The Regulation of Bone Metabolism and Disorders by Wnt Signaling

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Abstract

Wnt, a secreted glycoprotein, has an approximate molecular weight of 40 kDa, and it is a cytokine involved in various biological phenomena including ontogeny, morphogenesis, carcinogenesis, and maintenance of stem cells. The Wnt signaling pathway can be classified into two main pathways: canonical and non-canonical. Of these, the canonical Wnt signaling pathway promotes osteogenesis. Sclerostin produced by osteocytes is an inhibitor of this pathway, thereby inhibiting osteogenesis. Recently, osteoporosis treatment using an anti-sclerostin therapy has been introduced. In this review, the basics of Wnt signaling, its role in bone metabolism and its involvement in skeletal disorders have been covered. Furthermore, the clinical significance and future scopes of Wnt signaling in osteoporosis, osteoarthritis, rheumatoid arthritis and neoplasia are discussed.

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Most cited references 177

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WNT signaling in bone homeostasis and disease: from human mutations to treatments.

Roland Baron, Michaela Kneissel (2013)

Low bone mass and strength lead to fragility fractures, for example, in elderly individuals affected by osteoporosis or children with osteogenesis imperfecta. A decade ago, rare human mutations affecting bone negatively (osteoporosis-pseudoglioma syndrome) or positively (high-bone mass phenotype, sclerosteosis and Van Buchem disease) have been identified and found to all reside in components of the canonical WNT signaling machinery. Mouse genetics confirmed the importance of canonical Wnt signaling in the regulation of bone homeostasis, with activation of the pathway leading to increased, and inhibition leading to decreased, bone mass and strength. The importance of WNT signaling for bone has also been highlighted since then in the general population in numerous genome-wide association studies. The pathway is now the target for therapeutic intervention to restore bone strength in millions of patients at risk for fracture. This paper reviews our current understanding of the mechanisms by which WNT signalng regulates bone homeostasis.

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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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Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours.

O Delattre, J Zucman, B Plougastel … (1992)

Ewing's sarcoma and related subtypes of primitive neuroectodermal tumours share a recurrent and specific t(11;22) (q24;q12) chromosome translocation, the breakpoints of which have recently been cloned. Phylogenetically conserved restriction fragments in the vicinity of EWSR1 and EWSR2, the genomic regions where the breakpoints of chromosome 22 and chromosome 11 are, respectively, have allowed identification of transcribed sequences from these regions and has indicated that a hybrid transcript might be generated by the translocation. Here we use these fragments to screen human complementary DNA libraries to show that the translocation alters the open reading frame of an expressed gene on chromosome 22 gene by substituting a sequence encoding a putative RNA-binding domain for that of the DNA-binding domain of the human homologue of murine Fli-1.

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Author and article information

Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 06 November 2019

Publication date Collection: November 2019

Volume: 20

Issue: 22

Electronic Location Identifier: 5525

Affiliations

[1 ]Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; tom_kayama@ 123456jikei.ac.jp (T.K.); xlink67@ 123456gol.com (M.S.);

[2 ]Institute for Oral Science, Matsumoto Dental University, 1780 Gohara Hiro-Oka, Shiojiri, Nagano 399-0781, Japan; yasuhiro.kobayashi@ 123456mdu.ac.jp (Y.K.); masanori.koide@ 123456mdu.ac.jp (M.K.)

[3 ]Department of Biochemistry, Matsumoto Dental University, 1780 Gohara Hiro-Oka, Shiojiri, Nagano 399-0781, Japan; shunsuke.uehara@ 123456mdu.ac.jp

[4 ]Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan; ryouyuma@ 123456shinshu-u.ac.jp

[5 ]Hiruma dental clinic, 5-34-16-4F Kameari, Katsushika-ku, Tokyo 125-0061, Japan; akistep40@ 123456gmail.com

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[* ]Correspondence: maeda@ 123456jikei.ac.jp ; Tel.: +81-3-3433-1111

Author information

Yasuhiro Kobayashi https://orcid.org/0000-0002-0903-3226

Masanori Koide https://orcid.org/0000-0002-6511-9999

Masanori Okamoto https://orcid.org/0000-0003-0351-865X

Article

Publisher ID: ijms-20-05525

DOI: 10.3390/ijms20225525

PMC ID: 6888566

PubMed ID: 31698687

SO-VID: 2a6bf319-ade5-4cf4-8fb4-89431559a278

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

The Regulation of Bone Metabolism and Disorders by Wnt Signaling

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Neuronal Signaling

Most cited references 177

WNT signaling in bone homeostasis and disease: from human mutations to treatments.

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

Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours.

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