TSH and Bone

描述（由申请人提供）：已知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，伴有高骨折风险。我们报道了缺乏TSH受体（TSHR）的TSH信号传导缺陷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丢失。单倍不足的甲状腺功能正常的TSHR小鼠具有同样深刻的表型，这表明TSH的作用不依赖于甲状腺激素。尽管如此，目前还不清楚是否通过刺激抗体激活甲状腺高血压引起的甲状腺高血压减少骨质流失，这是由于高甲状腺激素和低TSH。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TNF α的产生。当TNFa从TSHR-/-破骨细胞消融时，增强的破骨细胞生成和骨质减少都被挽救，表明TNFa在甲状腺毒性骨疾病中起关键作用。最近，我们观察到，当每隔两周间歇注射一次TSH时，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丢失。我们推测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功能亢进症的骨丢失。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TNF α或其受体p55或p75，或通过在TSHR-/-破骨细胞或成骨细胞中转基因重建TSHR来挽救TSHR-/-表型。接下来，我们将确定是否刺激抗TSHR抗体通过注射或在体内产生的腺TSHR免疫减弱甲亢性骨丢失。最后，使用小鼠，其中TSHR恢复细胞选择性破骨细胞或成骨细胞的TSHR-/-背景下，我们将检查哪种细胞有助于预防和恢复卵巢切除术后的骨质流失的TSH。这些基础研究应该使我们考虑在绝经后妇女的TSH水平被抑制的非癌症原因的甲状腺素治疗的TSH骨骼保护。

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.