Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone

Xiaolin Tu, Jesus Delgado-Calle, Keith W. Condon, Marta Maycas, Huajia Zhang, Nadia Carlesso, Makoto M. Taketo, David B. Burr, Lilian I. Plotkin, Teresita Bellido

Research output: Contribution to journalArticle

113 Scopus citations

Abstract

Osteocytes, >90% of the cells in bone, lie embedded within the mineralized matrix and coordinate osteoclast and osteoblast activity on bone surfaces by mechanisms still unclear. Bone anabolic stimuli activate Wnt signaling, and human mutations of components along this pathway underscore its crucial role in bone accrual and maintenance. However, the cell responsible for orchestrating Wnt anabolic actions has remained elusive. We show herein that activation of canonical Wnt signaling exclusively in osteocytes [dominant active (da)βcatOt mice] induces bone anabolism and triggers Notch signaling without affecting survival. These features contrast with those of mice expressing the same daβ-catenin in osteoblasts, which exhibit decreased resorption and perinatal death from leukemia. daβcatOt mice exhibit increased bone mineral density in the axial and appendicular skeleton, and marked increase in bone volume in cancellous/trabecular and cortical compartments compared with littermate controls. daβcatOt mice display increased resorption and formation markers, high number of osteoclasts and osteoblasts in cancellous and cortical bone, increased bone matrix production, and markedly elevated periosteal bone formation rate. Wnt and Notch signaling target genes, osteoblast and osteocyte markers, and proosteoclastogenic and antiosteoclastogenic cytokines are elevated in bones of daβcatOt mice. Further, the increase in RANKL depends on Sost/sclerostin. Thus, activation of osteocytic β-catenin signaling increases both osteoclasts and osteoblasts, leading to bone gain, and is sufficient to activate the Notch pathway. These findings demonstrate disparate outcomes of β-catenin activation in osteocytes versus osteoblasts and identify osteocytes as central target cells of the anabolic actions of canonical Wnt/β-catenin signaling in bone.

Original languageEnglish (US)
Pages (from-to)E478-E486
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number5
DOIs
StatePublished - Feb 3 2015

Keywords

  • Beta-catenin
  • Bone anabolism
  • Canonical Wnt
  • Notch signaling
  • Osteocytes

ASJC Scopus subject areas

  • General

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