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Title: Polycystin-1 interacts with TAZ to stimulate osteoblastogenesis and inhibit adipogenesis

Abstract

The molecular mechanisms that transduce the osteoblast response to physical forces in the bone microenvironment are poorly understood. In this paper, we used genetic and pharmacological experiments to determine whether the polycystins PC1 and PC2 (encoded by Pkd1 and Pkd2) and the transcriptional coactivator TAZ form a mechanosensing complex in osteoblasts. Compound-heterozygous mice lacking 1 copy of Pkd1 and Taz exhibited additive decrements in bone mass, impaired osteoblast-mediated bone formation, and enhanced bone marrow fat accumulation. Bone marrow stromal cells and osteoblasts derived from these mice showed impaired osteoblastogenesis and enhanced adipogenesis. Increased extracellular matrix stiffness and application of mechanical stretch to multipotent mesenchymal cells stimulated the nuclear translocation of the PC1 C-terminal tail/TAZ (PC1-CTT/TAZ) complex, leading to increased runt-related transcription factor 2–mediated (Runx2-mediated) osteogenic and decreased PPARγ-dependent adipogenic gene expression. Using structure-based virtual screening, we identified a compound predicted to bind to PC2 in the PC1:PC2 C-terminal tail region with helix:helix interaction. This molecule stimulated polycystin- and TAZ-dependent osteoblastogenesis and inhibited adipogenesis. Therefore, we show that polycystins and TAZ integrate at the molecular level to reciprocally regulate osteoblast and adipocyte differentiation, indicating that the polycystins/TAZ complex may be a potential therapeutic target to increase bone mass.

Authors:
ORCiD logo [1];  [2];  [1];  [1];  [3];  [3];  [3];  [4];  [4];  [2];  [1]
  1. Univ. of Tennessee Health Science Center, Memphis, TN (United States). Dept. of Medicine
  2. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). UT/ORNL Center for Molecular Biophysics; Univ. of Tennessee, Knoxville, TN (United States). Dept. of Biochemistry and Cellular and Molecular Biology
  3. Univ. of Tennessee Health Science Center, Memphis, TN (United States). Dept. of Pharmaceutical Sciences
  4. Univ. of Tennessee Health Science Center, Memphis, TN (United States). Dept. of Physiology
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee Health Science Center, Memphis, TN (United States)
Sponsoring Org.:
USDOE; National Inst. of Health (NIH) (United States)
OSTI Identifier:
1435199
Grant/Contract Number:  
AC05-00OR22725; R01-DK083303; R01-AR045955; R01-AR37308; HL123540; HL131526
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Clinical Investigation
Additional Journal Information:
Journal Volume: 128; Journal Issue: 1; Journal ID: ISSN 0021-9738
Publisher:
American Society for Clinical Investigation
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Xiao, Zhousheng, Baudry, Jerome, Cao, Li, Huang, Jinsong, Chen, Hao, Yates, Charles R., Li, Wei, Dong, Brittany, Waters, Christopher M., Smith, Jeremy C., and Quarles, L. Darryl. Polycystin-1 interacts with TAZ to stimulate osteoblastogenesis and inhibit adipogenesis. United States: N. p., 2017. Web. doi:10.1172/JCI93725.
Xiao, Zhousheng, Baudry, Jerome, Cao, Li, Huang, Jinsong, Chen, Hao, Yates, Charles R., Li, Wei, Dong, Brittany, Waters, Christopher M., Smith, Jeremy C., & Quarles, L. Darryl. Polycystin-1 interacts with TAZ to stimulate osteoblastogenesis and inhibit adipogenesis. United States. doi:10.1172/JCI93725.
Xiao, Zhousheng, Baudry, Jerome, Cao, Li, Huang, Jinsong, Chen, Hao, Yates, Charles R., Li, Wei, Dong, Brittany, Waters, Christopher M., Smith, Jeremy C., and Quarles, L. Darryl. Mon . "Polycystin-1 interacts with TAZ to stimulate osteoblastogenesis and inhibit adipogenesis". United States. doi:10.1172/JCI93725. https://www.osti.gov/servlets/purl/1435199.
@article{osti_1435199,
title = {Polycystin-1 interacts with TAZ to stimulate osteoblastogenesis and inhibit adipogenesis},
author = {Xiao, Zhousheng and Baudry, Jerome and Cao, Li and Huang, Jinsong and Chen, Hao and Yates, Charles R. and Li, Wei and Dong, Brittany and Waters, Christopher M. and Smith, Jeremy C. and Quarles, L. Darryl},
abstractNote = {The molecular mechanisms that transduce the osteoblast response to physical forces in the bone microenvironment are poorly understood. In this paper, we used genetic and pharmacological experiments to determine whether the polycystins PC1 and PC2 (encoded by Pkd1 and Pkd2) and the transcriptional coactivator TAZ form a mechanosensing complex in osteoblasts. Compound-heterozygous mice lacking 1 copy of Pkd1 and Taz exhibited additive decrements in bone mass, impaired osteoblast-mediated bone formation, and enhanced bone marrow fat accumulation. Bone marrow stromal cells and osteoblasts derived from these mice showed impaired osteoblastogenesis and enhanced adipogenesis. Increased extracellular matrix stiffness and application of mechanical stretch to multipotent mesenchymal cells stimulated the nuclear translocation of the PC1 C-terminal tail/TAZ (PC1-CTT/TAZ) complex, leading to increased runt-related transcription factor 2–mediated (Runx2-mediated) osteogenic and decreased PPARγ-dependent adipogenic gene expression. Using structure-based virtual screening, we identified a compound predicted to bind to PC2 in the PC1:PC2 C-terminal tail region with helix:helix interaction. This molecule stimulated polycystin- and TAZ-dependent osteoblastogenesis and inhibited adipogenesis. Therefore, we show that polycystins and TAZ integrate at the molecular level to reciprocally regulate osteoblast and adipocyte differentiation, indicating that the polycystins/TAZ complex may be a potential therapeutic target to increase bone mass.},
doi = {10.1172/JCI93725},
journal = {Journal of Clinical Investigation},
number = 1,
volume = 128,
place = {United States},
year = {2017},
month = {11}
}

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    Works referencing / citing this record:

    Polycystins and Mechanotransduction in Human Disease
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