TSH and Bone

描述(由申请人提供)：甲状腺毒性骨质疏松症，伴随着高骨折风险，已知是由高甲状腺激素的促吸收作用引起的。我们报道，缺乏TSH受体(TSHR)的TSH信号缺陷小鼠表现出严重的骨质疏松症，这表明低TSH水平也导致甲状腺毒性骨丢失。单倍性甲状腺功能不全的TSHR小鼠具有同样深刻的表型，这表明TSH的作用独立于甲状腺激素。然而，目前尚不清楚Graves病患者通过刺激抗体激活TSHR是否能减少由于高甲状腺激素和低TSH引起的甲亢性骨丢失。我们进一步表明，TSHR的激活抑制了破骨细胞的形成、功能和存活，以及TNFa的产生。TSHR-/-破骨细胞去除TNFa后，破骨细胞生成增强，骨量减少，提示TNFa在甲亢性骨病中起关键作用。最近，我们观察到，当TSH每隔两周间歇注射一次时，可以通过抑制骨吸收和刺激骨形成来预防和恢复卵巢切除所致的骨丢失。我们假设TSH通过强大的抗吸收和合成代谢作用来保护骨骼，这些作用的丧失导致甲亢的骨丢失。我们将使用转基因小鼠和最先进的分子方法来了解TSH在甲亢性骨丢失中的作用。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，或者在TSHR-/-破骨细胞或成骨细胞中转基因重组TSHR-/-来挽救TSHR-/-表型。接下来，我们将确定通过注射或在体通过腺-TSHR免疫产生的刺激性抗TSHR抗体是否可以减少甲亢性骨丢失。最后，利用TSHR-/-背景下TSHR在破骨细胞或成骨细胞中选择性修复TSHR的小鼠，我们将检验哪种细胞对TSH预防和修复卵巢切除后的骨丢失起作用。这些基础研究应该允许我们考虑TSH对绝经后妇女的骨骼保护作用，这些妇女的TSH水平因非癌症原因而被甲状腺激素治疗抑制。公共卫生相关性：每1000名美国妇女中就有一人患有甲亢，并伴有骨质疏松症和高骨折风险。我们发现，垂体激素TSH的减少伴随着甲状腺激素水平的升高，这两者都是导致骨质丢失的原因。这项建议研究了TSH直接作用于骨骼的分子机制。

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.