Sequential and opposing activities of Wnt and BMP coordinate zebrafish bone regeneration

Cell Rep. 2014 Feb 13;6(3):482-98. doi: 10.1016/j.celrep.2014.01.010. Epub 2014 Jan 31.

Abstract

Zebrafish fully regenerate lost bone, including after fin amputation, through a process mediated by dedifferentiated, lineage-restricted osteoblasts. Mechanisms controlling the osteoblast regenerative program from its initiation through reossification are poorly understood. We show that fin amputation induces a Wnt/β-catenin-dependent epithelial to mesenchymal transformation (EMT) of osteoblasts in order to generate proliferative Runx2(+) preosteoblasts. Localized Wnt/β-catenin signaling maintains this progenitor population toward the distal tip of the regenerative blastema. As they become proximally displaced, preosteoblasts upregulate sp7 and subsequently mature into re-epithelialized Runx2(-)/sp7(+) osteoblasts that extend preexisting bone. Autocrine bone morphogenetic protein (BMP) signaling promotes osteoblast differentiation by activating sp7 expression and counters Wnt by inducing Dickkopf-related Wnt antagonists. As such, opposing activities of Wnt and BMP coordinate the simultaneous demand for growth and differentiation during bone regeneration. This hierarchical signaling network model provides a conceptual framework for understanding innate bone repair and regeneration mechanisms and rationally designing regenerative therapeutics.

Publication types

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

MeSH terms

  • Animal Fins / cytology
  • Animal Fins / physiology
  • Animals
  • Bone Morphogenetic Proteins / metabolism*
  • Bone Regeneration / genetics
  • Bone Regeneration / physiology*
  • Cell Dedifferentiation / genetics
  • Cell Lineage
  • Epithelial-Mesenchymal Transition / genetics
  • Gene Expression Regulation
  • Osteoblasts / cytology
  • Osteoblasts / metabolism
  • Signal Transduction / genetics
  • Smad Proteins / metabolism
  • Wnt Proteins / metabolism*
  • Zebrafish / genetics
  • Zebrafish / physiology*
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*
  • beta Catenin / metabolism

Substances

  • Bone Morphogenetic Proteins
  • Smad Proteins
  • Wnt Proteins
  • Zebrafish Proteins
  • beta Catenin