AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
Powered by AMiner. Clicking this button will take you away from SciOpen.
Home Bone Research Article
PDF (2.5 MB)
Cite
EndNote(RIS) BibTeX
Collect
Submit Manuscript AI Chat Paper
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Original Article | Open Access

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

Zhousheng Xiao1 ( ), Li Cao1, Micholas Dean Smith2,3, Hanxuan Li4, Wei Li4, Jeremy C. Smith2,3, Leigh Darryl Quarles1
Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, TN 37830, USA
Department of Biochemistry and Cellular and Molecular Biology, The University of Tennessee-Knoxville, Knoxville, TN 37996-1939, USA
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA
Show Author Information

Abstract

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 Pkd1flox/+;Wwtr1flox/+, Pkd1Oc-cKO, Wwtr1Oc-cKO, and Pkd1/Wwtr1Oc-cKO mice to investigate genetic interactions. Consistent with an interaction between polycystins and Wwtr1 in bone in vivo, Pkd1/Wwtr1Oc-cKO mice exhibited greater reductions of BMD and periosteal MAR than either Wwtr1Oc-cKO or Pkd1Oc-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/Wwtr1Oc-cKO mice compared to either Pkd1Oc-cKO or Wwtr1Oc-cKO mice. Pkd1/Wwtr1Oc-cKO mice also displayed additive reductions in mechanosensing and osteogenic gene expression profiles in bone compared to Pkd1Oc-cKO or Wwtr1Oc-cKO mice. Moreover, we found that Pkd1/Wwtr1Oc-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/Wwtr1Oc-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.

References

1

Qin, L., Liu, W., Cao, H. & Xiao, G. Molecular mechanosensors in osteocytes. Bone Res. 8, 23 (2020).
Crossref Google Scholar
2

Xiao, Z. et al. Polycystin-1 interacts with TAZ to stimulate osteoblastogenesis and inhibit adipogenesis. J. Clin. Investig. 128, 157–174 (2018).
Crossref Google Scholar
3

Xiao, Z. et al. Conditional deletion of Pkd1 in osteocytes disrupts skeletal mechanosensing in mice. FASEB J 25, 2418–2432 (2011).
Crossref Google Scholar
4

Xiao, Z. et al. Osteoblast-specific deletion of Pkd2 leads to low-turnover osteopenia and reduced bone marrow adiposity. PLoS One 9, e114198 (2014).
Crossref Google Scholar
5

Qiu, N., Xiao, Z., Cao, L., David, V. & Quarles, L. D. Conditional mesenchymal disruption of pkd1 results in osteopenia and polycystic kidney disease. PLoS One 7, e46038 (2012).
Crossref Google Scholar
6

Xiao, Z. et al. Conditional disruption of Pkd1 in osteoblasts results in osteopenia due to direct impairment of bone formation. J. Biol. Chem. 285, 1177–1187 (2010).
Crossref Google Scholar
7

Xiao, Z., Zhang, S., Magenheimer, B. S., Luo, J. & Quarles, L. D. Polycystin-1 regulates skeletogenesis through stimulation of the osteoblast-specific transcription factor Runx2-Ⅱ. J. Biol. Chem. 283, 12624–12634 (2008).
Crossref Google Scholar
8

Xiao, Z. et al. Cilia-like structures and polycystin-1 in osteoblasts/osteocytes and associated abnormalities in skeletogenesis and Runx2 expression. J. Biol. Chem. 281, 30884–30895 (2006).
Crossref Google Scholar
9

Qiu, N., Cao, L., David, V., Quarles, L. D. & Xiao, Z. Kif3a deficiency reverses the skeletal abnormalities in Pkd1 deficient mice by restoring the balance between osteogenesis and adipogenesis. PLoS One 5, e15240 (2010).
Crossref Google Scholar
10

Evenepoel, P. et al. A distinct bone phenotype in ADPKD patients with end-stage renal disease. Kidney Int. 95, 412–419 (2019).
Crossref Google Scholar
11

Gitomer, B. et al. Mineral bone disease in autosomal dominant polycystic kidney disease. Kidney Int. 99, 977–985 (2021).
Crossref Google Scholar
12

De Rechter, S. et al. Evidence for bone and mineral metabolism alterations in children with autosomal dominant polycystic kidney disease. J. Clin. Endocrinol. Metab 102, 4210–4217 (2017).
Crossref Google Scholar
13

Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).
Crossref Google Scholar
14

Aragona, M. et al. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154, 1047–1059 (2013).
Crossref Google Scholar
15

Dupont, S. Role of YAP/TAZ in cell-matrix adhesion-mediated signalling and mechanotransduction. Exp. Cell Res. 343, 42–53 (2016).
Crossref Google Scholar
16

Panciera, T., Azzolin, L., Cordenonsi, M. & Piccolo, S. Mechanobiology of YAP and TAZ in physiology and disease. Nat. Rev. Mol. Cell Biol. 18, 758–770 (2017).
Crossref Google Scholar
17

Merrick, D. et al. Polycystin-1 regulates bone development through an interaction with the transcriptional coactivator TAZ. Hum. Mol. Genet. 28, 16–30 (2019).
Crossref Google Scholar
18

Hong, J. H. et al. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 309, 1074–1078 (2005).
Crossref Google Scholar
19

Yang, J. Y. et al. Osteoblast-targeted overexpression of TAZ increases bone mass in vivo. PLoS One 8, e56585 (2013).
Crossref Google Scholar
20

Hossain, Z. et al. Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1. Proc. Natl. Acad. Sci. USA 104, 1631–1636 (2007).
Crossref Google Scholar
21

Varelas, X. The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease. Development 141, 1614–1626 (2014).
Crossref Google Scholar
22

Tian, Y. et al. TAZ promotes PC2 degradation through a SCFbeta-Trcp E3 ligase complex. Mol. Cell Biol. 27, 6383–6395 (2007).
Crossref Google Scholar
23

Piontek, K., Menezes, L. F., Garcia-Gonzalez, M. A., Huso, D. L. & Germino, G. G. A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat. Med. 13, 1490–1495 (2007).
Crossref Google Scholar
24

Lin, F. et al. Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc. Natl. Acad. Sci. USA 100, 5286–5291 (2003).
Crossref Google Scholar
25

Kegelman, C. D. et al. Skeletal cell YAP and TAZ combinatorially promote bone development. FASEB J. 32, 2706–2721 (2018).
Crossref Google Scholar
26

Furuya, Y. et al. Increased bone mass in mice after single injection of anti-receptor activator of nuclear factor-kappaB ligand-neutralizing antibody: evidence for bone anabolic effect of parathyroid hormone in mice with few osteoclasts. J. Biol. Chem. 286, 37023–37031 (2011).
Crossref Google Scholar
27

Kegelman, C. D., Collins, J. M., Nijsure, M. P., Eastburn, E. A. & Boerckel, J. D. Gone caving: roles of the transcriptional regulators YAP and TAZ in skeletal development. Curr. Osteoporos. Rep. 18, 526–540 (2020).
Crossref Google Scholar
28

Zarka, M. et al. Mechanical loading activates the YAP/TAZ pathway and chemokine expression in the MLO-Y4 osteocyte-like cell line. Lab. Investig. 101, 1597–1604 (2021).
Crossref Google Scholar
29

Chen, Z., Luo, Q., Lin, C. & Song, G. Simulated microgravity inhibits osteogenic differentiation of mesenchymal stem cells through down regulating the transcriptional co-activator TAZ. Biochem. Biophys. Res. Commun. 468, 21–26 (2015).
Crossref Google Scholar
30

Chen, Z., Luo, Q., Lin, C., Kuang, D. & Song, G. Simulated microgravity inhibits osteogenic differentiation of mesenchymal stem cells via depolymerizing F-actin to impede TAZ nuclear translocation. Sci. Rep. 6, 30322 (2016).
Crossref Google Scholar
31

Li, X. et al. Stimulation of Piezo1 by mechanical signals promotes bone anabolism. Elife 8, e49631 (2019).
Crossref Google Scholar
32

Kim, K. M. et al. Shear stress induced by an interstitial level of slow flow increases the osteogenic differentiation of mesenchymal stem cells through TAZ activation. PLoS One 9, e92427 (2014).
Crossref Google Scholar
33

Zubidat, D. et al. Bone health in autosomal dominant polycystic kidney disease (ADPKD) patients after kidney transplantation. Bone Rep. 18, 101655 (2023).
Crossref Google Scholar
34

Kim, J. M., Lin, C., Stavre, Z., Greenblatt, M. B. & Shim, J. H. Osteoblast-osteoclast communication and bone homeostasis. Cells 9, 2073 (2020).
Crossref Google Scholar
35

Xiong, J., Almeida, M. & O’Brien, C. A. The YAP/TAZ transcriptional co-activators have opposing effects at different stages of osteoblast differentiation. Bone 112, 1–9 (2018).
Crossref Google Scholar
36

Xiong, J. & O’Brien, C. A. Osteocyte RANKL: new insights into the control of bone remodeling. J. Bone Miner. Res. 27, 499–505 (2012).
Crossref Google Scholar
37

Kim, H. N. et al. Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence. JCI Insight 5, e138815 (2020).
Crossref Google Scholar
38

Yang, W. et al. TAZ inhibits osteoclastogenesis by attenuating TAK1/NF-kappaB signaling. Bone Res. 9, 33 (2021).
Crossref Google Scholar
39

Yeung, D. K. et al. Osteoporosis is associated with increased marrow fat content and decreased marrow fat unsaturation: a proton MR spectroscopy study. J. Magn. Reson. Imaging 22, 279–285 (2005).
Crossref Google Scholar
40

Suchacki, K. J., Cawthorn, W. P. & Rosen, C. J. Bone marrow adipose tissue: formation, function and regulation. Curr. Opin. Pharmacol. 28, 50–56 (2016).
Crossref Google Scholar
41

Al Saedi, A. et al. Age-related increases in marrow fat volumes have regional impacts on bone cell numbers and structure. Calcif Tissue Int. 107, 126–134 (2020).
Crossref Google Scholar
42

Justesen, J. et al. Adipocyte tissue volume in bone marrow is increased with aging and in patients with osteoporosis. Biogerontology 2, 165–171 (2001).
Crossref Google Scholar
43

Salmi, A., Quacquarelli, F., Chauveau, C., Clabaut, A. & Broux, O. An integrative bioinformatics approach to decipher adipocyte-induced transdifferentiation of osteoblast. Genomics 114, 110422 (2022).
Crossref Google Scholar
44

Clabaut, A. et al. Adipocyte-induced transdifferentiation of osteoblasts and its potential role in age-related bone loss. PLoS One 16, e0245014 (2021).
Crossref Google Scholar
45

Gao, L., Gong, F. Z., Ma, L. Y. & Yang, J. H. Uncarboxylated osteocalcin promotes osteogenesis and inhibits adipogenesis of mouse bone marrow-derived mesenchymal stem cells via the PKA-AMPK-SIRT1 axis. Exp. Ther. Med. 22, 880 (2021).
Crossref Google Scholar
46

Palhinha, L. et al. Leptin induces proadipogenic and proinflammatory signaling in adipocytes. Front. Endocrinol. 10, 841 (2019).
Crossref Google Scholar
47

Yue, R., Zhou, B. O., Shimada, I. S., Zhao, Z. & Morrison, S. J. Leptin receptor promotes adipogenesis and reduces osteogenesis by regulating mesenchymal stromal cells in adult bone marrow. Cell Stem Cell 18, 782–796 (2016).
Crossref Google Scholar
48

Xiao, Z. & Quarles, L. D. Physiological mechanisms and therapeutic potential of bone mechanosensing. Rev. Endocr. Metab. Disord. 16, 115–129 (2015).
Crossref Google Scholar
49

Li, H., Xiao, Z., Quarles, L. D. & Li, W. Osteoporosis: mechanism, molecular target and current status on drug development. Curr. Med. Chem. 28, 1489–1507 (2021).
Crossref Google Scholar
50

Reginensi, A. et al. Yap- and Cdc42-dependent nephrogenesis and morphogenesis during mouse kidney development. PLoS Genet. 9, e1003380 (2013).
Crossref Google Scholar
51

Piontek, K. B. et al. A functional floxed allele of Pkd1 that can be conditionally inactivated in vivo. J. Am. Soc. Nephrol. 15, 3035–3043 (2004).
Crossref Google Scholar
52

Zhang, M. et al. Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization. J. Biol. Chem. 277, 44005–44012 (2002).
Crossref Google Scholar
53

Naim, M. et al. Solvated interaction energy (SIE) for scoring protein-ligand binding affinities. 1. Exploring the parameter space. J. Chem. Inf. Model 47, 122–133 (2007).
Crossref Google Scholar
54

Maier, J. A. et al. ff14SB: Improving the accuracy of protein side chain and backbone parameters from ff99SB. J. Chem. Theory Comput. 11, 3696–3713 (2015).
Crossref Google Scholar
55

Gerber, P. R. & Muller, K. MAB, a generally applicable molecular force field for structure modelling in medicinal chemistry. J. Comput. Aided Mol. Des. 9, 251–268 (1995).
Crossref Google Scholar
Bone Research
Volume 11,
December 2023
Article number: 57
DOI: 10.1038/s41413-023-00295-4
Cite this article:
Xiao Z, Cao L, Smith MD, et al. Genetic interactions between polycystin-1 and Wwtr1 in osteoblasts define a novel mechanosensing mechanism regulating bone formation in mice. Bone Research, 2023, 11: 57. https://doi.org/10.1038/s41413-023-00295-4

114

Views

1

Downloads

4

Crossref

5

Web of Science

5

Scopus

Altmetrics
Received: 19 May 2023
Revised: 30 August 2023
Accepted: 18 September 2023
Published: 26 October 2023
© The Author(s) 2023

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Return