TSH and Bone

描述（由申请人提供）：甲状腺毒性骨质疏松症是由高甲状腺激素的促吸收作用引起的，并伴有较高的骨折风险。我们报道了缺乏TSH受体（TSHR）的TSH信号缺陷小鼠表现出严重的骨质疏松症，表明低TSH水平也有助于甲状腺毒性骨质流失。单倍体不足的正常甲状腺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，目前尚不清楚在Graves病中通过刺激抗体激活TSHR是否能减少高甲状腺激素和低TSH引起的甲状腺机能亢进性骨质流失。我们进一步发现TSHR激活抑制破骨细胞的形成、功能和存活，以及TNFa的产生。当从TSHR-/-破骨细胞中去除TNFa后，增强的破骨细胞生成和骨质减少都得以恢复，这表明TNFa在甲状腺毒性骨病中起关键作用。最近，我们观察到间歇注射TSH，间隔较远，每两周注射一次，通过抑制骨吸收和刺激骨形成来预防和恢复卵巢切除术引起的骨质流失。我们假设TSH通过有效的抗吸收和合成代谢作用来保护骨骼，而这些作用的丧失会导致甲状腺机能亢进的骨质流失。我们将使用转基因小鼠和最先进的分子方法来了解TSH在甲状腺机能亢进骨质流失中的作用。我们将首先尝试通过删除双突变体中的TNFa或其受体p55或p75，或通过转基因重建TSHR-/-破骨细胞或成骨细胞中的TSHR-/-表型来挽救TSHR-/-表型。接下来，我们将确定通过注射或通过腺- tshr免疫在体内产生的抗tshr抗体是否能减轻甲亢性骨质流失。最后，在TSHR-/-背景下，使用破骨细胞或成骨细胞选择性地恢复tshs的小鼠，我们将研究哪种细胞有助于TSH预防和恢复卵巢切除术后骨质流失。这些基础研究应该允许我们考虑经非癌症原因的甲状腺素治疗抑制TSH水平的绝经后妇女的TSH对骨骼的保护作用。公共卫生相关性：甲状腺机能亢进影响1000名美国妇女，并伴有骨质疏松症和高骨折风险。我们发现垂体激素TSH的下降伴随着高甲状腺激素水平，这两者都有助于骨质流失。本研究探讨了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.