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，它仅归因于 甲状腺激素过量。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-/- 小鼠的骨质流失导致 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 全球甲状腺功能亢进患者队列中的水平、骨质流失和高骨折风险4-24。此外，我们 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） 等，PNAS，2013，PMID：23716650）25,26。这就引出了一个问题：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 不足？具体目标 1 将研究在成骨细胞中选择性删除 Tshr 的小鼠，或 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。经其他团体确认的第二个数据集27-33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，重要的是 T4 水平没有升高（Sun 等人，PNAS，2008，PMID： 18332426)37.因此出现了一个后续问题：Tshr 是可药物靶点吗？为了寻找答案，我们 将利用遗传和药理学方法。在具体目标 2 中，我们将检查是否高 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 控制在高出约 30 倍的循环水平。在具体目标 3 中，我们将研究小因素的影响 Tshr 的分子激活剂 MS438，我们发现它可以选择性地以纳摩尔浓度结合 Tshr 亲和力（Latif 等人，甲状腺，2015，PMID：25333622）38。我们还发现 MS438 显示出促成骨细胞和 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 丢失和/或恢复丢失的骨骼。总之，这些研究不仅应该让人们深入了解 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

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

• DOI: 10.7554/elife.65726
• 发表时间: 2021-04-20
• 期刊: eLife
• 影响因子: 7.7
• 作者: Tu YP;Iqbal J;O'Leary T
• 通讯作者: O'Leary T

FSH-blocking therapeutic for osteoporosis.

• DOI: 10.7554/elife.78022
• 发表时间: 2022-09-20
• 期刊: eLife
• 影响因子: 7.7
• 作者: Gera S;Kuo TC;Gumerova AA;Korkmaz F;Sant D;DeMambro V;Sudha K;Padilla A;Prevot G;Munitz J;Teunissen A;van Leent MMT;Post TGJM;Fernandes JC;Netto J;Sultana F;Shelly E;Rojekar S;Kumar P;Cullen L;Chatterjee J;Pallapati A;Miyashita S;Kannangara H;Bhongade M;Sengupta P;Ievleva K;Muradova V;Batista R;Robinson C;Macdonald A;Hutchison S;Saxena M;Meseck M;Caminis J;Iqbal J;New MI;Ryu V;Kim SM;Cao JJ;Zaidi N;Fayad ZA;Lizneva D;Rosen CJ;Yuen T;Zaidi M
• 通讯作者: Zaidi M

Brain atlas for glycoprotein hormone receptors at single-transcript level.

• DOI: 10.7554/elife.79612
• 发表时间: 2022-09-02
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Ryu, Vitaly;Gumerova, Anisa;Korkmaz, Funda;Kang, Seong Su;Katsel, Pavel;Miyashita, Sari;Kannangara, Hasni;Cullen, Liam;Chan, Pokman;Kuo, TanChun;Padilla, Ashley;Sultana, Farhath;Wizman, Soleil A.;Kramskiy, Natan;Zaidi, Samir;Kim, Se-Min;New, Maria, I;Rosen, Clifford J.;Goosens, Ki A.;Frolinger, Tal;Haroutunian, Vahram;Ye, Keqiang;Lizneva, Daria;Davies, Terry F.;Yuen, Tony;Zaidi, Mone
• 通讯作者: Zaidi, Mone

An Atlas of Brain-Bone Sympathetic Neural Circuits.

脑骨交感神经回路图谱。

• DOI: 10.1101/2024.02.07.579382
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Ryu,Vitaly;Gumerova,Anisa;Witztum,Ronit;Korkmaz,Funda;Kannangara,Hasni;Moldavski,Ofer;Barak,Orly;Lizneva,Daria;Goosens,KiA;Stanley,Sarah;Kim,Se-Min;Yuen,Tony;Zaidi,Mone
• 通讯作者: Zaidi,Mone

Beyond bone biology: Lessons from team science.

• DOI: 10.1002/jor.24771
• 发表时间: 2020-11
• 期刊: Journal of orthopaedic research : official publication of the Orthopaedic Research Society
• 作者: Zaidi M;Lizneva D;Gera S;Taneja C;Korkmaz F;Gumerova A;Ievleva K;Ahmad N;Ryu V;Sun L;Kim SM;New MI;Haider S;Iqbal J;Rosen C;Yuen T
• 通讯作者: Yuen T