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BAP1 promotes osteoclast function by metabolic reprogramming
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DOI：10.1038/s41467-023-41629-4.png)
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摘要
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Treatment of osteoporosis commonly diminishes osteoclast number which suppresses bone formation thus compromising fracture prevention. Bone formation is not suppressed, however, when bone degradation is reduced by retarding osteoclast functional resorptive capacity, rather than differentiation. We find deletion of deubiquitinase, BRCA1-associated protein 1 (Bap1), in myeloid cells (Bap1 increment LysM), arrests osteoclast function but not formation. Bap1 increment LysM osteoclasts fail to organize their cytoskeleton which is essential for bone degradation consequently increasing bone mass in both male and female mice. The deubiquitinase activity of BAP1 modifies osteoclast function by metabolic reprogramming. Bap1 deficient osteoclast upregulate the cystine transporter, Slc7a11, by enhanced H2Aub occupancy of its promoter. SLC7A11 controls cellular reactive oxygen species levels and redirects the mitochondrial metabolites away from the tricarboxylic acid cycle, both being necessary for osteoclast function. Thus, in osteoclasts BAP1 appears to regulate the epigenetic-metabolic axis and is a potential target to reduce bone degradation while maintaining osteogenesis in osteoporotic patients. Here, the authors demonstrate that BRCA1-associated protein 1 (Bap1) regulates osteoclast's capacity to degrade bone. Reprogramming of epigenetic-metabolic axis upon Bap1 loss inhibits bone degradation, preserving bone mass, making it a potential therapeutic target for osteoporosis.
Keyword:
BONE-RESORPTION
EPIGENETIC REGULATION
DIFFERENTIATION
PACKAGE
STIMULATION
INTEGRINS
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期刊
IF:
15.7
论文数:
9.3W
被引数:
91.2W
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