Sequential and Opposing Activities of Wnt and BMP Coordinate Zebrafish Bone Regeneration

Scott Stewart,Alan W Gomez,Benjamin E Armstrong,Astra Henner,Kryn Stankunas

doi:10.1016/j.celrep.2014.01.010

Scott Stewart, Alan W Gomez + Show 3 more

Open Access

https://doi.org/10.1016/j.celrep.2014.01.010

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Journal: Cell Reports	Publication Date: Jan 31, 2014
Citations: 105	License type: cc-by

Affiliation: University of Oregon

Abstract

SUMMARYZebrafish 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. Auto-crine 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.

Highlights

Among mammalian organs, bones have unusually effective repair mechanisms, as demonstrated by continuous bone remodeling throughout life and the scarless healing of some fractures
Runx2+ blastema cells observed at 24 or 48 hpa were derived from mosaiclabeled osteoblasts (Figure S1). These results demonstrate that fin amputation triggers the migration of osteoblasts closely associated with the bone ray into the nascent blastema following their upregulation of Runx2
A later treatment with IWP-2 from 48 to 72 hpa abolished twist2 expression (Figures 4Q and 4R). These results demonstrate that Wnt initiates osteoblast epithelial-to-mesenchymal transformation (EMT) and maintains the mesenchymal state of preosteoblasts by promoting twist2 expression

Summary

Introduction

Bones have unusually effective repair mechanisms, as demonstrated by continuous bone remodeling throughout life and the scarless healing of some fractures. An appealing alternative is to recapitulate mechanisms observed in animals with remarkable capacities for self-repair, including fish and salamanders. Osteoblasts are specialized bone producing cells that deposit a unique extracellular matrix, the osteoid, that mineralizes to form mature bone. Runx and sp7/ Osterix (Osx), are key determinants of the osteoblast lineage (Long, 2012). Sp7-deficient mice do not form bone due to a failure of osteoblasts to differentiate (Nakashima et al, 2002). Transcriptional control of Runx and Sp7 is mediated via cell signaling including by the Wnt and bone morphogenetic protein (BMP) pathways, both central components of bone developmental regulatory networks (Long, 2012)

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