Thyrotropin Receptor, Thyrotropin and Mechanisms of Bone Loss

促甲状腺素受体、促甲状腺素与骨丢失机制

• 批准号: 10182095
• 负责人: TERRY Francis DAVIES
• 金额: $ 40.78万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10182095
• 关键词: Affect; Affinity; Agonist; American; Anterior Pituitary Gland; Anterior Pituitary Hormones; Binding; Bone Diseases; Bone Marrow Cells; Bone Resorption; Bone remodeling; Cells; Clinical; Clinical Research; Closure by clamp; Coculture Techniques; Data; Defect; Dominant-Negative Mutation; Dose; Excision; Flow Cytometry; Genes; Genetic; Health; Hormone replacement therapy; Hormone secretion; Hyperthyroidism; Hypothyroidism; Implant; In Vitro; Incidence; Injections; Mediating; Mediation; Mesenchymal; Methimazole; Modeling; Molecular; Mus; Myocardial Infarction; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporotic; Ovariectomy; Patients; Pharmacology; Phenotype; Pituitary Hormones; Postmenopause; Prevention; Production; Rattus; Replacement Therapy; Reproducibility; Role; Serum; Signal Transduction; Skeleton; Specificity; Stroke; Stromal Cells; TNF gene; The Sun; Thyroid Function Tests; Thyroid Gland; Thyroid Hormone Receptor Beta; Thyroid Hormones; Thyrotropin; Thyrotropin Receptor; Tumor Necrosis Factor Receptor; United States; Woman; autoimmune thyroid disease; bone; bone cell; bone loss; bone mass; cellular targeting; cohort; cytokine; druggable target; experimental study; follow-up; fracture risk; malignant breast neoplasm; men; mouse model; mutant; nanomolar; novel; novel strategies; osteoclastogenesis; osteoporosis with pathological fracture; overexpression; prevent; restoration; skeletal; small molecule

PROJECT SUMMARY In 2003, we showed that the anterior pituitary hormone thyrotropin (a.k.a. TSH), hitherto known to promote thyroid hormone secretion, is a potent direct regulator of bone mass (Abe et al, Cell, 2003, PMID: 14567913)1. This finding underscored a potential role for low circulating TSH levels in causing the bone loss that has been recognized in patients with hyperthyroidism for over a century2, and, by tradition, has been attributed solely to thyroid hormone excess. We found instead that Tsh receptor-deficient Tshr-/- mice had profound osteoporosis, even when rendered euthyroid1. Importantly, we showed more recently that bone loss in Tshr-/- mice rendered hyperthyroid significantly exceeded that in wild type hyperthyroid mice (Baliram et al, J Clin Invest, 2012, PMID: 22996689)3 – this finding not only confirmed a direct permissive action of Tshr deficiency on bone, but also buttressed multiple clinical studies showing a tight and highly reproducible correlation between low TSH levels, bone loss, and a high fracture risk in cohorts of hyperthyroid patients worldwide4-24. Furthermore, we found that the osteoclastogenic cytokine, Tnfα, was grossly elevated in Tshr-/- mice, and that its genetic deletion rescued the skeletal phenotype of Tshr deficiency (Hase et al, PNAS, 2006, PMID: 16908863; Sun et al, PNAS, 2013, PMID: 23716650)25,26. This led to the question: which cell – osteoblast or osteoclast – drives the effect, and which of the two Tnf receptors, Tnfrsf1a or Tnfrsf1b, mediate the action of Tnfα in Tshr deficiency? Specific Aim 1 will study mice in which the Tshr is deleted selectively in osteoblasts or osteoclasts, as well as double mutants in which both the Tshr and either Tnfrsf1a or Tnfrsf1b are deleted. Complementary co-culture experiments will determine if osteoblastic Tnfα mediates the hyper-resorption in Tshr-/- mice. A second corpus of data, confirmed by other groups27-33, showed that Tsh displays both anti- resorptive and anabolic actions1,34-37. For example, intermittent low dose Tsh injections restored the lost bone 7 months post-ovariectomy, importantly without elevating T4 levels (Sun et al, PNAS, 2008, PMID: 18332426)37. A follow-up question thus arises: is the Tshr a druggable target? Towards finding an answer, we will utilize both genetic and pharmacological approaches. In Specific Aim 2, we will examine whether high Tsh levels are anabolic using mice in which the expression of dominant-negative Trβ337 in the thyrotrope clamps Tsh at ~30-fold higher circulating levels. In Specific Aim 3, we will study the effects of a small molecule activator of the Tshr, MS438, which, we have found, binds Tshrs selectively and with a nanomolar affinity (Latif et al, Thyroid, 2015, PMID: 25333622)38. We also find that MS438 displays pro-osteoblastic and anti-osteoclastic actions in vitro, and does not elevate serum T4. We will thus inject mice with MS438 immediately (‘prevention’) or 7-months following (‘restoration’) ovariectomy to determine if it can prevent bone loss and/or restore the lost bone. Together, these studies should not only allow an in-depth understanding of Tsh action on bone, but also provide proof-of-concept for a new approach that targets the skeletal Tshr.

项目概要 2003 年，我们发现垂体前叶激素促甲状腺素（又名 TSH）迄今为止已知可促进 甲状腺激素分泌是骨量的有效直接调节剂（Abe 等人，Cell，2003，PMID：14567913）1。 这一发现强调了低循环 TSH 水平在导致骨质流失方面的潜在作用。 一个多世纪以来，甲状腺功能亢进症患者就已认识到这一点2，并且按照传统，它被完全归因于 相反，我们发现 Tsh 受体缺陷的 Tshr-/- 小鼠患有严重的骨质疏松症， 即使甲状腺功能正常1。重要的是，我们最近发现 Tshr-/- 小鼠的骨质流失也发生了。 甲状腺功能亢进明显超过野生型甲状腺功能亢进小鼠（Baliram 等人，J Clin Invest，2012， PMID: 22996689)3 – 这一发现不仅证实了 Tshr 缺乏对骨骼的直接许可作用，而且 还支持多项临床研究，显示低 TSH 之间存在紧密且高度可重复的相关性 全球甲状腺机能亢进患者群体中的骨质流失和高骨折风险4-24 此外，我们还发现， 发现破骨细胞因子 Tnfα 在 Tshr-/- 小鼠中显着升高，并且其遗传因素 删除挽救了 Tshr 缺陷的骨骼表型（Hase 等人，PNAS，2006，PMID：16908863；Sun 等人） al, PNAS, 2013, PMID: 23716650)25,26 这引出了一个问题：哪种细胞（成骨细胞或破骨细胞）驱动。 效应，以及两种 Tnf 受体 Tnfrsf1a 或 Tnfrsf1b 中哪一个介导 Tshr 中 Tnfα 的作用 具体目标 1 将研究成骨细胞或 Tshr 被选择性删除的小鼠。 破骨细胞，以及 Tshr 和 Tnfrsf1a 或 Tnfrsf1b 都被删除的双突变体。 补充共培养实验将确定成骨细胞 Tnfα 是否介导 Tshr-/- 小鼠的第二个数据集经其他组27-33 证实，表明 Tsh 表现出两种抗- 再吸收和合成代谢作用1,34-37 例如，间歇性低剂量 Tsh 注射可恢复丢失的骨质。 卵巢切除术后 7 个月，T4 水平显着升高（Sun 等人，PNAS，2008，PMID： 18332426)37. 因此出现了一个后续问题：Tshr 是一个可药物靶点吗？ 在具体目标 2 中，我们将利用遗传和药理学方法来检查是否高。 使用促甲状腺素中显性失活 Trβ337 表达的小鼠进行合成代谢 Tsh 水平 将 Tsh 控制在约 30 倍的循环水平上。在具体目标 3 中，我们将研究小量的影响。 Tshr 的分子激活剂 MS438，我们发现它可以选择性地结合 Tshr，并且具有纳摩尔浓度 亲和力（Latif 等人，甲状腺，2015，PMID：25333622）38 我们还发现 MS438 具有促成骨细胞和促成骨细​​胞作用。 体外具有抗破骨作用，并且不会升高血清 T4，因此我们将给小鼠注射 MS438。 立即（“预防”）或在卵巢切除术后 7 个月（“恢复”）以确定是否可以预防骨质疏松 总之，这些研究不仅应该能够深入了解骨骼的丢失和/或恢复。 Tsh 对骨骼的作用，同时也为针对骨骼 Tshr 的新方法提供了概念验证。

项目成果

FSIP1 regulates autophagy in breast cancer.

FSIP1 调节乳腺癌中的自噬。

• 发表时间: 2018
• 影响因子: 11.1
• 作者: Liu, Caigang;Sun, Lisha;Yang, Jie;Liu, Tong;Yang, Yongliang;Kim, Se;Ou, Xunyan;Wang, Yining;Sun, Li;Zaidi, Mone;New, Maria I;Yuen, Tony;Guo, Qiyong
• 通讯作者: Guo, Qiyong

Sensitivity of ID NOW and RT-PCR for detection of SARS-CoV-2 in an ambulatory population.

ID NOW 和 RT-PCR 在流动人群中检测 SARS-CoV-2 的敏感性。

• 发表时间: 2021-04-20
• 影响因子: 7.7
• 作者: Tu, Yuan;Iqbal, Jameel;O'Leary, Timothy
• 通讯作者: O'Leary, Timothy

Development and biophysical characterization of a humanized FSH-blocking monoclonal antibody therapeutic formulated at an ultra-high concentration.

以超高浓度配制的人源化 FSH 阻断单克隆抗体治疗剂的开发和生物物理表征。

• 发表时间: 2023-06-19
• 影响因子: 7.7
• 作者: Rojekar, Satish;Pallapati, Anusha R;Gimenez;Korkmaz, Funda;Sultana, Farhath;Sant, Damini;Haeck, Clement M;Macdonald, Anne;Kim, Se;Rosen, Clifford J;Barak, Orly;Meseck, Marcia;Caminis, John;Lizneva, Daria;Yuen, Tony;Zaidi, Mo
• 通讯作者: Zaidi, Mo

FSH Beyond Fertility.

FSH 超越生育能力。

• 发表时间: 2019
• 作者: Lizneva, Daria;Rahimova, Alina;Kim, Se;Atabiekov, Ihor;Javaid, Seher;Alamoush, Bateel;Taneja, Charit;Khan, Ayesha;Sun, Li;Azziz, Ricardo;Yuen, Tony;Zaidi, Mone
• 通讯作者: Zaidi, Mone

First-in-class humanized FSH blocking antibody targets bone and fat.

一流的人源化 FSH 阻断抗体针对骨骼和脂肪。

• 发表时间: 2020
• 影响因子: 11.1
• 作者: Gera, Sakshi;Sant, Damini;Haider, Shozeb;Korkmaz, Funda;Kuo, Tan;Mathew, Mehr;Perez;Xie, Honglin;Chen, Hao;Batista, Rogerio;Ma, Kejun;Cheng, Zhen;Hadelia, Elina;Robinson, Cemre;Macdonald, Anne;Miyashita, Sari;Williams, An
• 通讯作者: Williams, An