Lrp5 Functions in Bone to Regulate Bone Mass

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2011 May 24

PMID 21602802

Citations 246

Authors

Yajun Cui

Paul J Niziolek

Bryan T MacDonald

Cassandra R Zylstra

Natalia Alenina

Daniel R Robinson

Zhendong Zhong

Susann Matthes

Christina M Jacobsen

Ronald A Conlon

Robert Brommage

Qingyun Liu

Faika Mseeh

David R Powell

Qi M Yang

Brian Zambrowicz

Han Gerrits

Jan A Gossen

Xi He

Michael Bader

Bart O Williams

Matthew L Warman

Alexander G Robling

Affiliations

Soon will be listed here.

Abstract

The human skeleton is affected by mutations in low-density lipoprotein receptor-related protein 5 (LRP5). To understand how LRP5 influences bone properties, we generated mice with osteocyte-specific expression of inducible Lrp5 mutations that cause high and low bone mass phenotypes in humans. We found that bone properties in these mice were comparable to bone properties in mice with inherited mutations. We also induced an Lrp5 mutation in cells that form the appendicular skeleton but not in cells that form the axial skeleton; we observed that bone properties were altered in the limb but not in the spine. These data indicate that Lrp5 signaling functions locally, and they suggest that increasing LRP5 signaling in mature bone cells may be a strategy for treating human disorders associated with low bone mass, such as osteoporosis.

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References

Yadav V, Balaji S, Suresh P, Liu X, Lu X, Li Z . Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis. Nat Med. 2010; 16(3):308-12. PMC: 2836724. DOI: 10.1038/nm.2098. View

Fuccillo M, Joyner A, Fishell G . Morphogen to mitogen: the multiple roles of hedgehog signalling in vertebrate neural development. Nat Rev Neurosci. 2006; 7(10):772-83. DOI: 10.1038/nrn1990. View

Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M . Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet. 2001; 10(5):537-43. DOI: 10.1093/hmg/10.5.537. View

Alenina N, Kikic D, Todiras M, Mosienko V, Qadri F, Plehm R . Growth retardation and altered autonomic control in mice lacking brain serotonin. Proc Natl Acad Sci U S A. 2009; 106(25):10332-7. PMC: 2700938. DOI: 10.1073/pnas.0810793106. View

Dacquin R, Starbuck M, Schinke T, Karsenty G . Mouse alpha1(I)-collagen promoter is the best known promoter to drive efficient Cre recombinase expression in osteoblast. Dev Dyn. 2002; 224(2):245-51. DOI: 10.1002/dvdy.10100. View

Robling A, Niziolek P, Baldridge L, Condon K, Allen M, Alam I . Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem. 2007; 283(9):5866-75. DOI: 10.1074/jbc.M705092200. View

Long F . When the gut talks to bone. Cell. 2008; 135(5):795-6. DOI: 10.1016/j.cell.2008.11.007. View

Ai M, Holmen S, Van Hul W, Williams B, Warman M . 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. 2005; 25(12):4946-55. PMC: 1140571. DOI: 10.1128/MCB.25.12.4946-4955.2005. View

Maretto S, Cordenonsi M, Dupont S, Braghetta P, Broccoli V, Hassan A . Mapping Wnt/beta-catenin signaling during mouse development and in colorectal tumors. Proc Natl Acad Sci U S A. 2003; 100(6):3299-304. PMC: 152286. DOI: 10.1073/pnas.0434590100. View

10.

Kokubu C, Heinzmann U, Kokubu T, Sakai N, Kubota T, Kawai M . Skeletal defects in ringelschwanz mutant mice reveal that Lrp6 is required for proper somitogenesis and osteogenesis. Development. 2004; 131(21):5469-80. DOI: 10.1242/dev.01405. View

11.

Brunkow M, Gardner J, Van Ness J, Paeper B, Kovacevich B, Proll S . Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet. 2001; 68(3):577-89. PMC: 1274471. DOI: 10.1086/318811. View

12.

Li X, Ominsky M, Niu Q, Sun N, Daugherty B, DAgostin D . Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res. 2008; 23(6):860-9. DOI: 10.1359/jbmr.080216. View

13.

MacDonald B, Joiner D, Oyserman S, Sharma P, Goldstein S, He X . Bone mass is inversely proportional to Dkk1 levels in mice. Bone. 2007; 41(3):331-9. PMC: 2865902. DOI: 10.1016/j.bone.2007.05.009. View

14.

Van Wesenbeeck L, Cleiren E, Gram J, Beals R, Benichou O, Scopelliti D . Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet. 2003; 72(3):763-71. PMC: 1180253. DOI: 10.1086/368277. View

15.

Dong Y, Lathrop W, Weaver D, Qiu Q, Cini J, Bertolini D . Molecular cloning and characterization of LR3, a novel LDL receptor family protein with mitogenic activity. Biochem Biophys Res Commun. 1998; 251(3):784-90. DOI: 10.1006/bbrc.1998.9545. View

16.

Clement-Lacroix P, Ai M, Morvan F, Roman-Roman S, Vayssiere B, Belleville C . Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice. Proc Natl Acad Sci U S A. 2005; 102(48):17406-11. PMC: 1297659. DOI: 10.1073/pnas.0505259102. View

17.

Bonewald L, Johnson M . Osteocytes, mechanosensing and Wnt signaling. Bone. 2008; 42(4):606-15. PMC: 2349095. DOI: 10.1016/j.bone.2007.12.224. View

18.

Balemans W, Piters E, Cleiren E, Ai M, Van Wesenbeeck L, Warman M . The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass LRP5 mutations. Calcif Tissue Int. 2008; 82(6):445-53. DOI: 10.1007/s00223-008-9130-9. View

19.

Day T, Guo X, Garrett-Beal L, Yang Y . Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell. 2005; 8(5):739-50. DOI: 10.1016/j.devcel.2005.03.016. View

20.

Sawakami K, Robling A, Ai M, Pitner N, Liu D, Warden S . The Wnt co-receptor LRP5 is essential for skeletal mechanotransduction but not for the anabolic bone response to parathyroid hormone treatment. J Biol Chem. 2006; 281(33):23698-711. DOI: 10.1074/jbc.M601000200. View