Mechanism of action of PTH: New signaling components that regulate bone formation and bone marrow fat

PTH的作用机制：调节骨形成和骨髓脂肪的新信号成分

• 批准号: 10159214
• 负责人: ROLAND E BARON
• 金额: $ 55.09万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-05 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10159214
• 关键词: Adipocytes; Adipose tissue; Aging; Animal Model; Bone Density; Bone Marrow; Bone Regeneration; Bone Resorption; Cell Lineage; Cell Therapy; Cells; Chronic; Clinic; Clinical; Development; Elderly; Equilibrium; Estrogens; Event; Fatty acid glycerol esters; Forteo; Fracture; Fracture Healing; Functional disorder; Future; Genes; Glucocorticoids; Goals; Grant; Homeostasis; Human; Impairment; Injections; Lead; Link; Maintenance; Marrow; Mediating; Mesenchymal Stem Cells; Molecular; Obesity; Osteoblasts; Osteocytes; Osteogenesis; Osteoporosis; Osteoporosis prevention; Parathyroid Hormone Receptor; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Play; Process; Receptor Signaling; Regulation; Repression; Rodent; Role; Signal Pathway; Signal Transduction; Skeleton; Testing; Therapeutic Effect; Therapeutic Uses; WNT Signaling Pathway; Work; adipocyte differentiation; bone; bone fragility; bone loss; bone mass; clinically relevant; fracture risk; health economics; improved; innovation; lipid biosynthesis; mechanical load; novel; osteoblast differentiation; parathyroid hormone-related protein; prevent; receptor; repaired; response; skeletal; socioeconomics; stem cell fate specification; transcription factor; treatment effect

Abstract Teriparatide (PTH1-34) and Abaloparatide (modified PTHrP1-34) are approved anabolic drugs for the treatment of osteoporosis, a widespread bone fragility chronic condition linked to aging, with important health and socio-economic consequences. Osteoporosis and aging involve dysfunctions of cells in bone, often associated with an increase in bone marrow adipose tissue (BMAT). Estrogen deficiency, glucocorticoid treatment or decreased mechanical loading lower bone mass but also increase BMAT. PTH and WNT signaling oppose both effects, further suggesting a clinical link between low bone mass and high marrow adiposity. The maintenance of bone mass is essential for the prevention of osteoporosis and fractures in the elderly, whereas the consequences of excessive BMAT are still not understood. Because osteoblasts (OBs) and adipocytes (ADs) share a common precursor in the mesenchymal stem cell (MSC) lineage it is thought that the increase in bone marrow ADs is linked to the decrease in OB differentiation. Moreover, MSCs derived from bone marrow or from fat are used in bone regeneration, and PTH is now widely used clinically for fracture healing. The mechanisms by which PTH favors bone at the expense of BMAT and the role of BMAT reduction in the response of bone to PTH are however not known. Characterization of novel downstream PTH effectors in MSCs for the OB versus AD cell fate decision and in the crosstalk between PTH and WNT could have a significant impact on the development or understanding of anabolic osteoporosis treatment as well as on the use of MSCs for bone regeneration. The proposed work is innovative because it focuses on the anti- adipogenic responses to PTH/PTHrP treatment and their implication in anabolic responses of the skeleton. The main goal of this application is to identify the components of the signal transduction machinery that allows intermittent PTH (iPTH) to promote bone formation and repress BMAT, in order to determine whether interfering with the anti-adipogenic factor Zfp521 or the pro-adipogenic factors Zfp467 and Zfp423, can enhance the therapeutic effects of treatment with iPTH, i.e. whether preventing the AD differentiation may enhance the anabolic effects of iPTH. We will determine whether enhancing (via deletion of the anti-ADgenic factor Zfp521) or blocking (via deletion of the pro-ADgenic factors Zfp467 or Zfp423) pro-adipogenic signals downstream of the PPR could impair or favor, respectively, the bone anabolic responses to iPTH treatment. To this end, we will identify the PPR signaling events that repress adipogenic targets in order to possibly improve bone anabolic responses by enhancing the anti-adipogenic effects of iPTH. For this reason, and since we have identified three key regulators of adipogenesis in MSCs, we propose to dissect the signaling pathways downstream of the PPR that lead to the increased expression of Zfp521 and the repression of Zfp467 and Zfp423. !

摘要 Teriparatide(PTH1-34)和Abaloparatide(改良的PTHrP1-34)是被批准用于治疗 治疗骨质疏松症，一种广泛存在的与衰老有关的骨骼脆性慢性疾病，与重要的健康 和社会经济后果。骨质疏松症和衰老涉及骨骼中细胞的功能障碍，通常 与骨髓脂肪组织(BMAT)增加有关。雌激素缺乏症、糖皮质激素缺乏 治疗或降低机械负荷，降低骨量，但也增加BMAT。PTH和WNT 信号信号反对这两种效应，进一步表明低骨量和高骨髓之间存在临床联系 肥胖症。保持骨量是预防骨质疏松症和骨折的关键 然而，过量的BMAT的后果仍不清楚。因为成骨细胞(OBS) 脂肪细胞(ADS)被认为是间充质干细胞(MSC)谱系的共同前体 骨髓ADS的增加与OB分化的减少有关。此外，骨髓间充质干细胞来源 来自骨髓或脂肪的甲状旁腺素用于骨再生，甲状旁腺激素现在被广泛用于临床治疗。 骨折愈合。甲状旁腺素以BMAT为代价促进骨骼生长的机制及BMAT的作用 然而，甲状旁腺激素对骨骼反应的减少尚不清楚。新型下游甲状旁腺素的表征 MSCs中决定OB和AD细胞命运的效应分子以及PTH和WNT之间的串扰中可能 对开发或理解合成代谢性骨质疏松症治疗以及 关于骨髓间充质干细胞用于骨再生的研究。这项拟议的工作具有创新性，因为它专注于反 PTH/PTHrP治疗的成脂反应及其在骨骼合成代谢反应中的意义。这个 此应用程序的主要目标是识别信号转导机制的组件，以允许 间歇性甲状旁腺激素(IPTH)促进骨形成和抑制BMAT，以确定是否 干扰抗成脂因子Zfp521或促进成脂因子Zfp467和Zfp423，可以 增强iPTH治疗的疗效，即阻止AD分化是否可以 增强iPTH的合成代谢作用。我们将确定是否通过删除抗ADgene来增强( 因子Zfp521)或阻断(通过删除促肥胖因子Zfp467或Zfp423)促脂肪信号 PPR的下游可以分别削弱或有利于iPTH治疗的骨合成代谢反应。至 为此，我们将确定抑制成脂靶点的PPR信号事件，以便可能改善 通过增强iPTH的抗脂作用引起的骨合成代谢反应。出于这个原因，既然我们已经 确定了骨髓间充质干细胞脂肪形成的三个关键调控因子，我们建议剖析信号通路 PPR下游导致Zfp521表达增加，Zfp467和 Zfp423。 好了！