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: 10370393
• 负责人: ROLAND E BARON
• 金额: $ 56.22万
• 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/10370393
• 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; 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 fracture repair; bone fragility; bone loss; 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. !

摘要 Teriparlavine（PTH 1 -34）和Abaloparlavine（修饰的PTHrP 1 -34）是批准用于 治疗骨质疏松症，一种与衰老有关的广泛的骨脆性慢性疾病， 和社会经济后果。骨质疏松症和衰老涉及骨细胞功能障碍，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降低骨量，但也增加BMAT。PTH和WNT 信号传导与这两种效应相反，进一步表明低骨量和高骨髓 肥胖症维持骨量对于预防骨质疏松症和骨折至关重要， 老年人，而过度的BMAT的后果仍然不清楚。因为成骨细胞（OBs） 在间充质干细胞（MSC）谱系中，脂肪细胞（AD）和脂肪细胞（AD）有着共同的前体， 骨髓AD的增加与OB分化的减少有关。此外，MSC衍生 来自骨髓或脂肪的PTH用于骨再生，并且PTH现在广泛用于临床， 骨折愈合PTH以BMAT为代价促进骨的机制和BMAT的作用 然而，骨对PTH的反应的降低是未知的。新型下游PTH的表征 MSC中OB与AD细胞命运决定的效应物以及PTH与WNT之间的串扰可以 对合成代谢性骨质疏松症治疗的发展或理解产生重大影响， 关于骨髓间充质干细胞在骨再生中的应用拟议的工作是创新的，因为它侧重于反- 对PTH/PTHrP治疗的成脂反应及其在骨骼合成代谢反应中的意义。的 本申请的主要目的是鉴定信号转导机制的组分， 间歇性PTH（iPTH）促进骨形成和抑制BMAT，以确定是否 干扰抗脂肪形成因子Zfp 521或促脂肪形成因子Zfp 467和Zfp 423，可以 增强用iPTH治疗的治疗效果，即预防AD分化是否可以 增强iPTH的合成代谢作用。我们将确定是否增强（通过删除抗AD基因 因子Zfp 521）或阻断（通过缺失前AD生成因子Zfp 467或Zfp 423）前脂肪生成信号 PPR下游的蛋白质可能分别损害或促进对iPTH治疗的骨合成代谢反应。到 为此，我们将确定抑制脂肪形成靶点的PPR信号传导事件，以便可能改善 通过增强iPTH的抗脂肪形成作用来促进骨合成代谢反应。由于这个原因，由于我们有 确定了三个关键的调控脂肪细胞，我们建议剖析信号通路 在PPR下游，导致Zfp 521的表达增加和Zfp 467的抑制， ZFP 423。 !