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

Xiao, Zhousheng; Cao, Li; Smith, Micholas Dean; Li, Hanxuan; Li, Wei; Smith, Jeremy C.; Quarles, Leigh Darryl

doi:10.1038/s41413-023-00295-4

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

Journal Article · Thu Oct 26 00:00:00 EDT 2023 · Bone Research

DOI:https://doi.org/10.1038/s41413-023-00295-4· OSTI ID:2406741

^[1]; Cao, Li ^[1]; Smith, Micholas Dean ^[2]; Li, Hanxuan ^[1]; ^[1]; ^[2]; ^[1]

University of Tennessee Health Science Center, Memphis, TN (United States)
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Center for Molecular Biophysics; Univ. of Tennessee, Knoxville, TN (United States)

Molecular mechanisms transducing physical forces in the bone microenvironment to regulate bone mass are poorly understood. Here, we used mouse genetics, mechanical loading, and pharmacological approaches to test the possibility that polycystin-1 and Wwtr1 have interdependent mechanosensing functions in osteoblasts. We created and compared the skeletal phenotypes of control Pkd1^flox/+;Wwtr1^flox/+, Pkd1^Oc-cKO, Wwtr1^Oc-cKO, and Pkd1/Wwtr1^Oc-cKO mice to investigate genetic interactions. Consistent with an interaction between polycystins and Wwtr1 in bone in vivo, Pkd1/Wwtr1^Oc-cKO mice exhibited greater reductions of BMD and periosteal MAR than either Wwtr1^Oc-cKO or Pkd1^Oc-cKO mice. Micro-CT 3D image analysis indicated that the reduction in bone mass was due to greater loss in both trabecular bone volume and cortical bone thickness in Pkd1/Wwtr1^Oc-cKO mice compared to either Pkd1^Oc-cKO or Wwtr1^Oc-cKO mice. Pkd1/Wwtr1^Oc-cKO mice also displayed additive reductions in mechanosensing and osteogenic gene expression profiles in bone compared to Pkd1^Oc-cKO or Wwtr1^Oc-cKO mice. Moreover, we found that Pkd1/Wwtr1^Oc-cKO mice exhibited impaired responses to tibia mechanical loading in vivo and attenuation of load-induced mechanosensing gene expression compared to control mice. Finally, control mice treated with a small molecule mechanomimetic, MS2 that activates the polycystin complex resulted in marked increases in femoral BMD and periosteal MAR compared to vehicle control. In contrast, Pkd1/Wwtr1^Oc-cKO mice were resistant to the anabolic effects of MS2. These findings suggest that PC1 and Wwtr1 form an anabolic mechanotransduction signaling complex that mediates mechanical loading responses and serves as a potential novel therapeutic target for treating osteoporosis.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 2406741

Journal Information:: Bone Research, Journal Name: Bone Research Journal Issue: 1 Vol. 11; ISSN 2095-6231

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

References (54)

Osteocyte RANKL: New insights into the control of bone remodeling Xiong, Jinhu; O'Brien, Charles A. Journal of Bone and Mineral Research, Vol. 27, Issue 3 https://doi.org/10.1002/jbmr.1547	journal	February 2012
Osteoporosis is associated with increased marrow fat content and decreased marrow fat unsaturation: A proton MR spectroscopy study Yeung, David K. W.; Griffith, James F.; Antonio, Gregory E. Journal of Magnetic Resonance Imaging, Vol. 22, Issue 2 https://doi.org/10.1002/jmri.20367	journal	July 2005
MAB, a generally applicable molecular force field for structure modelling in medicinal chemistry Gerber, Paul R.; M�ller, Klaus Journal of Computer-Aided Molecular Design, Vol. 9, Issue 3 https://doi.org/10.1007/BF00124456	journal	June 1995
Age-Related Increases in Marrow Fat Volumes have Regional Impacts on Bone Cell Numbers and Structure Al Saedi, Ahmed; Chen, Lulu; Phu, Steven Calcified Tissue International, Vol. 107, Issue 2 https://doi.org/10.1007/s00223-020-00700-8	journal	April 2020
Physiological mechanisms and therapeutic potential of bone mechanosensing Xiao, Zhousheng; Quarles, Leigh Darryl Reviews in Endocrine and Metabolic Disorders, Vol. 16, Issue 2 https://doi.org/10.1007/s11154-015-9313-4	journal	June 2015
Gone Caving: Roles of the Transcriptional Regulators YAP and TAZ in Skeletal Development Kegelman, Christopher D.; Collins, Joseph M.; Nijsure, Madhura P. Current Osteoporosis Reports, Vol. 18, Issue 5 https://doi.org/10.1007/s11914-020-00605-3	journal	July 2020
Simulated microgravity inhibits osteogenic differentiation of mesenchymal stem cells through down regulating the transcriptional co-activator TAZ Chen, Zhe; Luo, Qing; Lin, Chuanchuan Biochemical and Biophysical Research Communications, Vol. 468, Issue 1-2 https://doi.org/10.1016/j.bbrc.2015.11.006	journal	December 2015
The YAP/TAZ transcriptional co-activators have opposing effects at different stages of osteoblast differentiation Xiong, Jinhu; Almeida, Maria; O'Brien, Charles A. Bone, Vol. 112 https://doi.org/10.1016/j.bone.2018.04.001	journal	July 2018
Bone health in autosomal dominant polycystic kidney disease (ADPKD) patients after kidney transplantation Zubidat, Dalia; Hanna, Christian; Randhawa, Amarjyot K. Bone Reports, Vol. 18 https://doi.org/10.1016/j.bonr.2023.101655	journal	June 2023
A Mechanical Checkpoint Controls Multicellular Growth through YAP/TAZ Regulation by Actin-Processing Factors Aragona, Mariaceleste; Panciera, Tito; Manfrin, Andrea Cell, Vol. 154, Issue 5 https://doi.org/10.1016/j.cell.2013.07.042	journal	August 2013
Bone marrow adipose tissue: formation, function and regulation Suchacki, Karla J.; Cawthorn, William P.; Rosen, Clifford J. Current Opinion in Pharmacology, Vol. 28 https://doi.org/10.1016/j.coph.2016.03.001	journal	June 2016
A distinct bone phenotype in ADPKD patients with end-stage renal disease Evenepoel, Pieter; Claes, Kathleen; Cavalier, Etienne Kidney International, Vol. 95, Issue 2 https://doi.org/10.1016/j.kint.2018.09.018	journal	February 2019
Mineral bone disease in autosomal dominant polycystic kidney disease Gitomer, Berenice; Pereira, Renata; Salusky, Isidro B. Kidney International, Vol. 99, Issue 4 https://doi.org/10.1016/j.kint.2020.07.041	journal	April 2021
Leptin Receptor Promotes Adipogenesis and Reduces Osteogenesis by Regulating Mesenchymal Stromal Cells in Adult Bone Marrow Yue, Rui; Zhou, Bo O.; Shimada, Issei S. Cell Stem Cell, Vol. 18, Issue 6 https://doi.org/10.1016/j.stem.2016.02.015	journal	June 2016
Role of YAP/TAZ in cell-matrix adhesion-mediated signalling and mechanotransduction Dupont, Sirio Experimental Cell Research, Vol. 343, Issue 1 https://doi.org/10.1016/j.yexcr.2015.10.034	journal	April 2016
An integrative bioinformatics approach to decipher adipocyte-induced transdifferentiation of osteoblast Salmi, Ayyoub; Quacquarelli, Federica; Chauveau, Christophe Genomics, Vol. 114, Issue 4 https://doi.org/10.1016/j.ygeno.2022.110422	journal	July 2022
ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB Maier, James A.; Martinez, Carmenza; Kasavajhala, Koushik Journal of Chemical Theory and Computation, Vol. 11, Issue 8 https://doi.org/10.1021/acs.jctc.5b00255	journal	July 2015
Solvated Interaction Energy (SIE) for Scoring Protein−Ligand Binding Affinities. 1. Exploring the Parameter Space Naïm, Marwen; Bhat, Sathesh; Rankin, Kathryn N. Journal of Chemical Information and Modeling, Vol. 47, Issue 1 https://doi.org/10.1021/ci600406v	journal	January 2007
Role of YAP/TAZ in mechanotransduction Dupont, Sirio; Morsut, Leonardo; Aragona, Mariaceleste Nature, Vol. 474, Issue 7350 https://doi.org/10.1038/nature10137	journal	June 2011
A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1 Piontek, Klaus; Menezes, Luis F.; Garcia-Gonzalez, Miguel A. Nature Medicine, Vol. 13, Issue 12 https://doi.org/10.1038/nm1675	journal	October 2007
Mechanobiology of YAP and TAZ in physiology and disease Panciera, Tito; Azzolin, Luca; Cordenonsi, Michelangelo Nature Reviews Molecular Cell Biology, Vol. 18, Issue 12 https://doi.org/10.1038/nrm.2017.87	journal	September 2017
Mechanical loading activates the YAP/TAZ pathway and chemokine expression in the MLO-Y4 osteocyte-like cell line Zarka, Mylene; Etienne, Francois; Bourmaud, Morgane Laboratory Investigation, Vol. 101, Issue 12 https://doi.org/10.1038/s41374-021-00668-5	journal	December 2021
Molecular mechanosensors in osteocytes Qin, Lei; Liu, Wen; Cao, Huiling Bone Research, Vol. 8, Issue 1 https://doi.org/10.1038/s41413-020-0099-y	journal	June 2020
TAZ inhibits osteoclastogenesis by attenuating TAK1/NF-κB signaling Yang, Wanlei; Lu, Xuanyuan; Zhang, Tan Bone Research, Vol. 9, Issue 1 https://doi.org/10.1038/s41413-021-00151-3	journal	July 2021
Simulated microgravity inhibits osteogenic differentiation of mesenchymal stem cells via depolymerizing F-actin to impede TAZ nuclear translocation Chen, Zhe; Luo, Qing; Lin, Chuanchuan Scientific Reports, Vol. 6, Issue 1 https://doi.org/10.1038/srep30322	journal	July 2016
Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1 Hossain, Z.; Ali, S. M.; Ko, H. L. Proceedings of the National Academy of Sciences, Vol. 104, Issue 5 https://doi.org/10.1073/pnas.0605266104	journal	January 2007
Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease Lin, Fangming; Hiesberger, Thomas; Cordes, Kimberly Proceedings of the National Academy of Sciences, Vol. 100, Issue 9 https://doi.org/10.1073/pnas.0836980100	journal	April 2003
Conditional Disruption of Pkd1 in Osteoblasts Results in Osteopenia Due to Direct Impairment of Bone Formation Xiao, Zhousheng; Zhang, Shiqin; Cao, Li Journal of Biological Chemistry, Vol. 285, Issue 2 https://doi.org/10.1074/jbc.M109.050906	journal	November 2009
Increased Bone Mass in Mice after Single Injection of Anti-receptor Activator of Nuclear Factor-κB Ligand-neutralizing Antibody Furuya, Yuriko; Mori, Kaoru; Ninomiya, Tadashi Journal of Biological Chemistry, Vol. 286, Issue 42 https://doi.org/10.1074/jbc.M111.246280	journal	October 2011
Osteoblast-specific Knockout of the Insulin-like Growth Factor (IGF) Receptor Gene Reveals an Essential Role of IGF Signaling in Bone Matrix Mineralization Zhang, Mei; Xuan, Shouhong; Bouxsein, Mary L. Journal of Biological Chemistry, Vol. 277, Issue 46 https://doi.org/10.1074/jbc.M208265200	journal	November 2002
Cilia-like Structures and Polycystin-1 in Osteoblasts/Osteocytes and Associated Abnormalities in Skeletogenesis and Runx2 Expression Xiao, Zhousheng; Zhang, Shiqin; Mahlios, Josh Journal of Biological Chemistry, Vol. 281, Issue 41 https://doi.org/10.1074/jbc.M604772200	journal	August 2006
Polycystin-1 Regulates Skeletogenesis through Stimulation of the Osteoblast-specific Transcription Factor RUNX2 -II Xiao, Zhousheng; Zhang, Shiqin; Magenheimer, Brenda S. Journal of Biological Chemistry, Vol. 283, Issue 18 https://doi.org/10.1074/jbc.M710407200	journal	March 2008
Polycystin-1 regulates bone development through an interaction with the transcriptional coactivator TAZ Merrick, David; Mistry, Kavita; Wu, Jingshing Human Molecular Genetics, Vol. 28, Issue 1 https://doi.org/10.1093/hmg/ddy322	journal	September 2018
Conditional deletion of Pkd1 in osteocytes disrupts skeletal mechanosensing in mice Xiao, Zhousheng; Dallas, Mark; Qiu, Ni The FASEB Journal, Vol. 25, Issue 7 https://doi.org/10.1096/fj.10-180299	journal	July 2011
Skeletal cell YAP and TAZ combinatorially promote bone development Kegelman, Christopher D.; Mason, Devon E.; Dawahare, James H. The FASEB Journal, Vol. 32, Issue 5 https://doi.org/10.1096/fj.201700872R	journal	January 2018
A Functional Floxed Allele of Pkd1 that Can Be Conditionally Inactivated In Vivo Piontek, Klaus B.; Huso, David L.; Grinberg, Alexander Journal of the American Society of Nephrology, Vol. 15, Issue 12 https://doi.org/10.1097/01.ASN.0000144204.01352.86	journal	December 2004
TAZ, a Transcriptional Modulator of Mesenchymal Stem Cell Differentiation Hong, J. -H. Science, Vol. 309, Issue 5737 https://doi.org/10.1126/science.1110955	journal	August 2005
TAZ Promotes PC2 Degradation through a SCF -Trcp E3 Ligase Complex Tian, Y.; Kolb, R.; Hong, J. -H. Molecular and Cellular Biology, Vol. 27, Issue 18 https://doi.org/10.1128/MCB.00254-07	journal	July 2007
Polycystin-1 interacts with TAZ to stimulate osteoblastogenesis and inhibit adipogenesis Xiao, Zhousheng; Baudry, Jerome; Cao, Li Journal of Clinical Investigation, Vol. 128, Issue 1 https://doi.org/10.1172/JCI93725	journal	November 2017
Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence Kim, Ha-Neui; Xiong, Jinhu; MacLeod, Ryan S. JCI Insight, Vol. 5, Issue 19 https://doi.org/10.1172/jci.insight.138815	journal	October 2020
Evidence for Bone and Mineral Metabolism Alterations in Children With Autosomal Dominant Polycystic Kidney Disease De Rechter, Stéphanie; Bacchetta, Justine; Godefroid, Nathalie The Journal of Clinical Endocrinology & Metabolism, Vol. 102, Issue 11 https://doi.org/10.1210/jc.2017-01157	journal	September 2017
The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease Varelas, X. Development, Vol. 141, Issue 8 https://doi.org/10.1242/dev.102376	journal	April 2014
Yap- and Cdc42-Dependent Nephrogenesis and Morphogenesis during Mouse Kidney Development Reginensi, Antoine; Scott, Rizaldy P.; Gregorieff, Alex PLoS Genetics, Vol. 9, Issue 3 https://doi.org/10.1371/journal.pgen.1003380	journal	March 2013
Kif3a Deficiency Reverses the Skeletal Abnormalities in Pkd1 Deficient Mice by Restoring the Balance Between Osteogenesis and Adipogenesis Qiu, Ni; Cao, Li; David, Valentin PLoS ONE, Vol. 5, Issue 12 https://doi.org/10.1371/journal.pone.0015240	journal	December 2010
Conditional Mesenchymal Disruption of Pkd1 Results in Osteopenia and Polycystic Kidney Disease Qiu, Ni; Xiao, Zhousheng; Cao, Li PLoS ONE, Vol. 7, Issue 9 https://doi.org/10.1371/journal.pone.0046038	journal	September 2012
Osteoblast-Targeted Overexpression of TAZ Increases Bone Mass In Vivo Yang, Jae-Yeon; Cho, Sun Wook; An, Jee Hyun PLoS ONE, Vol. 8, Issue 2 https://doi.org/10.1371/journal.pone.0056585	journal	February 2013
Shear Stress Induced by an Interstitial Level of Slow Flow Increases the Osteogenic Differentiation of Mesenchymal Stem Cells through TAZ Activation Kim, Kyung Min; Choi, Yoon Jung; Hwang, Jun-Ha PLoS ONE, Vol. 9, Issue 3 https://doi.org/10.1371/journal.pone.0092427	journal	March 2014
Osteoblast-Specific Deletion of Pkd2 Leads to Low-Turnover Osteopenia and Reduced Bone Marrow Adiposity Xiao, Zhousheng; Cao, Li; Liang, Yingjuan PLoS ONE, Vol. 9, Issue 12 https://doi.org/10.1371/journal.pone.0114198	journal	December 2014
Adipocyte-induced transdifferentiation of osteoblasts and its potential role in age-related bone loss Clabaut, Aline; Grare, Céline; Rolland-Valognes, Gaëlle PLOS ONE, Vol. 16, Issue 1 https://doi.org/10.1371/journal.pone.0245014	journal	January 2021
Osteoporosis: Mechanism, Molecular Target and Current Status on Drug Development Li, Hanxuan; Xiao, Zhousheng; Quarles, L. Darryl Current Medicinal Chemistry, Vol. 28, Issue 8 https://doi.org/10.2174/0929867327666200330142432	journal	March 2021
Leptin Induces Proadipogenic and Proinflammatory Signaling in Adipocytes Palhinha, Lohanna; Liechocki, Sally; Hottz, Eugenio D. Frontiers in Endocrinology, Vol. 10 https://doi.org/10.3389/fendo.2019.00841	journal	December 2019
Osteoblast-Osteoclast Communication and Bone Homeostasis Kim, Jung-Min; Lin, Chujiao; Stavre, Zheni Cells, Vol. 9, Issue 9 https://doi.org/10.3390/cells9092073	journal	September 2020
Uncarboxylated osteocalcin promotes osteogenesis and inhibits adipogenesis of mouse bone marrow‑derived mesenchymal stem cells via the PKA‑AMPK‑SIRT1 axis Gao, Le; Gong, Fang-Zi; Ma, Lu-Yao Experimental and Therapeutic Medicine, Vol. 22, Issue 2 https://doi.org/10.3892/etm.2021.10312	journal	June 2021
Stimulation of Piezo1 by mechanical signals promotes bone anabolism Li, Xuehua; Han, Li; Nookaew, Intawat eLife, Vol. 8 https://doi.org/10.7554/eLife.49631	journal	October 2019

Similar Records

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

Journal Article · Sun Nov 26 19:00:00 EST 2017 · Journal of Clinical Investigation · OSTI ID:1435199

Hepatocyte growth factor regulated tyrosine kinase substrate in the peripheral development and function of B-cells

Journal Article · Thu Jan 09 23:00:00 EST 2014 · Biochemical and Biophysical Research Communications · OSTI ID:22242253

Integrin αv in the mechanical response of osteoblast lineage cells

Journal Article · Fri May 02 00:00:00 EDT 2014 · Biochemical and Biophysical Research Communications · OSTI ID:22416417

Related Subjects

60 APPLIED LIFE SCIENCES
biomechanics
bone
bone quality

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

Citation Formats

References (54)

Similar Records

Related Subjects