Disturbed ATP and AMPK homeostasis in an Ank _F377del mouse model for craniometaphyseal dysplasia

Area of Science:

• Genetics
• Metabolic Disorders
• Skeletal Dysplasias

Background:

• Craniometaphyseal dysplasia (CMD) is a rare genetic disorder causing bone overgrowth.
• Mutations in the ANKH gene, responsible for ATP and citrate transport, cause the dominant form of CMD.
• The precise mechanisms by which ANK mutations impact cellular metabolism and disease progression in CMD are not fully understood.

Purpose of the Study:

• To investigate the effects of ANK mutations on ATP/citrate homeostasis in a mouse model of CMD.
• To explore the role of the ATP-AMPK signaling pathway in CMD pathogenesis, particularly in osteoclasts.
• To evaluate the therapeutic potential of targeting AMPK in CMD.

Main Methods:

• Utilized ANK F377del knock-in (Ank KI/KI) mice to model CMD.
• Analyzed cellular ATP export, intracellular ATP levels, and plasma citric acid.
• Performed metabolomic analysis and pathway enrichment.
• Examined phospho-AMPK levels in osteoclasts.
• Administered an AMPK inhibitor (SBI-0206965) systemically and during osteoclast fusion.

Main Results:

• Ank KI/KI mice exhibited reduced cellular ATP export, intracellular ATP, and plasma citric acid.
• Phospho-AMPK was significantly upregulated in fusing Ank KI/KI osteoclasts.
• Targeting AMPK during osteoclast fusion partially restored osteoclast function.
• Systemic AMPK inhibition improved incisor positioning but did not correct other skeletal abnormalities.

Conclusions:

• ANK mutations in CMD disrupt ATP and citrate homeostasis, leading to altered energy metabolism.
• The ATP-AMPK axis is critically involved in CMD pathogenesis, particularly within osteoclasts.
• Targeting AMPK represents a potential therapeutic strategy for CMD, though systemic administration has limitations.