Sun Li
Mount Sinai School Of Medicinecity: New York country: United States (us)
Grant 5R01DK080459-04 from National Institute Of Diabetes And Digestive And Kidney Diseases
Keywords: Acute; Affect; Agonist; American; Anterior Pituitary Hormones; Antibodies; Attenuated; bone; bone cell; Bone Diseases; bone loss; Bone Resorption; C-telopeptide; Cell Culture Techniques; Cells; Cessation of life; Chronic; Coculture Techniques; cytokine; Data; disability; Disease; Excision; Foundations; Fracture; Future; Goals; Health; Hip Fractures; Hip region structure; Human; human data; human MPP1 protein; Hyperthyroidism; Immunization; implantation; In Vitro; in vivo; Injection of therapeutic agent; ITGAM gene; Measures; Modeling; Molecular; Monoclonal Antibodies; Mus; mutant; Mutation; Osteoblasts; osteoclastogenesis; Osteoclasts; Osteogenesis; Osteopenia; Osteoporosis; Ovariectomy; Patients; Phenotype; Pituitary Hormones; Play; Population; Postmenopause; prevent; Prevention; Production; Rattus; receptor; Receptor Activation; Receptor Signaling; reconstitution; Reporting; restoration; Risk; Role; Serum; Signal Transduction; skeletal; Skeleton; Spinal Fractures; spine bone structure; Stromal Cells; Therapeutic; Thyroid Function Tests; Thyroid Hormones; Thyrotropin; Thyrotropin Receptor; Thyroxine; Time; transcriptional coactivator p75; TSH receptor antibody; Woman
Relevance: Hyperthyroidism affects one in 1000 American women and is accompanied by osteoporosis and a high fracture risk. We showed that decrements in the pituitary hormone TSH accompany the high thyroid hormone levels, both of which contribute to the bone loss. This proposal examines the molecular mechanism through which TSH acts directly on the skeleton
Project start date: 2009-01-05
Project end date: 2013-11-30
Budget start date: 1-DEC-2011
Budget end date: 30-NOV-2012
5R01DK080459-04 (2012): $440341
Sponsored Links Excellgen http://Excellgen.com
Sun Li
Mount Sinai School Of Medicinecity: New York country: United States (us)
Grant 5R01DK080459-03 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Thyrotoxic osteoporosis, which is accompanied by a high fracture risk, is known to arise from pro-resorptive effects of high thyroid hormone. We reported that TSH-signaling deficient mice lacking the TSH receptor (TSHR) display severe osteoporosis, suggesting that low TSH levels also contribute to thyrotoxic bone loss. That haploinsufficient euthyroid TSHR mice had an equally profound phenotype suggested that the effects of TSH were independent of thyroid hormones. theless, it remains unclear whether TSHR activation by stimulating antibodies in Graves´ disease reduces the hyperthyroid bone loss that is due to high thyroid hormones and low TSH. We further showed that TSHR activation inhibits osteoclast formation, function and survival, as well as the production of TNFa. When TNFa is ablated from TSHR-/- osteoclasts the enhanced osteoclastogenesis and osteopenia are both rescued, suggesting that TNFa plays a key role in thyrotoxic bone disease. Recently, we observed that TSH, when injected intermittently as far apart as once every two weeks, prevented and restored ovariectomy-induced bone loss by inhibiting bone resorption and stimulating bone formation. We hypothesize that TSH preserves the skeleton through potent anti-resorptive and anabolic actions, and that a loss of these actions contributes to the bone loss of hyperthyroidism. We will use genetically modified mice and state-of-the-art molecular approaches to understand the role of TSH in hyperthyroid bone loss. We will first attempt to rescue the TSHR-/- phenotype by deleting TNFa or its receptors, p55 or p75, in double mutants, or by transgenically reconstituting TSHRs in TSHR-/- osteoclasts or osteoblasts. Next, we will determine whether stimulating anti-TSHR antibodies given by injection or produced in vivo by adeno-TSHR immunization attenuate hyperthyroid bone loss. Finally, using mice in which TSHRs are restored cell-selectively in osteoclasts or osteoblasts on a TSHR-/- background, we will examine which cell contributes to the prevention and restoration of post-ovariectomy bone loss by TSH. These foundation studies should allow us to consider skeletal protection by TSH in post-menopausal women whose TSH levels are suppressed by thyroxine therapy for non-cancer causes. Hyperthyroidism affects one in 1000 American women and is accompanied by osteoporosis and a high fracture risk. We showed that decrements in the pituitary hormone TSH accompany the high thyroid hormone levels, both of which contribute to the bone loss. This proposal examines the molecular mechanism through which TSH acts directly on the skeleton
Keywords: 3, 5, 3`, 5`-Tetraiodothyronine; 55 kDa Erythrocyte Membrane Protein; Abscission; Acute; Adenohypophyseal Hormones; Affect; Agonist; American; Anterior Pituitary Hormones; Antibodies; Attenuated; Basedow`s Disease; biological signal transduction; Blood Serum; bone; Bone; Bone and Bones; bone cell; Bone Diseases; bone disorder; Bone Formation; bone fracture; bone loss; Bone Resorption; Bone structure of spine; Bones and Bone Tissue; C-telopeptide; CD11b; Cell Communication and Signaling; Cell Culture Techniques; Cell Signaling; Cells; Cessation of life; Chronic; Co-culture; Cocultivation; Coculture; Coculture Techniques; Common Rat Strains; Coxa; CR3A; cytokine; Data; Death; disability; EMP55; Erythrocyte Membrane Protein p55; Excision; Extirpation; female gonadectomy; Foundations; Fracture; Future; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Goals; Goiter, Exophthalmic; Graves` Disease; Health; Hip; Hip Fractures; Hip region structure; Human; human data; human MPP1 protein; Human, General; Hyperthyroidism; Immunization; Immunologic Stimulation; Immunological Stimulation; Immunostimulation; implantation; In Vitro; in vivo; Injection of therapeutic agent; Injections; Intracellular Communication and Signaling; ITGAM; ITGAM gene; L-3, 5, 3`, 5`-Tetraiodothyronine; L-Thyroxine; Levothyroxine; MAC-1; MAC1A; Mammals, Mice; Mammals, Rats; Man (Taxonomy); Man, Modern; Measures; membrane protein, palmitoylated 1, 55kDa, human; Mice; MO1A; Moab, Clinical Treatment; Modeling; Molecular; Monoclonal Antibodies; MPP1 protein, human; Murine; Mus; mutant; Mutation; O-(4-Hydroxy-3, 5-diiodophenyl) 3, 5-diiodo-L-tyrosine; O-(4-Hydroxy-3, 5-diiodophenyl)-3, 5-diiodotyrosine; Oophorectomy; Osteoblasts; Osteoclastic Bone Loss; osteoclastogenesis; Osteoclasts; Osteogenesis; Osteopenia; Osteoporosis; Ovariectomy; overactive thyroid; p55; p75; p75 transcription factor; palmitoylated erythrocyte membrane protein p55, human; Palmitoylated Membrane Protein 1; Palmitoylated Membrane Protein 1 55kD; Patients; PEMP; Phenotype; Pituitary Hormones; Pituitary Hormones, Anterior; Play; Population; post-menopausal; Post-menopausal Period; Post-Menopause; postmenopausal; Postmenopausal Period; Postmenopause; prevent; preventing; Prevention; Production; Rat; Rattus; receptor; Receptor Activation; Receptor Protein; Receptor Signaling; Receptors, Thyroid Stimulating Hormone; Recombinant Thyroid-Stimulating Hormone; Recombinant TSH; reconstitute; reconstitution; Removal; Reporting; resection; restoration; Risk; Role; Sensitization, Immunologic; Sensitization, Immunological; Serum; Signal Transduction; Signal Transduction Systems; Signaling; skeletal; Skeleton; social role; Spinal Fractures; spine bone structure; Stromal Cells; Surgical Removal; T4 Thyroid Hormone; Therapeutic; Therapeutic Levothyroxine; Thyreotropin; thyroid function; Thyroid Function Tests; Thyroid Gland Function Tests; Thyroid Gland Hormone; Thyroid Hormones; Thyroid Stimulating Hormone; Thyroid-Stimulating Hormone; Thyrotropin; Thyrotropin Receptor; thyroxin; Thyroxine; Time; transcriptional coactivator p75; TSH receptor antibody; TSH Receptors; Tyrosine, O-(4-hydroxy-3, 5-diiodophenyl)-3, 5-diiodo-; Vertebrae; Vertebral; vertebral fracture; Woman
Relevance: Hyperthyroidism affects one in 1000 American women and is accompanied by osteoporosis and a high fracture risk. We showed that decrements in the pituitary hormone TSH accompany the high thyroid hormone levels, both of which contribute to the bone loss. This proposal examines the molecular mechanism through which TSH acts directly on the skeleton
Project start date: 2009-01-05
Project end date: 2013-11-30
Budget start date: 1-DEC-2010
Budget end date: 30-NOV-2011
PFA/PA: PA-07-070
5R01DK080459-03 (2011): $454660