University of Oulu

Riikka E. Mäkitie, Tuukka Niinimäki, Miika T. Nieminen, Camilla Schalin-Jäntti, Jaakko Niinimäki, Outi Mäkitie, Impaired WNT signaling and the spine—Heterozygous WNT1 mutation causes severe age-related spinal pathology, Bone, Volume 101, 2017, Pages 3-9, ISSN 8756-3282,

Impaired WNT signaling and the spine : heterozygous WNT1 mutation causes severe age-related spinal pathology

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Author: Mäkitie, Riikka E.1; Niinimäki, Tuukka2; Nieminen, Miika T.3,4;
Organizations: 1Folkhälsan Institute of Genetics, University of Helsinki, Helsinki FI-00290, Finland
2Department of Orthopedics, Oulu University Hospital, Oulu FI-90220, Finland
3Research Unit of Medical Imaging, Physics and Technology, Department of Diagnostic Radiology, Oulu University Hospital, Oulu FI-90220, Finland
4Medical Research Center, University of Oulu and Oulu University Hospital, Oulu FI-90220, Finland
5Endocrinology, Abdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki FI-00290, Finland
6Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki FI-00290, Finland
7Center for Molecular Medicine, Karolinska Institutet, and Clinical Genetics, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 0.5 MB)
Persistent link:
Language: English
Published: Elsevier, 2017
Publish Date: 2019-12-16


Background: WNT signaling plays a major role in bone and cartilage metabolism. Impaired WNT/β-catenin signaling leads to early-onset osteoporosis, but specific features in bone and other tissues remain inadequately characterized. We have identified two large Finnish families with early-onset osteoporosis due to a heterozygous WNT1 mutation c.652T > G, p.C218G. This study evaluated the impact of impaired WNT/β-catenin signaling on spinal structures.

Methods: Altogether 18 WNT1 mutation-positive (age range 11–76 years, median 49 years) and 14 mutation-negative subjects (10–77 years, median 43 years) underwent magnetic resonance imaging (MRI) of the spine. The images were reviewed for spinal alignment, vertebral compression fractures, intervertebral disc changes and possible endplate deterioration. The findings were correlated with clinical data.

Results: Vertebral compression fractures were present in 78% (7/9) of those aged over 50 years but were not seen in younger mutation-positive subjects. All those with fractures had several severely compressed vertebrae. Altogether spinal compression fractures were present in 39% of those with a WNT1 mutation. Only 14% (2/14) mutation-negative subjects had one mild compressed vertebra each. The mutation-positive subjects had a higher mean spinal deformity index (4.0 ± 7.3 vs 0.0 ± 0.4) and more often increased thoracic kyphosis (Z-score > + 2.0 in 33% vs 0%). Further, they had more often Schmorl nodes (61% vs 36%), already in adolescence, and their intervertebral discs were enlarged.

Conclusion: Compromised WNT signaling introduces severe and progressive changes to the spinal structures. Schmorl nodes are prevalent even at an early age and increased thoracic kyphosis and compression fractures become evident after the age of 50 years. Therapies targeting the WNT pathway may be an effective way to prevent spinal pathology not only in those harboring a mutation but also in the general population with similar pathology.

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Series: Bone
ISSN: 8756-3282
ISSN-E: 8756-3282
ISSN-L: 8756-3282
Volume: 101
Pages: 3 - 9
DOI: 10.1016/j.bone.2017.04.001
Type of Publication: A1 Journal article – refereed
Field of Science: 217 Medical engineering
Funding: This study was supported by the Sigrid Jusélius Foundation, the Folkhälsan Research Foundation, the Academy of Finland (277843), the Foundation for Pediatric Research, the Helsinki University Research Funds, the Swedish Research Council (2013-2603), the Novo Nordisk Foundation, the European Society for Paediatric Endocrinology Research Unit, the Swedish Childhood Cancer Foundation, and through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet. The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Copyright information: © 2017 The Authors. Published by Elsevier Inc. This manuscript version is made available under the CC-BY-NC-ND 4.0 license