The Glycogen Synthase Kinase-3β Inhibitor LSN 2105786 Promotes Zebrafish Fin Regeneration

Area of Science:

• Molecular Biology
• Developmental Biology
• Regenerative Medicine

Background:

• The Wnt signaling pathway is crucial for maintaining bone homeostasis and influences bone disease.
• Glycogen synthase kinase-3β (GSK3β) plays a regulatory role in Wnt signaling.
• Dysregulation of GSK3β is implicated in various bone pathologies.

Purpose of the Study:

• To investigate the effect of a synthetic GSK3β inhibitor (LSN 2105786) on bone healing using a zebrafish fin regeneration model.
• To determine the optimal dosing regimen for GSK3β inhibition in promoting bone regeneration.
• To explore the impact of Wnt pathway activation on cellular processes during bone repair.

Main Methods:

• Utilized zebrafish caudal fin regeneration as a model for bone healing.
• Administered a synthetic, orally bioavailable GSK3β inhibitor (LSN 2105786) at various concentrations and dosing schedules.
• Assessed regenerative outgrowth, Wnt responsive gene expression, cell proliferation, and osteoblast differentiation.

Main Results:

• Continuous low-dose (4-5 nM) GSK3β inhibitor treatment significantly enhanced fin regeneration compared to intermittent dosing.
• Higher concentrations of the inhibitor showed inhibitory effects, potentially due to excessive stimulation of differentiation.
• GSK3β inhibition led to increased Wnt responsive gene expression, cell proliferation, and osteoblast differentiation in fin regenerates.

Conclusions:

• Activating Wnt signaling via GSK3β inhibition promotes bone healing in zebrafish fin regeneration.
• The zebrafish fin regeneration model is effective for evaluating the dose-dependent efficacy and potential toxicity of bone healing compounds.
• Optimized dosing regimens are critical for maximizing therapeutic benefits and avoiding adverse effects of Wnt pathway modulators.