Osteoporosis International

, Volume 29, Issue 2, pp 479–487 | Cite as

Defective WNT signaling associates with bone marrow fibrosis—a cross-sectional cohort study in a family with WNT1 osteoporosis

  • R. E. MäkitieEmail author
  • R. Niinimäki
  • S. Kakko
  • T. Honkanen
  • P. E. Kovanen
  • O. Mäkitie
Original Article



This study explores bone marrow function in patients with defective WNT1 signaling. Bone marrow samples showed increased reticulin and altered granulopoiesis while overall hematopoiesis was normal. Findings did not associate with severity of osteoporosis. These observations provide new insight into the role of WNT signaling in bone marrow homeostasis.


WNT signaling regulates bone homeostasis and survival and self-renewal of hematopoietic stem cells. Aberrant activation may lead to osteoporosis and bone marrow pathology. We aimed to explore bone marrow findings in a large family with early-onset osteoporosis due to a heterozygous WNT1 mutation.


We analyzed peripheral blood samples, and bone marrow aspirates and biopsies from 10 subjects with WNT1 mutation p.C218G. One subject was previously diagnosed with idiopathic myelofibrosis and others had no previously diagnosed hematologic disorders. The findings were correlated with the skeletal phenotype, as evaluated by number of peripheral and spinal fractures and bone mineral density.


Peripheral blood samples showed no abnormalities in cell counts, morphology or distributions but mild increase in platelet count. Bone marrow aspirates (from 8/10 subjects) showed mild decrease in bone marrow iron storages in 6 and variation in cell distributions in 5 subjects. Bone marrow biopsies (from 6/10 subjects) showed increased bone marrow reticulin (grade MF-2 in the myelofibrosis subject and grade MF-1 in 4 others), and an increase in overall, and a shift towards early-phase, granulopoiesis. The bone marrow findings did not associate with the severity of skeletal phenotype.


Defective WNT signaling associates with a mild increase in bone marrow reticulin and may predispose to myelofibrosis, while overall hematopoiesis and peripheral blood values are unaltered in individuals with a WNT1 mutation. In this family with WNT1 osteoporosis, bone marrow findings were not related to the severity of osteoporosis.


Hematopoiesis Hematopoietic stem cells Myelofibrosis Osteoporosis WNT signaling 



All research protocols were approved by the Research Ethics Board of Helsinki University Hospital, Helsinki, Finland. All study subjects gave their written informed consent before participation.


This study was financially supported by the Sigrid Jusélius Foundation, the Folkhälsan Research Foundation, the Academy of Finland, the Foundation for Pediatric Research, the Helsinki University Research Funds, the Swedish Research Council, the Novo Nordisk Foundation, the Swedish Childhood Cancer Foundation, Helsinki University and Helsinki University Hospital through the Doctoral Programme in Clinical Research, the Biomedicum Helsinki Foundation, the Finnish Medical Foundation, the Jalmari and Rauha Ahokas Foundation, and through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet.

Compliance with ethical standards

Conflicts of interest


Supplementary material

198_2017_4309_MOESM1_ESM.pdf (38 kb)
ESM 1 (PDF 38.0 kb).
198_2017_4309_MOESM2_ESM.pdf (41 kb)
ESM 2 (PDF 40.8 kb).
198_2017_4309_MOESM3_ESM.docx (136 kb)
ESM 3 (DOCX 135 kb).


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Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2017

Authors and Affiliations

  • R. E. Mäkitie
    • 1
    Email author
  • R. Niinimäki
    • 2
  • S. Kakko
    • 3
  • T. Honkanen
    • 4
  • P. E. Kovanen
    • 5
  • O. Mäkitie
    • 1
    • 6
    • 7
  1. 1.Folkhälsan Institute of GeneticsUniversity of HelsinkiHelsinkiFinland
  2. 2.Department of Children and AdolescentsOulu University Hospital and Oulu UniversityOuluFinland
  3. 3.Internal Medicine and Clinical Research CenterUniversity of OuluOuluFinland
  4. 4.Department of HematologyPäijät-Häme Central HospitalLahtiFinland
  5. 5.HUSLAB, Helsinki University Hospital and Department of PathologyUniversity of HelsinkiHelsinkiFinland
  6. 6.Children’s HospitalUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
  7. 7.Center for Molecular Medicine, Karolinska Institutet and Clinical GeneticsKarolinska University HospitalStockholmSweden

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