Foxk1 promotes bone formation through inducing aerobic glycolysis

Area of Science:

• Bone Biology
• Molecular Metabolism
• Cellular Differentiation

Background:

• Transcription factor Foxk1 regulates various cellular processes but its role in bone formation remains unexplored.
• Foxk1 expression is reduced in aged mice and osteoporosis patients' bone tissue.

Purpose of the Study:

• To investigate the function of Foxk1 in bone formation and osteoblast metabolism.
• To elucidate the molecular mechanisms underlying Foxk1's role in bone health.

Main Methods:

• Knockdown and conditional knockout of Foxk1 in murine osteoblasts and mice.
• CUT&Tag analysis to identify Foxk1 target genes.
• Assessment of osteoblast differentiation, proliferation, bone mass, and mechanical strength.
• Glycolysis inhibition studies using 2-deoxy-D-glucose (2DG).

Main Results:

• Foxk1 deficiency in osteoblasts impaired differentiation and proliferation, reducing bone formation and strength.
• Foxk1 directly targets glycolytic enzyme genes, and its absence reduces aerobic glycolysis in osteoblasts.
• Inhibition of glycolysis counteracted Foxk1 overexpression-induced osteoblastogenesis.
• Overexpression of Foxk1 in aged mice increased bone mass and strength, an effect blunted by glycolysis inhibition.

Conclusions:

• Foxk1 is essential for regulating osteoblast metabolism and promoting bone formation.
• Foxk1's role in stimulating bone formation is mediated through the regulation of aerobic glycolysis.
• Targeting Foxk1 and glycolysis presents a potential strategy for combating age-related bone loss and osteoporosis.