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J Clin Endocrinol Metab. 2018 May 1;103(5):1985-1996. doi: 10.1210/jc.2017-02585.

Altered MicroRNA Profile in Osteoporosis Caused by Impaired WNT Signaling.

Author information

1
Folkhälsan Institute of Genetics and University of Helsinki, Helsinki, Finland.
2
TAmiRNA GmbH, Vienna, Austria.
3
Department of Children and Adolescents, Oulu University Hospital, and PEDEGO Research Unit, University of Oulu, Oulu, Finland.
4
Internal Medicine and Clinical Research Center, University of Oulu, Oulu, Finland.
5
Christian Doppler Laboratory on Biotechnology of Skin Aging, Department of Biotechnology, University of Natural Resources and Life Sciences Vienna, Vienna, Austria.
6
Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
7
Center for Molecular Medicine, Karolinska Institutet and Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.

Abstract

Context:

WNT signaling is fundamental to bone health, and its aberrant activation leads to skeletal pathologies. The heterozygous missense mutation p.C218G in WNT1, a key WNT pathway ligand, leads to severe early-onset and progressive osteoporosis with multiple peripheral and spinal fractures. Despite the severe skeletal manifestations, conventional bone turnover markers are normal in mutation-positive patients.

Objective:

This study sought to explore the circulating microRNA (miRNA) pattern in patients with impaired WNT signaling.

Design and Setting:

A cross-sectional cohort study at a university hospital.

Participants:

Altogether, 12 mutation-positive (MP) subjects (median age, 39 years; range, 11 to 76 years) and 12 mutation-negative (MN) subjects (35 years; range, 9 to 59 years) from two Finnish families with WNT1 osteoporosis due to the heterozygous p.C218G WNT1 mutation.

Methods and Main Outcome Measure:

Serum samples were screened for 192 miRNAs using quantitative polymerase chain reaction. Findings were compared between WNT1 MP and MN subjects.

Results:

The pattern of circulating miRNAs was significantly different in the MP subjects compared with the MN subjects, with two upregulated (miR-18a-3p and miR-223-3p) and six downregulated miRNAs (miR-22-3p, miR-31-5p, miR-34a-5p, miR-143-5p, miR-423-5p, and miR-423-3p). Three of these (miR-22-3p, miR-34a-5p, and miR-31-5p) are known inhibitors of WNT signaling: miR-22-3p and miR-34a-5p target WNT1 messenger RNA, and miR-31-5p is predicted to bind to WNT1 3'UTR.

Conclusions:

The circulating miRNA pattern reflects WNT1 mutation status. The findings suggest that the WNT1 mutation disrupts feedback regulation between these miRNAs and WNT1, providing insights into the pathogenesis of WNT-related bone disorders. These miRNAs may have potential in the diagnosis and treatment of osteoporosis.

PMID:
29506076
DOI:
10.1210/jc.2017-02585
[Indexed for MEDLINE]

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