PUBLICATION

Wnt16 Elicits a Protective Effect Against Fractures and Supports Bone Repair in Zebrafish

Authors
McGowan, L.M., Kague, E., Vorster, A., Newham, E., Cross, S., Hammond, C.L.
ID
ZDB-PUB-210330-10
Date
2021
Source
JBMR plus   5: e10461 (Journal)
Registered Authors
Hammond, Chrissy, Kague, Erika
Keywords
FRACTURE HEALING, GENETIC ANIMAL MODELS, OSTEOBLASTS, OSTEOPOROSIS, WNT
MeSH Terms
none
PubMed
33778326 Full text @ JBMR Plus
Abstract
Bone homeostasis is a dynamic, multicellular process that is required throughout life to maintain bone integrity, prevent fracture, and respond to skeletal damage. WNT16 has been linked to bone fragility and osteoporosis in human genome wide-association studies, as well as the functional hematopoiesis of leukocytes in vivo. However, the mechanisms by which WNT16 promotes bone health and repair are not fully understood. In this study, CRISPR-Cas9 was used to generate mutant zebrafish lacking Wnt16 (wnt16-/- ) to study its effect on bone dynamically. The wnt16 mutants displayed variable tissue mineral density (TMD) and were susceptible to spontaneous fractures and the accumulation of bone calluses at an early age. Fractures were induced in the lepidotrichia of the caudal fins of wnt16-/- and WT zebrafish; this model was used to probe the mechanisms by which Wnt16 regulates skeletal and immune cell dynamics in vivo. In WT fins, wnt16 expression increased significantly during the early stages for bone repair. Mineralization of bone during fracture repair was significantly delayed in wnt16 mutants compared with WT zebrafish. Surprisingly, there was no evidence that the recruitment of innate immune cells to fractures or soft callus formation was altered in wnt16 mutants. However, osteoblast recruitment was significantly delayed in wnt16 mutants postfracture, coinciding with precocious activation of the canonical Wnt signaling pathway. In situ hybridization suggests that canonical Wnt-responsive cells within fractures are osteoblast progenitors, and that osteoblast differentiation during bone repair is coordinated by the dynamic expression of runx2a and wnt16. This study highlights zebrafish as an emerging model for functionally validating osteoporosis-associated genes and investigating fracture repair dynamically in vivo. Using this model, it was found that Wnt16 protects against fracture and supports bone repair, likely by modulating canonical Wnt activity via runx2a to facilitate osteoblast differentiation and bone matrix deposition. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
Genes / Markers
Figures
Figure Gallery (5 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
b1212TgTransgenic Insertion
    bsl451
      Indel
      bsl667
        Insertion
        gl23TgTransgenic Insertion
          hu5910TgTransgenic Insertion
            ia4TgTransgenic Insertion
              nz50TgTransgenic Insertion
                1 - 7 of 7
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                Human Disease / Model
                No data available
                Sequence Targeting Reagents
                Target Reagent Reagent Type
                wnt16CRISPR1-wnt16CRISPR
                wnt16CRISPR2-wnt16CRISPR
                1 - 2 of 2
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                Fish
                Antibodies
                Name Type Antigen Genes Isotypes Host Organism
                Ab1-col2amonoclonal
                  IgG1Mouse
                  Ab2-lcp1polyclonalRabbit
                  Ab16-GFPpolyclonalIgYChicken
                  1 - 3 of 3
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                  Orthology
                  No data available
                  Engineered Foreign Genes
                  Marker Marker Type Name
                  DsRed2EFGDsRed2
                  EGFPEFGEGFP
                  GFPEFGGFP
                  mCherryEFGmCherry
                  1 - 4 of 4
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                  Mapping
                  No data available