New Avenues in the LRP5-mediated Bone Mass Acquisition

Je-Yong Choi

doi:10.11005/kjbm.2012.19.1.1

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Choi: New Avenues in the LRP5-mediated Bone Mass Acquisition

Review Article

Korean Journal of Bone Metabolism

Korean Journal of Bone Metabolism 2012; 19(1): 1-9.

Published online: 18 May 2012

DOI: https://doi.org/10.11005/kjbm.2012.19.1.1

New Avenues in the LRP5-mediated Bone Mass Acquisition

Je-Yong Choi

Department of Biochemistry and Cell Biology, Skeletal Diseases Genome Research Center, School of Medicine, Kyungpook National University, Daegu, Korea.

Address for Correspondence: Je-Yong Choi, Department of Biochemistry and Cell Biology, Skeletal Diseases Genome Research Center, School of Medicine, Kyungpook National University, Daegu 700-721, Korea. Tel: +82-53-420-4823, Fax: +82-53-422-1466, jechoi@knu.ac.kr

Received 1 May 2012 Revised 2 May 2012 Accepted 4 May 2012

(open-access):

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/).

Abstract

Lipoprotein receptor-related protein (LRP5) signaling is well correlated with the bone mass in both human and mice. Loss-of-function mutations of LRP5 result in osteopenia or osteoporosis. In contrast, gain-of-function mutations show high bone mass phenotype. To elucidate the molecular mechanism of the LRP5-mediated bone mass acquisition, several groups have genetically dissected the Wingless and Int-1 (Wnt)β-catenin signaling pathway using osteoblast-lineage specific Cre mice. Key players for LRP5-mediated bone mass acquisition turn out to be different molecules with respect to the expressing tissue and action mode of these molecules. One is serotonin, a tryptophan metabolite that originates from duodenum, which acts as a negative regulator for bone formation. LRP5 suppresses serotonin biosynthesis by inhibiting the expression of tryptophan hydroxylase 1 in the gut. The other is sclerostin, an osteocyte-producing antagonist for LRP5 signaling. Here is a summary of recent findings about these two molecules, providing a chance to speculate new avenues in the LRP5-mediated bone mass acquisition.

Keywords: Bone mass, LRP5, Sclerostin, Serotonin, Wnt signaling

Figures and Tables

Fig. 1

Lipoprotein receptor-related protein 5 (LRP5) and Wingless and Int-1 (Wnt) signaling pathway. Wnt signaling pathway consists of β-catenin-dependent canonical and noncanonical pathways (not shown). Binding of Wnt to its receptor (Fz) and coreceptor (LRP) allows recruiting of Dishevelled (DV) and Axin (AX) to Fz and LRP5/6/4, respectively, and results in stabilization of β-catenin. Extracellular portion of LRP5/6 can bind to various proteins like Sclerostin (Sost), Wise, R-spondin (Rspo) and Dickkopf (Dkk). Complex formation of Dkk with Kremen and LRP5/6 allow to internalization of complex into cells.

Fig. 2

Comparision of Lipoprotein receptor-related protein (LRP)4/5/6 amino acid sequences. LRP5 has a putative transmembrane sequence as signal peptide by search program (see in the text), which was not revealed in LRP4 and LRP6 (A). LRP5/6/4 show similar structure with 4 propellers in extracellular portion (B). Analyses of amino acid sequences of LRP5/6/4 show a high identity and similarity between LRP5 and LRP6 (C). LRP5, LRP6 and LRP4 belong to low density lipoprotein receptor (LDLR). Although LRP5/6/4 show similar structure and function, knockout of each gene reveals different phenotypes, which indicates that there is no compensatory function among them.

Fig. 3

Bone mass regulation in Lipoprotein receptor-related protein (LRP)5 signaling pathway via Serotonin and Sclerostin. Regulation of bone mass by LRP5 mutations is not directly correlated with the involvement of β-catenin mediated canonical Wnt pathway. High bone mass phenotypes of LRP5 gain-of-function mutations were explained by two different ways. One is local regulatory role of Sclerostin and Dickkopf (Dkk1) which are produced in bone cells and play as strong inhibitors for bone formation. They cannot bind to LRP5 with high bone mass mutations (left panel). Another explanation is systemic regulatory role of Serotonin which is produced in intestine and also play as strong inhibitor for bone formation. LRP5 gain-of-function mutations decreases blood Serotonin level by inhibition of trypthopan hydroxylase 1 expression in enterochromaffiin cells. Serotonin decreases osteoblast number and function through Serotonin receptor (Htr1b) in osteoblasts (right panel).

Notes

This study was supported by a grant of the Korea Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A010252) and WCU program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (R32-10064).

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