Mechanical loading regulates NFATc1 and beta-catenin signaling through a GSK3beta control node

Area of Science:

• Biomedical Engineering
• Stem Cell Biology
• Mechanobiology

Background:

• Mechanical stimulation influences mesenchymal stem cell (MSC) differentiation.
• This effect is linked to beta-catenin levels, impacting adipogenic and osteogenic outcomes.
• The precise role of beta-catenin in mechanical regulation of MSC lineage selection requires further elucidation.

Purpose of the Study:

• To investigate the critical role of mechanical up-regulation of beta-catenin in reducing adipogenesis.
• To explore other mechanical events that induce alternate MSC lineage selection.
• To determine the downstream signaling pathways involved in mechanical regulation of MSC differentiation.

Main Methods:

• Mesenchymal stem cells (MSCs) were cultured under strong adipogenic conditions.
• Mechanical load was applied (3600 cycles/day, 2% strain).
• Gene silencing techniques (siRNA) were used to target GSK3beta, beta-catenin, and NFATc1.

Main Results:

• Mechanical load inactivated GSK3beta, leading to beta-catenin and COX2 up-regulation.
• Beta-catenin knockdown blocked the reduction of adipogenic markers (peroxisome proliferator-activated receptor gamma, adiponectin) under mechanical load.
• NFATc1 signaling, activated by GSK3beta inhibition and mechanical strain, was crucial for mechanical stimulation of COX2 and osteogenic differentiation.

Conclusions:

• Mechanical inhibition of GSK3beta activates both beta-catenin and NFATc1 signaling in MSCs.
• Beta-catenin limits adipogenesis, while NFATc1/COX2 signaling promotes osteoblastic differentiation.
• Mechanical loading regulates MSC differentiation via GSK3beta inhibition, impacting multiple downstream effectors.