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Mesenchymal Cell‐Derived Juxtacrine Wnt1 Signaling Regulates Osteoblast Activity and Osteoclast Differentiation
Author(s) -
Wang Fan,
Tarkkonen Kati,
NieminenPihala Vappu,
Nagano Kenichi,
Majidi Rana Al,
Puolakkainen Tero,
Rummukainen Petri,
Lehto Jemina,
Roivainen Anne,
Zhang FuPing,
Mäkitie Outi,
Baron Roland,
Kiviranta Riku
Publication year - 2019
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.3680
Subject(s) - osteoblast , mesenchymal stem cell , osteoclast , wnt signaling pathway , microbiology and biotechnology , bone resorption , bone remodeling , biology , cancer research , cellular differentiation , endocrinology , signal transduction , genetics , gene , in vitro
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 showed 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. © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.