BAP1 promotes osteoclast function by metabolic reprogramming.

Area of Science:

• Biochemistry
• Cell Biology
• Bone Biology

Background:

• Osteoporosis treatment often reduces osteoclast numbers, suppressing bone formation and hindering fracture prevention.
• Retarding osteoclast function, rather than differentiation, may preserve bone formation while reducing degradation.

Purpose of the Study:

• To investigate the role of the deubiquitinase BRCA1-associated protein 1 (BAP1) in osteoclast function and bone metabolism.
• To determine if targeting BAP1 in myeloid cells can modulate osteoclast activity and bone mass.

Main Methods:

• Generated myeloid-specific Bap1-deficient mice (Bap1^∆LysM).
• Assessed osteoclast formation, cytoskeleton organization, and resorptive capacity in Bap1^∆LysM mice.
• Analyzed the impact of BAP1 deficiency on osteoclast epigenetics and metabolism, including Slc7a11 expression and H2Aub occupancy.

Main Results:

• Deletion of Bap1 in myeloid cells (Bap1^∆LysM) arrested osteoclast function without affecting formation.
• Bap1^∆LysM osteoclasts exhibited impaired cytoskeleton organization, leading to reduced bone degradation.
• BAP1 deficiency in osteoclasts upregulated Slc7a11 via enhanced H2Aub promoter occupancy, altering cellular reactive oxygen species and mitochondrial metabolism.

Conclusions:

• BAP1 regulates osteoclast function through an epigenetic-metabolic reprogramming axis.
• Targeting BAP1 in osteoclasts offers a potential therapeutic strategy for osteoporosis, reducing bone degradation while maintaining bone formation.