Glucose Restriction Promotes Osteocyte Specification by Activating a PGC-1α-Dependent Transcriptional Program

Area of Science:

• Bone Biology
• Cellular Metabolism
• Transcriptional Regulation

Background:

• Osteocytes, the most abundant bone cells, are embedded within the bone matrix, limiting nutrient access and impacting their differentiation.
• The differentiation process of osteocytes remains poorly understood.

Purpose of the Study:

• To investigate the role of glucose supply in osteocyte differentiation.
• To elucidate the molecular mechanisms regulating osteocyte gene expression.

Main Methods:

• Utilized glucose deprivation and activators of the AMPK/PGC-1 pathway in cell cultures (IDG-SW3, murine primary osteoblasts, osteocytes) and ex vivo bone cultures.
• Generated mice with conditional ablation of PGC-1α and PGC-1β in osteoblasts and osteocytes.
• Assessed osteocyte gene expression and bone phenotype.

Main Results:

• Glucose restriction promoted the osteocyte transcriptional program and increased mitochondrial DNA levels.
• Activation of the AMPK/PGC-1 pathway enhanced osteocyte gene expression.
• Osteoblasts and osteocytes lacking PGC-1α/β were unresponsive to glucose restriction.
• Conditional ablation of PGC-1α/β in mice led to osteopenia and reduced osteocytic gene expression.

Conclusions:

• Glucose restriction is a key regulator of osteocyte gene expression via the AMPK/PGC-1 pathway.
• PGC-1 (Peroxisome proliferator-activated receptor gamma coactivator 1) plays a critical role in osteocyte function and bone homeostasis.