Riikka E Mäkitie1, Tuukka Niinimäki2, Miika T Nieminen3, Camilla Schalin-Jäntti4, Jaakko Niinimäki5, Outi Mäkitie6. 1. Folkhälsan Institute of Genetics, University of Helsinki, Helsinki FI-00290, Finland. Electronic address: riikka.makitie@helsinki.fi. 2. Department of Orthopedics, Oulu University Hospital, Oulu FI-90220, Finland. Electronic address: tuukka.niinimaki@oulu.fi. 3. Research Unit of Medical Imaging, Physics and Technology, Department of Diagnostic Radiology, Oulu University Hospital, Oulu FI-90220, Finland; Medical Research Center, University of Oulu and Oulu University Hospital, Oulu FI-90220, Finland. Electronic address: miika.nieminen@oulu.fi. 4. Endocrinology, Abdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki FI-00290, Finland. Electronic address: camilla.schalin-jantti@hus.fi. 5. Research Unit of Medical Imaging, Physics and Technology, Department of Diagnostic Radiology, Oulu University Hospital, Oulu FI-90220, Finland; Medical Research Center, University of Oulu and Oulu University Hospital, Oulu FI-90220, Finland. Electronic address: jaakko.niinimaki@oulu.fi. 6. Folkhälsan Institute of Genetics, University of Helsinki, Helsinki FI-00290, Finland; Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki FI-00290, Finland; Center for Molecular Medicine, Karolinska Institutet, and Clinical Genetics, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. Electronic address: outi.makitie@helsinki.fi.
Abstract
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 11-76years, median 49years) and 14 mutation-negative subjects (10-77years, median 43years) 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 50years 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 50years. 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.
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 11-76years, median 49years) and 14 mutation-negative subjects (10-77years, median 43years) 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 50years 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 50years. 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.
Authors: Arne C Lekven; Craig J Lilie; Holly C Gibbs; David G Green; Avantika Singh; Alvin T Yeh Journal: Dev Genes Evol Date: 2019-03-01 Impact factor: 0.900
Authors: Alice Costantini; Riikka E Mäkitie; Markus A Hartmann; Nadja Fratzl-Zelman; M Carola Zillikens; Uwe Kornak; Kent Søe; Outi Mäkitie Journal: J Bone Miner Res Date: 2022-09-11 Impact factor: 6.390
Authors: Riikka E Mäkitie; Tuukka Niinimäki; Maria Suo-Palosaari; Anders Kämpe; Alice Costantini; Sanna Toiviainen-Salo; Jaakko Niinimäki; Outi Mäkitie Journal: Front Endocrinol (Lausanne) Date: 2020-06-23 Impact factor: 5.555