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Skeletal Functions of Polycystins and TAZ

多囊蛋白和 TAZ 的骨骼功能

基本信息

批准号：
10443809
负责人：
Zhousheng Xiao
金额：
$ 33.11万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-24 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10443809
关键词：
Adipocytes Adipose tissue Age-Related Osteoporosis Aging Agonist Agreement Binding Bone Formation Inhibition Bone Marrow C-terminal Calcium Cell Communication Cells Chemicals Cilia Complex Critical Pathways Cues Development Exhibits Extracellular Matrix Fatty acid glycerol esters Future GTP-Binding Protein alpha Subunits, Gs Genetic Goals Homeostasis Impairment In Vitro Link Marrow Mechanical Stimulation Mechanics Mediating Microgravity Modeling Molecular Mus Mutant Strains Mice Nature Nuclear Translocation Osteoblasts Osteocalcin Osteogenesis Osteopenia Osteoporosis Osteoporosis prevention Outcome PKD2 protein PPAR gamma Pathogenesis Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Pharmacology Phenotype Prevention Process Proprotein Convertase 1 Proprotein Convertase 2 Role Signal Pathway Signal Transduction Stretching Stromal Cells Structure Tail Testing Transcription Coactivator Transcriptional Coactivator with PDZ-Binding Motif base bone bone disuse atrophy bone loss bone mass clinically relevant conditional knockout experimental study fluid flow gamma secretase genetic corepressor improved in vivo lipid biosynthesis loss of function mechanical force mechanical load mechanotransduction mouse model new therapeutic target novel physical inactivity polycystic kidney disease 1 protein pre-clinical prevent response sarcopenia shear stress skeletal skeletal unloading small molecule therapeutic target validation studies virtual screening

项目摘要

Defective bone mechanosensing and skeletal unloading contribute to age-related and disuse osteoporosis. The molecular mechanisms that transduce the osteoblast response to physical forces in the bone microenvironment to maintain skeletal homeostasis are poorly understood. We discovered a novel mechanosensing complex in osteoblasts created by an interaction between polycystins (PC1, Pkd1 and PC2, Pkd2) and TAZ (transcriptional coactivator with PDZ-binding motif). The PC1/PC2/TAZ complex functions to sense and transduce mechanical loading into anabolic bone responses. Loss of either Pkd1 or Taz in mice results in osteopenia characterized by a reciprocal decrease in osteoblast-mediated bone formation and an increase in adipocytes in bone marrow. Compound heterozygous mice lacking one copy of Pkd1 and TAZ exhibit additive decrements in bone mass, impaired osteoblast-mediated bone formation and enhanced accumulation of bone marrow fat. The PC1 C-ter- minal tail (PC1-CTT) binds to and facilitates TAZ nuclear translocation to co-activate Runx2-mediated osteoblas- togenesis and co-repress PPAR-mediated adipogenesis in vitro. Computational approaches using structure- based virtual screening discovered a novel agonist (mechanomimetic) that binds to the PC1:PC2 C-terminal tail helix: helix interaction region and activates polycystins/TAZ signaling. These observations provide the scientific premise for the hypothesis that skeletal responses to loading are transduced by a mechanosensing complex in osteoblasts formed by interactions between PC1, PC2 and TAZ. Aim 1 tests the hypothesis that Pkd1/TAZ have interdependent functions in mature osteoblasts to regulate bone mass through the reciprocal stimulation of os- teoblastogenesis and inhibition of adipogenesis. In this aim, we will examine the effects of TAZ to differentially regulate osteoblastogenesis and adipogenesis in vitro and in vivo by creating mice with conditional knockout of Taz in mature osteoblasts (TazOc-cko). We will further test for genetic interactions between Taz and Pkd1 by creating compound Pkd1Oc-cko/Taz Oc-cko mice. Aim 2 tests the hypothesis that the Pkd1/TAZ complex mediates the response of osteoblasts to mechanical loading in vivo and in vitro using single and compound Pkd1 and Taz loss-of-function mouse models and osteoblast cultures. Aim 3 tests the hypothesis that activation of the PC1/PC2/TAZ with a novel “mechanomimetic” will increase bone mass by stimulating osteoblastogenesis and inhibiting adipogenesis. Our impact will be to provide a new understanding of the molecular mechanisms medi- ating the skeletal response to loading by validating the PC1/PC2/TAZ mechanosensing complex in osteoblasts. In this new schema, PC1-CTT and TAZ form an integrative mechanosensing complex in cells within the osteo- blast lineage to differentially regulate Runx2-dependent osteoblastogenesis and PPARγ-mediated adipogenesis in response to physical cues in the bone microenvironment. The polycystins/TAZ complex is also a potential therapeutic target for treating osteoporosis caused by skeletal unloading; and the newly discovered first-in-class mechanomimetic provides a chemical probe to test if targeting polycystins/TAZ results in increased bone mass.

有缺陷的骨力学感知和骨骼卸载有助于年龄相关和废用性骨质疏松症。的

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genetic interactions between polycystin-1 and Wwtr1 in osteoblasts define a novel mechanosensing mechanism regulating bone formation in mice.

DOI：
10.1038/s41413-023-00295-4
发表时间：
2023-10-26
期刊：
BONE RESEARCH
影响因子：
12.7
作者：
Xiao, Zhousheng;Cao, Li;Smith, Micholas Dean;Li, Hanxuan;Li, Wei;Smith, Jeremy C.;Quarles, Leigh Darryl
通讯作者：
Quarles, Leigh Darryl

Recent Advances of Osterix Transcription Factor in Osteoblast Differentiation and Bone Formation.

Osterix转录因子在成骨细胞分化和骨形成中的研究进展

DOI：
10.3389/fcell.2020.601224
发表时间：
2020
期刊：
Frontiers in cell and developmental biology
影响因子：
5.5
作者：
Liu Q;Li M;Wang S;Xiao Z;Xiong Y;Wang G
通讯作者：
Wang G

Osteoporosis: Mechanism, Molecular Target and Current Status on Drug Development.

DOI：
10.2174/0929867327666200330142432
发表时间：
2021
期刊：
Current medicinal chemistry
影响因子：
4.1
作者：
Li H;Xiao Z;Quarles LD;Li W
通讯作者：
Li W

Systems genetics and bioinformatics analyses using ESR1-correlated genes identify potential candidates underlying female bone development.

DOI：
10.1016/j.ygeno.2023.110769
发表时间：
2024-01
期刊：
GENOMICS
影响因子：
4.4
作者：
Bajpai, Akhilesh K.;Gu, Qingqing;Jiao, Yan;Starlard-Davenport, Athena;Gu, Weikuan;Quarles, Leigh Darryl;Xiao, Zhousheng;Lu, Lu
通讯作者：
Lu, Lu