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Identification of novel osteogenic compounds by an ex-vivo sp7:luciferase zebrafish scale assay
Erik de Vrieze1, Jan Zethof1, Stefan Schulte-Merker2
1Department of Organismal Animal Physiology, Institute for Water and Wetland Research, Faculty of Science, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands.
Abstract:
Tight interactions among different cell types contributing to bone formation are of key importance in the maintenance of bone homeostasis. Based on the high similarity in responses to (anti)osteogenic signals between zebrafish scales and mammalian bone, we developed and validated a model to screen large numbers of compounds using ex-vivo cultured scales of a sp7:luciferase transgenic zebrafish. This model combines the high predictive value of explant cultures with quick, sensitive, and quantifiable readout converging the effects via various pathways including WNT-signaling, to SP7/osterix promoter activity. Sp7 is pivotal in osteoblast differentiation and activity and its promoter activity provides an excellent surrogate for sp7 expression. Bmp-2a was shown to dose-dependently increase sp7-driven luciferase activity ex vivo. Next, we identified novel effects on bone for 51.7% of the compounds from a small library of WNT-signaling modulators, including a strong osteogenic effect for niclosamide. From all previously characterized compounds, the effect on bone was correctly predicted for 70% of compounds, resulting in a 7% false positive- and 21% false negative rate. The proposed sp7:luciferase zebrafish scale model is unique, powerful and efficient new tool to assess compounds with osteogenic effects, prior to further testing in rodents.
Insights
Researchers developed a novel zebrafish scale model to screen compounds for bone formation effects. This efficient tool accurately predicts osteogenic potential, aiding drug discovery before rodent testing.
Area of Science:
- Bone Biology and Regenerative Medicine
- Zebrafish as a Model Organism
- Drug Discovery and Screening
Background:
- Bone homeostasis relies on intricate cell-type interactions.
- Zebrafish scales share similar responses to osteogenic signals as mammalian bone.
- Existing screening methods lack efficiency and predictive value.
Purpose of the Study:
- To develop and validate a novel ex-vivo zebrafish scale model for high-throughput compound screening.
- To assess the model's ability to predict osteogenic effects of compounds.
- To identify novel bone-active compounds using this platform.
Main Methods:
- Utilized a sp7:luciferase transgenic zebrafish model with ex-vivo cultured scales.
- Measured luciferase activity as a surrogate for SP7/osterix promoter activity, a key indicator of osteoblast differentiation.
- Screened a library of WNT-signaling modulators and characterized compound effects.
Main Results:
- The zebrafish scale model demonstrated a dose-dependent increase in SP7 activity with Bmp-2a.
- Identified novel bone-related effects for 51.7% of WNT-signaling modulators, including niclosamide.
- Achieved 70% prediction accuracy for known compounds, with low false positive (7%) and false negative (21%) rates.
Conclusions:
- The sp7:luciferase zebrafish scale model is a powerful and efficient tool for assessing osteogenic compound effects.
- This model offers a valuable preclinical screening method prior to rodent studies.
- The platform facilitates the discovery of novel bone-modulating agents.
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