Lrp5 functions in bone to regulate bone mass

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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 inducible Lrp5 mutations that cause high bone mass and low bone mass phenotypes in humans. We conditionally-induced Lrp5 mutations in osteocytes and found that bone properties in these mice were comparable to bone properties in mice with inherited mutations. We also conditionally-induced an Lrp5 mutation in cells that contribute to the appendicular skeleton, and not to the axial skeleton, and we observed bone properties were altered in the limbs, and not in the spine. These data indicate that Lrp5 signaling functions locally and suggest increasing LRP5 signaling in mature bone cells as a strategy to treat human low bone mass disorders, such as osteoporosis.

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Most cited references 51

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Wnt/β-Catenin/Tcf Signaling Induces the Transcription of Axin2, a Negative Regulator of the Signaling Pathway

Eek-hoon Jho, Tong Zhang, Claire Domon … (2002)

Axin2/Conductin/Axil and its ortholog Axin are negative regulators of the Wnt signaling pathway, which promote the phosphorylation and degradation of β-catenin. While Axin is expressed ubiquitously, Axin2 mRNA was seen in a restricted pattern during mouse embryogenesis and organogenesis. Because many sites of Axin2 expression overlapped with those of several Wnt genes, we tested whether Axin2 was induced by Wnt signaling. Endogenous Axin2 mRNA and protein expression could be rapidly induced by activation of the Wnt pathway, and Axin2 reporter constructs, containing a 5.6-kb DNA fragment including the promoter and first intron, were also induced. This genomic region contains eight Tcf/LEF consensus binding sites, five of which are located within longer, highly conserved noncoding sequences. The mutation or deletion of these Tcf/LEF sites greatly diminished induction by β-catenin, and mutation of the Tcf/LEF site T2 abolished protein binding in an electrophoretic mobility shift assay. These results strongly suggest that Axin2 is a direct target of the Wnt pathway, mediated through Tcf/LEF factors. The 5.6-kb genomic sequence was sufficient to direct the tissue-specific expression of d2EGFP in transgenic embryos, consistent with a role for the Tcf/LEF sites and surrounding conserved sequences in the in vivo expression pattern of Axin2 . Our results suggest that Axin2 participates in a negative feedback loop, which could serve to limit the duration or intensity of a Wnt-initiated signal.

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Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis.

Timothy F Day, Xizhi Guo, Lisa Garrett-Beal … (2005)

Chondrocytes and osteoblasts are two primary cell types in the skeletal system that are differentiated from common mesenchymal progenitors. It is believed that osteoblast differentiation is controlled by distinct mechanisms in intramembranous and endochondral ossification. We have found that ectopic canonical Wnt signaling leads to enhanced ossification and suppression of chondrocyte formation. Conversely, genetic inactivation of beta-catenin, an essential component transducing the canonical Wnt signaling, causes ectopic formation of chondrocytes at the expense of osteoblast differentiation during both intramembranous and endochondral ossification. Moreover, inactivation of beta-catenin in mesenchymal progenitor cells in vitro causes chondrocyte differentiation under conditions allowing only osteoblasts to form. Our results demonstrate that beta-catenin is essential in determining whether mesenchymal progenitors will become osteoblasts or chondrocytes regardless of regional locations or ossification mechanisms. Controlling Wnt/beta-catenin signaling is a common molecular mechanism underlying chondrocyte and osteoblast differentiation and specification of intramembranous and endochondral ossification.

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LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.

Yaoqin Gong, Roger B Slee, Naomi Fukai … (2001)

In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9502015

Journal ID (pubmed-jr-id): 8791

Journal ID (nlm-ta): Nat Med

Journal ID (iso-abbrev): Nat. Med.

Title: Nature medicine

ISSN (Print): 1078-8956

ISSN (Electronic): 1546-170X

Publication date Nihms-submitted: 24 May 2011

Publication date (Electronic): 22 May 2011

Publication date (Print): June 2011

Publication date PMC-release: 01 December 2011

Volume: 17

Issue: 6

Pages: 684-691

Affiliations

[1 ]Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Children’s Hospital, Boston, MA

[2 ]Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH

[3 ]Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN

[4 ]Departments of Anatomy & Cell Biology and Biomedical Engineering, Indiana University School of Medicine, Indianapolis, IN

[5 ]F. M. Kirby Neurobiology Center, Children’s Hospital, Boston, Department of Neurology, Harvard Medical School, Boston, MA

[6 ]Cell Signaling and Carcinogenesis Laboratory, Van Andel Research Institute, Grand Rapids, MI

[7 ]Max-Delbrück-Center for Molecular Medicine (MDC), Berlin-Buch, Germany

[8 ]Lexicon Pharmaceuticals Incorporated, The Woodlands, TX

[9 ]Merck Sharp & Dohme Research Laboratories, Oss, The Netherlands

[10 ]Howard Hughes Medical Institute, Children’s Hospital Boston, and Department of Genetics, Harvard Medical School, Boston, MA

Author notes

Correspondence to: Matthew L. Warman, M.D., Orthopaedic Research Laboratories, EN 250, Children’s Hospital, Boston, 320 Longwood Avenue, Boston, MA 02115, Phone 617-919-2371, Fax 617-730-0789, matthew.warman@ 123456childrens.harvard.edu

Article

Manuscript ID: nihpa292311

DOI: 10.1038/nm.2388

PMC ID: 3113461

PubMed ID: 21602802

SO-VID: e5dc6a7f-844b-4f68-9cda-05b4811b979b

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