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: 10598064
• 负责人: ROLAND E BARON
• 金额: $ 53.54万
• 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/10598064
• 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; Estrogen deficiency; Event; Fatty acid glycerol esters; Forteo; Fracture; Functional disorder; Future; Genes; Glucocorticoids; Goals; Grant; Homeostasis; Human; Impairment; Injections; 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 fracture repair; bone fragility; bone loss; bone marrow mesenchymal stem cell; bone mass; bone repair; clinically relevant; fracture risk; health economics; improved; innovation; lipid biosynthesis; mechanical load; novel; osteoblast differentiation; parathyroid hormone-related protein; prevent; receptor; 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. !

抽象的 Teriparatide（PTH1-34）和鲍鱼（修饰的PTHRP1-34）是批准的合成代谢药物 治疗骨质疏松症，这是一种与衰老有关的广泛骨骼脆弱性慢性病，重要的健康 和社会经济后果。骨质疏松症和衰老涉及骨中细胞功能障碍，通常 与骨髓脂肪组织（BMAT）的增加有关。雌激素缺乏，糖皮质激素 治疗或减少机械负荷较低的骨骼量，但也会增加BMAT。 pth和wnt 信号传递反对这两种效应，进一步表明低骨头和高骨髓之间的临床联系 肥胖。骨骼的维持对于预防骨质疏松症和骨折至关重要 老年人，尽管BMAT过多的后果仍然尚不清楚。因为成骨细胞（obs） 脂肪细胞（AD）在间充质干细胞（MSC）谱系中共有一个共同的前体 骨髓广告的增加与OB分化的减少有关。而且，MSC得出 从骨髓或脂肪中用于骨再生，PTH现在在临床上广泛使用 断裂愈合。 PTH以BMAT为代价和BMAT的作用的机制偏爱骨骼的机制 然而，骨头对PTH的反应减少尚不清楚。新颖下游PTH的表征 OB与AD细胞命运决策的MSC的效应子以及PTH和Wnt之间的串扰可以 对合成代谢骨质疏松症治疗的发展或理解以及 关于使用MSC进行骨骼再生。拟议的工作具有创新性，因为它专注于反 - 对PTH/PTHRP治疗的成脂反应及其对骨骼合成代谢反应的影响。这 该应用程序的主要目标是确定信号转导机械的组件，允许 间歇性PTH（IPTH）促进骨形成和抑制BMAT，以确定是否是否 干扰抗辅助因子ZFP521或促脂因素ZFP467和ZFP423可以 增强用IPTH治疗的治疗作用，即是否可以防止AD分化 增强IPTH的合成代谢作用。我们将确定是否增强（通过删除抗毒剂 因子ZFP521）或阻止（通过删除促助剂因子ZFP467或ZFP423）pr​​o-辅助信号 PPR的下游可能分别损害或偏爱骨合成代谢对IPTH治疗的反应。到 这一目的，我们将确定抑制脂肪生成靶的PPR信号事件，以便可能改善 骨合成代谢反应通过增强IPTH的抗辅助作用。因此，由于我们有 确定了MSC中脂肪形成的三个关键调节剂，我们建议剖析信号通路 PPR的下游导致ZFP521的表达增加以及ZFP467和 ZFP423。 呢