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PTH resistance and marrow adipogenesis

PTH 抵抗和骨髓脂肪生成

基本信息

批准号：
9401167
负责人：
ROLAND E BARON
金额：
$ 57.66万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9401167
关键词：
Adipocytes Adipose tissue Age Age-Related Bone Loss Age-Related Osteoporosis Animal Model Antibodies Area Bioenergetics Biopsy Birth Bone Marrow Bone Resorption Bone remodeling Cell Differentiation process Cell Separation Cells Characteristics Data Development Disease model Endocytosis Exhibits Fatty acid glycerol esters Female GTP-Binding Protein alpha Subunits, Gs Gene Expression Profile Genes Genetic Genetic Models Glycolysis Goals Histologic Histology Impairment In Vitro Individual Knockout Mice Lead Light Marrow Mediating Mediator of activation protein Mesenchymal Mesenchymal Differentiation Mesenchymal Stem Cells Messenger RNA Mus Mutant Strains Mice Obesity Osmium Osteoblasts Osteocytes Osteogenesis Osteoporosis Oxidative Phosphorylation PPAR gamma PTH gene Pathway interactions Peptides Peripheral Phenotype Population Production Proteins Recruitment Activity Role Serum Signal Transduction Signaling Protein Skeletal bone Skeleton Small Interfering RNA Sorting - Cell Movement Stem cells Stromal Cells Sum TNFSF11 gene Techniques Technology Testing Tomatoes Work Zinc Fingers adiponectin bone bone mass cortical bone driving force experimental study hormone resistance in vivo lipid biosynthesis male men microCT mouse model mutant new technology novel osteogenic osteoprogenitor cell parathyroid hormone (1-34)parathyroid hormone-related protein progenitor recombinase rosiglitazone skeletal transcription factor

项目摘要

Age-related osteoporosis is characterized by enhanced skeletal fragility, low bone mass, secondary increases in PTH, high bone resorption and marrow adiposity. Previous animal models for this disorder did not recapitulate all these features. However, we developed a mouse model of impaired PTH function that develops age-related bone loss relatively soon after birth. For example, we found that conditional deletion of the PTH1R using the Prx1Cre recombinase led to a substantial increase in marrow adipose tissue (MAT) by 3 weeks of age. This was accompanied by increased bone resorption, low bone mass and high RANKL expression in the bone marrow and serum, even in the absence of functional PTH activity, and no change in osteocyte number/area or lacunar area. Also we noted that PTH administration to the PTH1Rfl/fl control mice reduced MAT volume by 50% but did not change MAT in the mutant mice. Similar findings were noted in men treated with PTH for osteoporosis. To further delineate the origin of RANKL, we then isolated bone marrow adipocytes from the Prx1cre;PTH1Rfl/fl mice and their controls, and found consistently high expression of adipose-related genes; e.g., Pparγ, Cebp α,β,Δ, Fabp4 and Adiponectin as well as Rankl. Supernatant from spun marrow showed an increase in RANKL protein (p<0.03) in the Prx1cre;PTH1Rfl/fl mutant mice. Progenitor cells removed from the bottom layer of spun marrow in the mutant mice showed enhanced adipogenic differentiation, increased RANKL expression, and co-localization of adiponectin and tomato red in the MSCs. Further, we noted that Rankl mRNA was undetectable in any adipose depot outside the marrow. We also found that zinc finger protein 467 (Zfp467), an early mesenchymal transcription factor that up-regulates Rankl, but is down regulated by PTH, was 8 fold higher in mutant adipocytes, whereas treatment with PTH suppressed Zfp467 mRNA by 70% in cortical bone of controls but not in mutants. In this proposal we hypothesize that PTH regulates marrow adipogenesis through suppression of Zfp467 and that the marrow adipocytes induced by loss of PTH signaling are unique, arising from a mesenchymal progenitor, which expresses both adipogenic and osteogenic markers. We propose two specific aims to test this hypothesis: 1) Determine the role of PTH1R in cell fate decisions of mesenchymal progenitor cells using genetic mouse models, define the downstream mediator of PTH1R in regulating bone marrow adipogenesis, and perform bioenergetic analyses; 2) Determine whether bone marrow adipocytes are the driving force via RANKL to enhance bone resorption in the absence of PTH1R signaling exploiting new technology for: 1-lineage tracing, 2-sorting marrow adipocytes, 3-treating with OPG and 4- generating a novel mouse model. The results of these experiments could lead to new targets for treating osteoporosis.

年龄相关性骨质疏松症的特点是骨骼脆性增强，骨量低，继发性增加