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J Bone Miner Res. 2019 Jan 28. doi: 10.1002/jbmr.3680. [Epub ahead of print]

Mesenchymal Cell-Derived Juxtacrine Wnt1 Signaling Regulates Osteoblast Activity and Osteoclast Differentiation.

Author information

1
Institute of Biomedicine, University of Turku, Turku, Finland.
2
Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Harvard University, Boston, MA, USA.
3
Turku PET Centre and Turku Centre for Disease Modeling, University of Turku, Turku, Finland.
4
Turku Center for Disease Modeling, University of Turku, Turku, Finland.
5
Folkhälsan Institute of Genetics, Helsinki, Finland.
6
Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
7
Department of Endocrinology, Division of Medicine, University of Turku and Turku University Hospital, Turku, Finland.

Abstract

Human genetic evidence demonstrates that WNT1 mutations cause osteogenesis imperfecta (OI) and early-onset osteoporosis implicating WNT1 as a major regulator of bone metabolism. However, its main cellular source and mechanisms of action in bone remain elusive. We generated global and limb bud mesenchymal cell-targeted deletion of Wnt1 in mice. Heterozygous deletion of Wnt1 resulted in mild trabecular osteopenia due to decreased osteoblast function. Targeted deletion of Wnt1 in mesenchymal progenitors led to spontaneous fractures due to impaired osteoblast function and increased bone resorption, mimicking the severe OI phenotype in humans with homozygous WNT1 mutations. Importantly, we demonstrated for the first time that Wnt1 signals strictly in a juxtacrine manner to induce osteoblast differentiation and to suppress osteoclastogenesis, in part via canonical Wnt signaling. In conclusion, mesenchymal cell-derived Wnt1, acting in short range, is an essential regulator of bone homeostasis and an intriguing target for therapeutic interventions for bone diseases. This article is protected by copyright. All rights reserved.

KEYWORDS:

Juxtacrine signaling; OPG; RANKL; Wnt1; osteoblast; osteoclast; spontaneous fracture

PMID:
30690791
DOI:
10.1002/jbmr.3680

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