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 (4.4 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

Inhibiting WNT secretion reduces high bone mass caused by Sost loss-of-function or gain-of-function mutations in Lrp5

Cassandra R. Diegel1, Ina Kramer2, Charles Moes2, Gabrielle E. Foxa1, Mitchell J. McDonald1, Zachary B. Madaj3, Sabine Guth2, Jun Liu4, Jennifer L. Harris4, Michaela Kneissel2, Bart O. Williams1 ( )
Department of Cell Biology, Van Andel Institute, 333 Bostwick Ave., NE, Grand Rapids, MI 49503, USA
Diseases of Aging and Regenerative Medicine, Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland
Bioinformatics and Biostatistics Core, Van Andel Institute, 333 Bostwick Ave., NE, Grand Rapids, MI 49503, USA
Oncology, Novartis Institutes for Biomedical Research, San Diego, CA 92121, USA
Show Author Information

Abstract

Proper regulation of Wnt signaling is critical for normal bone development and homeostasis. Mutations in several Wnt signaling components, which increase the activity of the pathway in the skeleton, cause high bone mass in human subjects and mouse models. Increased bone mass is often accompanied by severe headaches from increased intracranial pressure, which can lead to fatality and loss of vision or hearing due to the entrapment of cranial nerves. In addition, progressive forehead bossing and mandibular overgrowth occur in almost all subjects. Treatments that would provide symptomatic relief in these subjects are limited. Porcupine-mediated palmitoylation is necessary for Wnt secretion and binding to the frizzled receptor. Chemical inhibition of porcupine is a highly selective method of Wnt signaling inhibition. We treated three different mouse models of high bone mass caused by aberrant Wnt signaling, including homozygosity for loss-of-function in Sost, which models sclerosteosis, and two strains of mice carrying different point mutations in Lrp5 (equivalent to human G171V and A214V), at 3 months of age with porcupine inhibitors for 5–6 weeks. Treatment significantly reduced both trabecular and cortical bone mass in all three models. This demonstrates that porcupine inhibition is potentially therapeutic for symptomatic relief in subjects who suffer from these disorders and further establishes that the continued production of Wnts is necessary for sustaining high bone mass in these models.

References

1

Williams, B. O. LRP5: from bedside to bench to bone. Bone 102, 26–30 (2017).
Crossref Google Scholar
2

Gong, Y. et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107, 513–523 (2001).
Crossref Google Scholar
3

Little, R. D. et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am. J. Hum. Genet. 70, 11–19 (2002).
Crossref Google Scholar
4

Boyden, L. M. et al. High bone density due to a mutation in LDL-receptor-related protein 5. N. Engl. J. Med. 346, 1513–1521 (2002).
Crossref Google Scholar
5

Burgers, T. A. & Williams, B. O. Regulation of Wnt/beta-catenin signaling within and from osteocytes. Bone 54, 244–249 (2013).
Crossref Google Scholar
6

Balemans, W. et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum. Mol. Genet. 10, 537–543 (2001).
Crossref Google Scholar
7

Staehling-Hampton, K. et al. A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population. Am. J. Med. Genet. 110, 144–152 (2002).
Crossref Google Scholar
8

Balemans, W. et al. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J. Med. Genet. 39, 91–97 (2002).
Crossref Google Scholar
9

Cheng, C., Wentworth, K. & Shoback, D. M. New frontiers in osteoporosis therapy. Annu. Rev. Med. 71, 277–288 (2020).
Crossref Google Scholar
10
Amgen and UCB announce increased cardiovascular risk in patients receiving romosozumab, an anti-sclerotin antibody. Rheumatology 56, e21 (2017).
Crossref
11

Wengenroth, M. et al. Case 150: Van Buchem disease (hyperostosis corticalis generalisata). Radiology 253, 272–276 (2009).
Crossref Google Scholar
12

de Andrade, E. M. et al. Management of trigeminal neuralgia in sclerosteosis. Surg. Neurol. Int. 4, S455–S459 (2013).
Crossref Google Scholar
13

Tholpady, S. et al. Cranial reconstruction for treatment of intracranial hypertension from sclerosteosis: case-based update. World Neurosurg. 81, 442.e1-5 (2014).
Crossref Google Scholar
14

Stein, S. A. et al. Sclerosteosis: neurogenetic and pathophysiologic analysis of an American kinship. Neurology 33, 267–277 (1983).
Crossref Google Scholar
15

Beighton, P. et al. Sclerosteosis—an autosomal recessive disorder. Clin. Genet. 11, 1–7 (1977).
Crossref Google Scholar
16

Joiner, D. M. et al. LRP5 and LRP6 in development and disease. Trends Endocrinol. Metab. 24, 31–39 (2013).
Crossref Google Scholar
17

Zhong, Z. A. et al. Regulation of Wnt receptor activity: implications for therapeutic development in colon cancer. J. Biol. Chem. 296, 100782 (2021).
Crossref Google Scholar
18

Li, X. et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J. Biol. Chem. 280, 19883–19887 (2005).
Crossref Google Scholar
19

Ellies, D. L. et al. Bone density ligand, Sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity. J. Bone Miner. Res. 21, 1738–1749 (2006).
Crossref Google Scholar
20

Williams, B. O. Insights into the mechanisms of sclerostin action in regulating bone mass accrual. J. Bone Miner. Res. 29, 24–28 (2014).
Crossref Google Scholar
21

Ke, J., Xu, H. E. & Williams, B. O. Lipid modification in Wnt structure and function. Curr. Opin. Lipidol. 24, 129–133 (2013).
Crossref Google Scholar
22

Liu, J. et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc. Natl. Acad. Sci. USA 110, 20224–20229 (2013).
Crossref Google Scholar
23

Jiang, X. et al. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc. Natl. Acad. Sci. USA 110, 12649–12654 (2013).
Crossref Google Scholar
24

Proffitt, K. D. et al. Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer. Cancer Res. 73, 502–507 (2013).
Crossref Google Scholar
25

Kahlert, U. D. et al. Pharmacologic Wnt inhibition reduces proliferation, survival, and clonogenicity of glioblastoma cells. J. Neuropathol. Exp. Neurol. 74, 889–900 (2015).
Crossref Google Scholar
26

Guimaraes, P. P. G. et al. Potent in vivo lung cancer Wnt signaling inhibition via cyclodextrin-LGK974 inclusion complexes. J. Control Release 290, 75–87 (2018).
Crossref Google Scholar
27

Madan, B. et al. Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy. Bone Res. 6, 17 (2018).
Crossref Google Scholar
28

Mirabelli, C. K. et al. Perspectives on the role of Wnt biology in cancer. Sci. Signal. 12, eaay4494 (2019).
Crossref Google Scholar
29

Zhang, L. S. & Lum, L. Chemical modulation of WNT signaling in cancer. Prog. Mol. Biol. Transl. Sci. 153, 245–269 (2018).
Crossref Google Scholar
30

Funck-Brentano, T. et al. Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice. J. Endocrinol. 238, 13–23 (2018).
Crossref Google Scholar
31

Shah, K., Panchal, S. & Patel, B. Porcupine inhibitors: novel and emerging anti-cancer therapeutics targeting the Wnt signaling pathway. Pharmacol. Res. 167, 105532 (2021).
Crossref Google Scholar
32

Niziolek, P. J., Warman, M. L. & Robling, A. G. Mechanotransduction in bone tissue: the A214V and G171V mutations in Lrp5 enhance load-induced osteogenesis in a surface-selective manner. Bone 51, 459–465 (2012).
Crossref Google Scholar
33

Cui, Y. et al. Lrp5 functions in bone to regulate bone mass. Nat. Med. 17, 684–691 (2011).
Crossref Google Scholar
34

Kramer, I. et al. Parathyroid hormone (PTH)-induced bone gain is blunted in SOST overexpressing and deficient mice. J. Bone Miner. Res. 25, 178–189 (2010).
Crossref Google Scholar
35

Cheng, D. et al. Discovery of pyridinyl acetamide derivatives as potent, selective, and orally bioavailable porcupine inhibitors. ACS Med. Chem. Lett. 7, 676–680 (2016).
Crossref Google Scholar
36

Ai, M. et al. Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling. Mol. Cell Biol. 25, 4946–4955 (2005).
Crossref Google Scholar
37

Semenov, M. V. & He, X. LRP5 mutations linked to high bone mass diseases cause reduced LRP5 binding and inhibition by SOST. J. Biol. Chem. 281, 38276–38284 (2006).
Crossref Google Scholar
38

Brunkow, M. E. et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am. J. Hum. Genet. 68, 577–589 (2001).
Crossref Google Scholar
39

Loots, G. G. et al. Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease. Genome Res. 15, 928–935 (2005).
Crossref Google Scholar
40

Cosman, F. et al. Romosozumab treatment in postmenopausal women with osteoporosis. N. Engl. J. Med. 375, 1532–1543 (2016).
Crossref Google Scholar
41

Saag, K. G. et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N. Engl. J. Med. 377, 1417–1427 (2017).
Crossref Google Scholar
42

Vestergaard Kvist, A. et al. Cardiovascular safety profile of romosozumab: a pharmacovigilance analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS). J. Clin. Med. 10, 1660 (2021).
Crossref Google Scholar
43

Whyte, M. P. et al. New explanation for autosomal dominant high bone mass: mutation of low-density lipoprotein receptor-related protein 6. Bone 127, 228–243 (2019).
Crossref Google Scholar
44

Brance, M. L. et al. High bone mass from mutation of low-density lipoprotein receptor-related protein 6 (LRP6). Bone 141, 115550 (2020).
Crossref Google Scholar
45

Takada, R. et al. Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion. Dev. Cell 11, 791–801 (2006).
Crossref Google Scholar
46

Langton, P. F., Kakugawa, S. & Vincent, J. P. Making, exporting, and modulating Wnts. Trends Cell Biol. 26, 756–765 (2016).
Crossref Google Scholar
47

Zhan, T., Rindtorff, N. & Boutros, M. Wnt signaling in cancer. Oncogene 36, 1461–1473 (2017).
Crossref Google Scholar
48

Morris, A. et al. Drug discovery efforts toward inhibitors of canonical Wnt/beta-catenin signaling pathway in the treatment of cancer: a composition-of-matter review (2010-2020). Drug Discov. Today 27, 1115–1127 (2022).
Crossref Google Scholar
49

Davis, S. L. et al. A phase 1b dose escalation study of Wnt pathway inhibitor vantictumab in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic pancreatic cancer. Invest. New Drugs 38, 821–830 (2020).
Crossref Google Scholar
50

Zhong, Z. et al. Wntless functions in mature osteoblasts to regulate bone mass. Proc. Natl. Acad. Sci. USA 109, E2197–E2204 (2012).
Crossref Google Scholar
51

Zhong, Z. A. et al. Wntless spatially regulates bone development through beta-catenin-dependent and independent mechanisms. Dev. Dyn. 244, 1347–1355 (2015).
Crossref Google Scholar
52

Maruyama, T., Jiang, M. & Hsu, W. Gpr177, a novel locus for bone mineral density and osteoporosis, regulates osteogenesis and chondrogenesis in skeletal development. J. Bone Miner. Res. 28, 1150–1159 (2013).
Crossref Google Scholar
53

Holmen, S. L. et al. Essential role of beta-catenin in postnatal bone acquisition. J. Biol. Chem. 22, 21162–21168 (2005).
Crossref Google Scholar
54

Glass, D. A.2nd et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev. Cell 8, 751–764 (2005).
Crossref Google Scholar
55

Madan, S. et al. A non-mosaic PORCN mutation in a male with severe congenital anomalies overlapping focal dermal hypoplasia. Mol. Genet. Metab. Rep. 12, 57–61 (2017).
Crossref Google Scholar
56

Bostwick, B. et al. Phenotypic and molecular characterization of focal dermal hypoplasia in 18 individuals. Am. J. Med. Genet. C Semin. Med. Genet. 172C, 9–20 (2016).
Crossref Google Scholar
57

Dreyer, T. et al. Recombinant sclerostin inhibits bone formation in vitro and in a mouse model of sclerosteosis. J. Orthop. Translat. 29, 134–142 (2021).
Crossref Google Scholar
58

O’Brien, S., Chidiac, R. & Angers, S. Modulation of Wnt-beta-catenin signaling with antibodies: therapeutic opportunities and challenges. Trends Pharmacol. Sci. 44, 354–365 (2023).
Crossref Google Scholar
59

Zhang, L. S. & Lum, L. Delivery of the porcupine inhibitor WNT974 in mice. Methods Mol. Biol. 1481, 111–117 (2016).
Crossref Google Scholar
60

Foxa, G. E. et al. Generation and characterization of mouse models for skeletal disease. Methods Mol. Biol. 2221, 165–191 (2021).
Crossref Google Scholar
Bone Research
Volume 11,
December 2023
Article number: 47
DOI: 10.1038/s41413-023-00278-5
Cite this article:
Diegel CR, Kramer I, Moes C, et al. Inhibiting WNT secretion reduces high bone mass caused by Sost loss-of-function or gain-of-function mutations in Lrp5. Bone Research, 2023, 11: 47. https://doi.org/10.1038/s41413-023-00278-5

113

Views

1

Downloads

4

Crossref

3

Web of Science

3

Scopus

Altmetrics
Received: 02 January 2023
Revised: 09 May 2023
Accepted: 03 July 2023
Published: 24 August 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