Osteoclasts control endochondral ossification via regulating acetyl-CoA availability

Area of Science:

• Cell Biology
• Metabolism
• Bone Biology

Background:

• Osteoclasts are crucial for bone health and fracture repair.
• The metabolic regulation of osteoclast function, particularly in relation to skeletal development and healing, is not fully understood.

Purpose of the Study:

• To investigate the role of osteoclast metabolic state in skeletal development and fracture healing.
• To elucidate the mechanisms by which Rheb1 influences osteoclast function and cathepsin K (CTSK) production.

Main Methods:

• Utilized osteoclast-specific Rheb1-knockout mouse models.
• Investigated the impact of Rheb1 on mitochondrial respiration and glycolysis in osteoclasts.
• Analyzed the relationship between Rheb1, mitochondrial acetyl-CoA generation, and CTSK production.

Main Results:

• Mitochondrial respiration, not glycolysis, is essential for osteoclast cathepsin K (CTSK) production.
• Rheb1 regulates CTSK production independently of the mTORC1 pathway.
• Rheb1 coordinates with mitochondrial acetyl-CoA generation to support CTSK activity.
• Impaired acetyl-CoA availability in osteoclasts centralizes CTSK elevation.
• Abnormal endochondral ossification, linked to alcohol consumption, may stem from dysregulated CTSK via acetyl-CoA.

Conclusions:

• Mitochondrial metabolism, specifically respiration and acetyl-CoA generation regulated by Rheb1, is critical for osteoclast function.
• Targeting Rheb1 offers a potential therapeutic strategy for bone disorders, including impaired fracture healing associated with alcohol consumption.