Loss of wnt/β-catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes

J Bone Miner Res. 2012 Nov;27(11):2344-58. doi: 10.1002/jbmr.1694.

Abstract

Wnt signaling is essential for osteogenesis and also functions as an adipogenic switch, but it is not known if interrupting wnt signaling via knockout of β-catenin from osteoblasts would cause bone marrow adiposity. Here, we determined whether postnatal deletion of β-catenin in preosteoblasts, through conditional cre expression driven by the osterix promoter, causes bone marrow adiposity. Postnatal disruption of β-catenin in the preosteoblasts led to extensive bone marrow adiposity and low bone mass in adult mice. In cultured bone marrow-derived cells isolated from the knockout mice, adipogenic differentiation was dramatically increased, whereas osteogenic differentiation was significantly decreased. As myoblasts, in the absence of wnt/β-catenin signaling, can be reprogrammed into the adipocyte lineage, we sought to determine whether the increased adipogenesis we observed partly resulted from a cell-fate shift of preosteoblasts that had to express osterix (lineage-committed early osteoblasts), from the osteoblastic to the adipocyte lineage. Using lineage tracing both in vivo and in vitro we showed that the loss of β-catenin from preosteoblasts caused a cell-fate shift of these cells from osteoblasts to adipocytes, a shift that may at least partly contribute to the bone marrow adiposity and low bone mass in the knockout mice. These novel findings indicate that wnt/β-catenin signaling exerts control over the fate of lineage-committed early osteoblasts, with respect to their differentiation into osteoblastic versus adipocytic populations in bone, and thus offers potential insight into the origin of bone marrow adiposity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / cytology*
  • Adipocytes / metabolism
  • Adipogenesis / genetics
  • Adiposity
  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism
  • Cell Lineage*
  • Cell Separation
  • Cells, Cultured
  • Gene Deletion
  • Gene Expression Regulation
  • Green Fluorescent Proteins / metabolism
  • Integrases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Osteoblasts / cytology*
  • Osteoblasts / metabolism*
  • Osteogenesis / genetics
  • Sp7 Transcription Factor
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Wnt Signaling Pathway*
  • beta Catenin / metabolism

Substances

  • Sp7 Transcription Factor
  • Sp7 protein, mouse
  • Transcription Factors
  • beta Catenin
  • Green Fluorescent Proteins
  • Cre recombinase
  • Integrases