of Dio2, encoding the type 2 deiodinase, have high bone mass and mineralisation despite essentially euthyroid status. No individuals with DIO2 mutations have been described and the adult phenotype of patients with THRA mutations is largely unknown. We hypothesised that screening euthyroid adults with high bone mineral density (BMD) could be used to identify individuals with mutations of THRA or DIO2.DesignThe Osteoporosis and Ultrasound Study (OPUS) is a 6-year prospective study of fracture-related factors from five European centres.MethodsA cohort of 100 healthy euthyroid post-menopausal women with the highest BMD was selected from the OPUS population. We sequenced the intron–exon boundaries and critical exons of THRA and DIO2 in these subjects. TSH, free 3,5,3′-l-triiodothyronine, free thyroxine, vitamin D, parathyroid hormone and bone turnover marker concentrations, and BMD measurements were available in all OPUS participants.ResultsNo coding sequence or splice site mutations affecting THRA or DIO2 were identified.ConclusionsMutations affecting THRA or DIO2 are not a common cause of high BMD in healthy euthyroid post-menopausal women.
- Published
- 2014
29. Author Correction: An atlas of genetic influences on osteoporosis in humans and mice
- Author
-
Graham R. Williams, Stephen Kaptoge, Yi-Hsiang Hsu, Natalie C. Butterfield, David J. Adams, Claes Ohlsson, Fernando Rivadeneira, Cyrus Cooper, Carolina Medina-Gomez, Thomas A. D. Hassall, Evangelos Evangelou, John P. Kemp, Naila S. Mannan, Aimée-Lee Luco, Cheryl L. Ackert-Bicknell, John A. Morris, Anne-Tounsia Adoum, Victoria D. Leitch, Elin Grundberg, Jonathan H Tobias, Douglas J. Adams, David Karasik, Marie-Michelle Simon, J. Brent Richards, Evangelia E. Ntzani, Michael-John G. Beltejar, Andrea S. Pollard, Elena J. Ghirardello, Celia L Gregson, Paul A. Baldock, John G. Logan, Laetitia Laurent, Davide Komla-Ebri, David M. Evans, Scott E. Youlten, Ryan C. Chai, Jonathan Reeve, C. Marcelo Sergio, Nicholas A. Vulpescu, Vincenzo Forgetta, David A. Hinds, Albena Pramatarova, Penny C. Sparkes, J. H. Duncan Bassett, Nicholas C. Harvey, Matthew T. Maurano, Suzanne M. Vaillancourt, Katerina Trajanoska, Douglas P. Kiel, Jinchu Vijay, Peter I. Croucher, David Goltzman, Katharine F. Curry, Christopher J. Lelliott, Hannah F. Dewhurst, Loan Nguyen-Yamamoto, Julian M.W. Quinn, Sindhu T. Mohanty, and Aaron Kleinman
- Subjects
medicine.anatomical_structure ,Atlas (anatomy) ,Published Erratum ,Genetics ,medicine ,Biology ,Cartography - Abstract
In the version of this article initially published, in Fig. 5a, the data in the right column of 'DAAM2 gRNA1' were incorrectly plotted as circles indicating 'untreated' rather than as squares indicating 'treated'. The error has been corrected in the HTML and PDF versions of the article.
- Published
- 2019
30. Mice Lacking the Calcineurin Inhibitor Rcan2 Have an Isolated Defect of Osteoblast Function
- Author
-
Peter I. Croucher, Graham R. Williams, John G. Logan, Sai Xu, Alan Boyde, Yoshiharu Murata, Xiao-yang Sun, Moira Cheung, J. H. Duncan Bassett, and Holly Evans
- Subjects
medicine.medical_specialty ,T-Lymphocytes ,Calcineurin Inhibitors ,Mice, Transgenic ,Biology ,Models, Biological ,Bone and Bones ,Bone resorption ,Bone remodeling ,Thyroid hormone receptor beta ,Mice ,Endocrinology ,Internal medicine ,medicine ,Animals ,Protein Isoforms ,RNA, Messenger ,Bone Resorption ,Phosphorylation ,Genes, Dominant ,Mice, Knockout ,Bone mineral ,Osteoblasts ,Intracellular Signaling Peptides and Proteins ,Proteins ,Thyroid Hormone Receptors beta ,Osteoblast ,X-Ray Microtomography ,Biomechanical Phenomena ,Calcineurin ,medicine.anatomical_structure ,Mutation ,Intramembranous ossification ,Cortical bone ,Thyroid Hormone Receptors alpha - Abstract
Calcineurin-nuclear factor of activated T cells signaling controls the differentiation and function of osteoclasts and osteoblasts, and regulator of calcineurin-2 (Rcan2) is a physiological inhibitor of this pathway. Rcan2 expression is regulated by T3, which also has a central role in skeletal development and bone turnover. To investigate the role of Rcan2 in bone development and maintenance, we characterized Rcan2−/− mice and determined its skeletal expression in T3 receptor (TR) knockout and thyroid-manipulated mice. Rcan2−/− mice had normal linear growth but displayed delayed intramembranous ossification, impaired cortical bone formation, and reduced bone mineral accrual during development as well as increased mineralization of adult bone. These abnormalities resulted from an isolated defect in osteoblast function and are similar to skeletal phenotypes of mice lacking the type 2 deiodinase thyroid hormone activating enzyme or with dominant-negative mutations of TRα, the predominant TR isoform in bone. Rcan2 mRNA was expressed in primary osteoclasts and osteoblasts, and its expression in bone was differentially regulated in TRα and TRβ knockout and thyroid-manipulated mice. However, in primary osteoblast cultures, T3 treatment did not affect Rcan2 mRNA expression or nuclear factor of activated T cells c1 expression and phosphorylation. Overall, these studies establish that Rcan2 regulates osteoblast function and its expression in bone is regulated by thyroid status in vivo.
- Published
- 2012
31. Hydrogen sulphide-releasing diclofenac derivatives inhibit breast cancer-induced osteoclastogenesis in vitro and prevent osteolysis ex vivo
- Author
-
John G. Logan, P. Del Soldato, S.H. Ralston, Patrick Mollat, J Frantzias, Anna Sparatore, and Aymen I. Idris
- Subjects
musculoskeletal diseases ,Pharmacology ,Osteolysis ,Chemistry ,Cellular differentiation ,Cancer ,Osteoblast ,IκB kinase ,medicine.disease ,medicine.anatomical_structure ,Osteoclast ,Apoptosis ,Immunology ,Cancer research ,medicine ,Ex vivo - Abstract
BACKGROUND AND PURPOSE Hydrogen sulphide (H2S) and prostaglandins are both involved in inflammation, cancer and bone turnover, and non-steroidal anti-inflammatory drugs (NSAIDs) and H2S donors exhibit anti-inflammatory and anti-tumour properties. H2S-releasing diclofenac (S-DCF) derivatives are a novel class of NSAIDs combining the properties of a H2S donor with those of a conventional NSAID. EXPERIMENTAL APPROACH We studied the effects of the S-DCF derivatives ACS15 and ACS32 on osteoclast and osteoblast differentiation and activity in vitro, human and mouse breast cancer cells support for osteoclast formation and signalling in vitro, and osteolysis ex vivo. KEY RESULTS The S-diclofenac derivatives ACS15 and ACS32 inhibited the increase in osteoclast formation induced by human MDA-MB-231 and MCF-7 and mouse 4T1 breast cancer cells without affecting breast cancer cell viability. Conditioned media from human MDA-MB-231 cells enhanced IκB phosphorylation and osteoclast formation and these effects were significantly inhibited following treatment by ACS15 and ACS32, whereas the parent compound diclofenac had no effects. ACS15 and ACS32 inhibited receptor activator of NFκB ligand-induced osteoclast formation and resorption, and caused caspase-3 activation and apoptosis in mature osteoclasts via a mechanism dependent on IKK/NFκB inhibition. In calvaria organ culture, human MDA-MB-231 cells caused osteolysis, and this effect was completely prevented following treatment with ACS15 and ACS32. CONCLUSIONS AND IMPLICATIONS S-diclofenac derivatives inhibit osteoclast formation and activity, suppress breast cancer cell support for osteoclastogenesis and prevent osteolysis. This suggests that H2S-releasing diclofenac derivatives exhibit anti-resorptive properties, which might be of clinical value in the treatment of osteolytic bone disease.
- Published
- 2012
32. Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites
- Author
-
John G. Logan, Ana Afonso, Iain W. McNae, Sandra Cheesman, Virgílio E. do Rosário, Pedro Cravo, Amar Bir Singh Sidhu, Stephanie G. Valderramos, Alison M. Creasey, Richard Carter, Paul Hunt, David A. Fidock, and Richard Culleton
- Subjects
Models, Molecular ,Genes, Protozoan ,Mutant ,Drug Resistance ,Artesunate ,Locus (genetics) ,Biology ,Microbiology ,Deubiquitinating enzyme ,Plasmodium chabaudi ,Antimalarials ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Parasitic Sensitivity Tests ,parasitic diseases ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Artemisinin ,Molecular Biology ,Gene ,Research Articles ,030304 developmental biology ,Genetics ,0303 health sciences ,Ubiquitin ,030306 microbiology ,Chloroquine ,Plasmodium falciparum ,biology.organism_classification ,Artemisinins ,3. Good health ,chemistry ,Mutation ,Mice, Inbred CBA ,biology.protein ,Female ,Sesquiterpenes ,medicine.drug - Abstract
Artemisinin- and artesunate-resistant Plasmodium chabaudi mutants, AS-ART and AS-ATN, were previously selected from chloroquine-resistant clones AS-30CQ and AS-15CQ respectively. Now, a genetic cross between AS-ART and the artemisinin-sensitive clone AJ has been analysed by Linkage Group Selection. A genetic linkage group on chromosome 2 was selected under artemisinin treatment. Within this locus, we identified two different mutations in a gene encoding a deubiquitinating enzyme. A distinct mutation occurred in each of the clones AS-30CQ and AS-ATN, relative to their respective progenitors in the AS lineage. The mutations occurred independently in different clones under drug selection with chloroquine (high concentration) or artesunate. Each mutation maps to a critical residue in a homologous human deubiquitinating protein structure. Although one mutation could theoretically account for the resistance of AS-ATN to artemisinin derivates, the other cannot account solely for the resistance of AS-ART, relative to the responses of its sensitive progenitor AS-30CQ. Two lines of Plasmodium falciparum with decreased susceptibility to artemisinin were also selected. Their drug-response phenotype was not genetically stable. No mutations in the UBP-1 gene encoding the P. falciparum orthologue of the deubiquitinating enzyme were observed. The possible significance of these mutations in parasite responses to chloroquine or artemisinin is discussed.
- Published
- 2007
33. Generation and culture of osteoclasts
- Author
-
David Mellis, John G. Logan, Mattia Capulli, and Silvia Marino
- Subjects
musculoskeletal diseases ,Stromal cell ,Monocyte ,Cellular differentiation ,Biology ,Article ,Bone resorption ,Cell biology ,Haematopoiesis ,medicine.anatomical_structure ,Osteoclast ,RANKL ,Immunology ,medicine ,biology.protein ,General Earth and Planetary Sciences ,Bone marrow ,General Environmental Science - Abstract
Osteoclasts are highly specialized cells of haematopoietic lineage that are uniquely responsible for bone resorption. In the past, osteoclasts were isolated as mature cells from chicken long bones, or were generated using osteoblasts or stromal cells to induce osteoclast formation in total bone marrow from mice or rabbits. The Copernican revolution in osteoclast biology began with the identification of macrophage-colony stimulating factor (M-CSF) and receptor activator NFκB-ligand (RANKL ) as the key regulators of osteoclast formation, fusion and function. The availability of recombinant human and mouse M-CSF and RANKL has enabled researchers to reliably generate osteoclasts from primary monocyte/macrophage cells as well as from cell lines such as RAW 264.7. This article summarizes the most commonly used procedures for the isolation, generation and characterization of human, rodent and chicken osteoclasts in vitro. Lists of further reading and recommendations are included to facilitate a successful application by the reader.
- Published
- 2014
34. Regulation of bone metastasis by the IKK[beta]/FoxO3a axis
- Author
-
John G. Logan, Aymen I. Idris, Patrick Mollat, Nadia Rucci, Stuart H. Ralston, Silvia Marino, Andrew H. Sims, Antonia Sophocleous, Luca Ventura, and Barbara Mognetti
- Subjects
Chemistry ,medicine ,Cancer research ,Bone metastasis ,General Medicine ,IκB kinase ,Beta (finance) ,medicine.disease - Published
- 2014
35. Thyroid hormones stimulate osteoclastogenesis via TR[alpha]-dependent actions in osteoblasts
- Author
-
John G. Logan, Graham R. Williams, and J. H. Duncan Bassett
- Subjects
medicine.medical_specialty ,Endocrinology ,Chemistry ,Internal medicine ,Thyroid hormones ,medicine ,Alpha (ethology) ,General Medicine - Published
- 2014
36. Paediatric Bone Physiology and Monitoring the Safety and Efficacy of Bone Drugs in Children
- Author
-
John G. Logan, J. H. Duncan Bassett, and Moira Cheung
- Subjects
Skeletal pharmacology ,medicine.medical_specialty ,Modalities ,Adult patients ,business.industry ,Bone physiology ,medicine ,Adverse effect ,Intensive care medicine ,business ,Bone health ,Paediatric patients ,Bone mass - Abstract
Many childhood diseases and their treatments can have adverse effects on the developing skeleton and the accrual of bone mass essential for normal adult bone health. Treatment with anti-resorptive and bone anabolic drugs can reduce such detrimental effects, but may also adversely affect bone development. Thus, in paediatric patients it is prudent to assess the skeleton carefully prior to commencing treatment, and to perform regular re-evaluation to monitor skeletal responses and to rapidly identify adverse events. The longitudinal follow-up of adult patients is relatively straightforward but similar longitudinal evaluation of the developing skeleton in paediatric patients is significantly more difficult and the data interpretation complex. This chapter highlights the underlying physiological basis for these difficulties and describes the modalities used for monitoring the efficacy and safety of skeletal pharmacology in paediatric patients.
- Published
- 2014
37. Advanced Bone Formation in Mice with a Dominant-negative Mutation in the Thyroid Hormone Receptor beta Gene due to Activation of Wnt/beta-Catenin Protein Signaling
- Author
-
Graham R. Williams, Sean Davis, Dong Wook Kim, Patrick J. O'Shea, Paul S. Meltzer, Sheue-yann Cheng, John G. Logan, and Robert L. Walker
- Subjects
endocrine system ,medicine.medical_specialty ,Beta-catenin ,endocrine system diseases ,Biochemistry ,Mice ,Osteogenesis ,Internal medicine ,medicine ,Animals ,Wnt Signaling Pathway ,Molecular Biology ,beta Catenin ,Osteoblasts ,Thyroid hormone receptor ,biology ,Protein Stability ,Wnt signaling pathway ,LRP6 ,Molecular Bases of Disease ,Thyroid Hormone Receptors beta ,LRP5 ,Cell Biology ,Mice, Mutant Strains ,Cell biology ,Endocrinology ,Pituitary Gland ,Catenin ,Mutation ,biology.protein ,Triiodothyronine ,Signal transduction ,Hormone - Abstract
Thyroid hormone (T(3)) acts in chondrocytes and bone-forming osteoblasts to control bone development and maintenance, but the signaling pathways mediating these effects are poorly understood. Thrb(PV/PV) mice have a severely impaired pituitary-thyroid axis and elevated thyroid hormone levels due to a dominant-negative mutant T(3) receptor (TRβ(PV)) that cannot bind T(3) and interferes with the actions of wild-type TR. Thrb(PV/PV) mice have accelerated skeletal development due to unknown mechanisms. We performed microarray studies in primary osteoblasts from wild-type mice and Thrb(PV/PV) mice. Activation of the canonical Wnt signaling in Thrb(PV/PV) mice was confirmed by in situ hybridization analysis of Wnt target gene expression in bone during postnatal growth. By contrast, T(3) treatment inhibited Wnt signaling in osteoblastic cells, suggesting that T(3) inhibits the Wnt pathway by facilitating proteasomal degradation of β-catenin and preventing its accumulation in the nucleus. Activation of the Wnt pathway in Thrb(PV/PV) mice, however, results from a gain of function for TRβ(PV) that stabilizes β-catenin despite the presence of increased thyroid hormone levels. These studies demonstrate novel interactions between T(3) and Wnt signaling pathways in the regulation of skeletal development and bone formation.
- Published
- 2012
38. Selective tyrosine kinase inhibition of insulin-like growth factor-1 receptor inhibits human and mouse breast cancer-induced bone cell activity, bone remodeling, and osteolysis
- Author
-
Aymen I. Idris, Valerie G. Brunton, Morwenna Muir, Antonia Sophocleous, Silvia Marino, and John G. Logan
- Subjects
musculoskeletal diseases ,medicine.medical_specialty ,Osteolysis ,Bone disease ,Endocrinology, Diabetes and Metabolism ,Osteoclasts ,Breast Neoplasms ,Bone resorption ,Bone remodeling ,Receptor, IGF Type 1 ,Mice ,Osteoclast ,Internal medicine ,Cell Line, Tumor ,Bone cell ,medicine ,Animals ,Humans ,Orthopedics and Sports Medicine ,biology ,Chemistry ,Imidazoles ,Osteoblast ,Protein-Tyrosine Kinases ,medicine.disease ,medicine.anatomical_structure ,Endocrinology ,RANKL ,Pyrazines ,biology.protein ,Female ,Bone Remodeling - Abstract
Insulin-like growth factor 1 (IGF-1) plays an important role in both bone metabolism and breast cancer. In this study, we investigated the effects of the novel IGF-1 receptor tyrosine kinase inhibitor cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP) on osteolytic bone disease associated with breast cancer. Human MDA-MB-231 and mouse 4T1 breast cancer cells enhanced osteoclast formation in receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) stimulated bone marrow cultures, and these effects were significantly inhibited by PQIP. Functional studies in osteoclasts showed that PQIP inhibited both IGF-1 and conditioned medium-induced osteoclast formation by preventing phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) activation without interfering with RANKL or M-CSF signaling. Treatment of osteoblasts with PQIP significantly inhibited the increase in RANKL/osteoprotegerin (OPG) ratio by IGF-1 and conditioned medium and totally prevented conditioned medium-induced osteoclast formation in osteoblast-bone marrow (BM) cell cocultures, thereby suggesting an inhibitory effect on osteoblast-osteoclast coupling. PQIP also inhibited IGF-1-induced osteoblast differentiation, spreading, migration, and bone nodule formation. Treatment with PQIP significantly reduced MDA-MB-231 conditioned medium-induced osteolytic bone loss in a mouse calvarial organ culture system ex vivo and in adult mice in vivo. Moreover, once daily oral administration of PQIP significantly decreased trabecular bone loss and reduced the size of osteolytic bone lesions following 4T1 intratibial injection in mice. Quantitative histomorphometry showed a significant reduction in bone resorption and formation indices, indicative of a reduced rate of cancer-associated bone turnover. We conclude that inhibition of IGF-1 receptor tyrosine kinase activity by PQIP suppresses breast cancer-induced bone turnover and osteolysis. Therefore, PQIP, and its novel derivatives that are currently in advanced clinical development for the treatment of a number of solid tumors, may be of value in the treatment of osteolytic bone disease associated with breast cancer.
- Published
- 2012
39. Genetic inactivation and pharmacological inhibition of IKKβ activityin cancer cells inhibit breast cancer-induced osteoclastogenesis,promotes osteoblast differentiation and prevents osteolysis
- Author
-
Patrick Mollat, Silvia Marino, Aymen I. Idris, Barbara Mognetti, John G. Logan, and S.H. Ralston
- Subjects
Histology ,Breast cancer ,medicine.anatomical_structure ,Osteolysis ,Physiology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Cancer cell ,medicine ,Cancer research ,Osteoblast ,medicine.disease ,business - Published
- 2012
40. The CB2 receptor regulates osteoclast formation, breast cancer cell migration and osteoclast/tumour cell interaction via the PI3 Kinase/AKT pathway
- Author
-
John G. Logan, Aymen I. Idris, S.H. Ralston, A. Mackintosh, Antonia Sophocleous, and Euphemie Landao-Bassonga
- Subjects
Histology ,Physiology ,Kinase ,Chemistry ,Endocrinology, Diabetes and Metabolism ,Cell ,medicine.anatomical_structure ,Osteoclast ,Cancer research ,medicine ,Cannabinoid receptor type 2 ,Breast cancer cells ,Protein kinase B ,PI3K/AKT/mTOR pathway - Published
- 2011
41. The novel and selective insulin-like growth factor-1 receptor kinase inhibitor PQIP suppresses bone cell function and osteoclast-breast cancer cell cross-talk in vitro
- Author
-
Valerie G. Brunton, Aymen I. Idris, John G. Logan, and Euphemie Landao-Bassonga
- Subjects
Histology ,biology ,Physiology ,Chemistry ,Cyclin-dependent kinase 4 ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Tropomyosin receptor kinase C ,Insulin-like growth factor ,medicine.anatomical_structure ,Growth factor receptor ,Osteoclast ,biology.protein ,medicine ,Cancer research ,Growth factor receptor inhibitor ,Receptor ,Platelet-derived growth factor receptor - Published
- 2011
42. Quantitative X-ray microradiography for high-throughput phenotyping of osteoarthritis in mice
- Author
-
Sahana Gopal, Julian A. Waung, Graham R. Williams, Stephanie A. Maynard, John G. Logan, Apostolos Gogakos, J. H. D. Bassett, Medical Research Council (MRC), and Arthritis Research UK
- Subjects
Male ,Pathology ,Knee Joint ,Bone density ,Destabilisation of the medial meniscus ,Male mice ,Osteoarthritis ,MOUSE ,Menisci, Tibial ,Mice ,Bone Density ,Orthopedics and Sports Medicine ,Brief Report ,Digital X-ray microradiography ,Subchondral bone ,Osteoarthritis, Knee ,Phenotype ,medicine.anatomical_structure ,SUBCHONDRAL BONE CHANGES ,Female ,Life Sciences & Biomedicine ,Medial meniscus ,Genetically modified mouse ,musculoskeletal diseases ,medicine.medical_specialty ,Bone mineral content ,Biomedical Engineering ,Rheumatology ,CARTILAGE ,REVEALS ,medicine ,Animals ,Tibia ,Science & Technology ,business.industry ,Cartilage ,Reproducibility of Results ,1103 Clinical Sciences ,medicine.disease ,Microradiography ,Arthritis & Rheumatology ,MODEL ,Mice, Inbred C57BL ,Disease Models, Animal ,Orthopedics ,business ,Mouse phenotyping - Abstract
summary Objective: To investigate and validate digital X-ray microradiography as a novel, high-throughput and cost-effective screening approach to identify abnormal joint phenotypes in mice. Method: Digital X-ray microradiography was used to quantify the subchondral bone mineral content (BMC) in the medial tibial plateau. Accuracy and reproducibility of the method were determined in 22 samples from C57BL/6(B6Brd;B6Dnk;B6N-Tyr c-Brd ) wild-type mice. The method was then validated in wild-type mice that had undergone surgical destabilisation of medial meniscus (DMM) and in a genetically modified mouse strain with an established increase in trabecular bone mass. Results: The measurement of subchondral BMC by digital X-ray microradiography had a coefficient of variation of 3.6%. Digital X-ray microradiography was able to demonstrate significantly increased subchondral BMC in the medial tibial plateau of male mice 4 and 8 weeks after DMM surgery and in female mice 8 weeks after surgery. Furthermore, digital X-ray microradiography also detected the increase in subchondral BMC in a genetically modified mouse strain with high trabecular bone mass. Conclusion: Quantitation of subchondral BMC by digital X-ray microradiography is a rapid, sensitive and cost-effective method to identify abnormal joint phenotypes in mice of both genders at several ages.
- Full Text
- View/download PDF
43. Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease
- Author
-
Siobhan E. Guilfoyle, John A. Morris, Scott E. Youlten, Graham R. Williams, Michael R.G. Dack, Elena J. Ghirardello, Amelia R. McGlade, Davide Komla-Ebri, John P. Kemp, Paul A. Baldock, David J. Adams, David M. Evans, J. H. Duncan Bassett, John G. Logan, Victoria D. Leitch, Fernando Rivadeneira, Eleftheria Zeggini, Michelle M. McDonald, Ryan C. Chai, Tri Giang Phan, Nenad Bartonicek, Melita Irving, Konstantinos Hatzikotoulas, Christopher J. Lelliott, Matt Jansson, Robert Brink, James T. Smith, Peter I. Croucher, Ana Beleza-Meireles, Claudio M Sergio, Sindhu T. Mohanty, J. Brent Richards, Alexander P. Corr, Natalie C. Butterfield, Emma L. Duncan, John A. Eisman, Julian M.W. Quinn, Youlten, Scott E [0000-0001-9314-2945], Kemp, John P [0000-0002-9105-2249], Sergio, Claudio M [0000-0002-5426-0583], Leitch, Victoria D [0000-0001-5760-2887], Butterfield, Natalie C [0000-0002-5209-7508], Komla-Ebri, Davide [0000-0002-8381-5381], Corr, Alexander P [0000-0002-8450-012X], Smith, James T [0000-0003-0528-0649], Mohanty, Sindhu T [0000-0001-7512-8808], Morris, John A [0000-0003-2769-8202], Quinn, Julian MW [0000-0001-9674-9646], Hatzikotoulas, Konstantinos [0000-0002-4699-3672], Rivadeneira, Fernando [0000-0001-9435-9441], Duncan, Emma [0000-0002-8143-4403], Richards, J Brent [0000-0002-3746-9086], Adams, David J [0000-0001-9490-0306], Lelliott, Christopher J [0000-0001-8087-4530], Phan, Tri Giang [0000-0002-4909-2984], Evans, David M [0000-0003-0663-4621], Zeggini, Eleftheria [0000-0003-4238-659X], Bassett, JH Duncan [0000-0003-0817-0082], Williams, Graham R [0000-0002-8555-8219], Croucher, Peter I [0000-0002-7102-2413], Apollo - University of Cambridge Repository, Wellcome Trust, and Internal Medicine
- Subjects
0301 basic medicine ,Male ,General Physics and Astronomy ,Transcriptome ,Mice ,0302 clinical medicine ,Skeletal disease ,Gene expression ,Homeostasis ,Mice, Knockout ,0303 health sciences ,Multidisciplinary ,Age Factors ,RNA sequencing ,Skeleton (computer programming) ,Cell biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Osteocyte ,Knockout mouse ,Female ,Bone Diseases ,Sequence analysis ,Bioinformatics ,Science ,Biology ,Osteocytes ,General Biochemistry, Genetics and Molecular Biology ,Article ,Bone and Bones ,03 medical and health sciences ,Gene expression analysis ,Sex Factors ,SDG 3 - Good Health and Well-being ,medicine ,Animals ,Humans ,Gene ,Skeleton ,030304 developmental biology ,Sequence Analysis, RNA ,Computational Biology ,General Chemistry ,030104 developmental biology ,Osteoporosis ,Bone structure ,030217 neurology & neurosurgery ,Function (biology) - Abstract
Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10−22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10−13) and osteoarthritis (P = 1.6 × 10−7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease., Osteocytes are the master regulatory cells within the skeleton. Here, the authors map the transcriptome of osteocytes from diverse skeletal sites, ages and between sexes and identify an osteocyte transcriptome signature associated with rare skeletal disorders and common complex skeletal diseases.
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.