TSH and Bone

TSH 和骨骼

基本信息

批准号：
7754649
负责人：
TERRY Francis DAVIES
金额：
$ 53.77万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-05 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7754649
关键词：
Acute Affect Agonist American Anterior Pituitary Hormones Antibodies Arts Attenuated Bone Diseases Bone Resorption C-telopeptide Cancer Etiology Cell Culture Techniques Cells Cessation of life Chronic Coculture Techniques Data Excision Foundations Fracture Future Goals Graves&apos Disease Hip region structure Human Hyperthyroidism ITGAM gene Immunization In Vitro Injection of therapeutic agent Measures Modeling Molecular Monoclonal Antibodies Mus Mutation Osteoblasts Osteoclasts Osteogenesis Osteopenia Osteoporosis Ovariectomy Patients Phenotype Pituitary Hormones Play Population Postmenopause Prevention Production Rattus Receptor Activation Receptor Signaling Reporting Risk Role Serum Signal Transduction Skeleton Spinal Fractures Stromal Cells TSH receptor antibody Therapeutic Thyroid Function Tests Thyroid Hormones Thyrotropin Thyrotropin Receptor Thyroxine Time Woman bone bone cell bone loss cytokine disability human MPP1 protein human data implantation in vivo mutant osteoclastogenesis prevent public health relevance receptor reconstitution restoration skeletal spine bone structure transcriptional coactivator p75

项目摘要

DESCRIPTION (provided by applicant): 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. Nonetheless, 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. PUBLIC HEALTH 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.

描述（由申请人提供）：伴有高断裂风险的甲状腺毒性骨质疏松症，是由高甲状腺激素的促敏作用引起的。我们报道说，缺乏TSH受体（TSHR）的TSH信号不足的小鼠表现出严重的骨质疏松症，这表明低TSH水平也有助于甲状腺毒性骨质流失。甲基甲状腺TSHR小鼠具有同样深刻的表型，表明TSH的作用与甲状腺激素无关。尽管如此，尚不清楚通过刺激坟墓疾病中的抗体而激活TSHR是否会降低甲状腺激素高甲状腺激素和低TSH造成的甲状腺功能亢进。我们进一步表明，TSHR激活抑制破骨细胞的形成，功能和存活以及TNFA的产生。当TNFA从TSHR - / - 破骨细胞中烧蚀时，拯救了破骨细胞的增强和骨质减少症，这表明TNFA在甲状腺毒性骨病中起关键作用。最近，我们观察到，当TSH间歇性地间歇性地注射每两周一次时，通过抑制骨吸收和刺激骨形成，可以防止和恢复卵巢切除术诱导的骨质。我们假设TSH通过有效的反应性和合成代谢作用保留了骨骼，并且这些动作的丧失会导致甲状腺功能亢进的骨骼丧失。我们将使用转基因的小鼠和最先进的分子方法来了解TSH在甲状腺功能亢进中的作用。我们将首先尝试通过在双突变体中删除TNFA或其受体P55或P75来挽救TSHR - / - 表型，或者通过在TSHR - / - 破骨细胞或成骨细胞中跨基因重构TSHR。接下来，我们将确定刺激注射剂给出的抗TSHR抗体或通过腺TSHR免疫在体内产生的抗体会减轻甲状腺功能亢进骨损失。最后，使用TSHR - / - 背景上的破骨细胞或成骨细胞中TSHR恢复细胞的小鼠，我们将检查哪些细胞有助于预防和恢复TSH的静脉切除术后切除术骨损失。这些基础研究应使我们可以考虑TSH在绝经后妇女中的骨骼保护，这些妇女的TSH水平被甲状腺素治疗抑制了非癌症原因。公共卫生相关性：甲状腺功能亢进会影响1000名美国女性，并伴有骨质疏松症和高骨折风险。我们表明，垂体激素TSH的下降伴随着高甲状腺激素水平，这两者都会导致骨质流失。该建议研究了TSH直接在骨骼上作用的分子机制。