Ascorbate synthesis pathway: dual role of ascorbate in bone homeostasis

Area of Science:

• Biochemistry
• Genetics
• Molecular Biology

Background:

• Ascorbate (ASC) synthesis is crucial for mammalian health.
• The specific enzymes responsible for ASC synthesis in mice were previously unidentified.

Purpose of the Study:

• To identify the key enzymes involved in D-glucuronate to L-gulonate conversion in mice.
• To investigate the in vivo roles of these enzymes in ASC synthesis and associated physiological processes.
• To elucidate the functions of ASC in bone metabolism and differentiation.

Main Methods:

• Utilized mouse gene knock-out (KO) models to study enzyme function.
• Generated single (GRKO, ARKO) and double (GRKO/ARKO) knock-out mice.
• Assessed ASC levels, bone health (osteopenia, fractures), osteoclast activity, and osteoblast differentiation.

Main Results:

• Aldehyde reductase (Akr1a4) and aldose reductase (Akr1b3) were identified as the primary enzymes for L-gulonate production.
• GRKO/ARKO mice exhibited a >95% deficit in ASC synthesis, leading to scurvy.
• GRKO mice showed severe osteopenia and fractures under increased ASC demand, with impaired osteoblast differentiation.

Conclusions:

• Aldehyde reductase and aldose reductase are essential for endogenous ascorbate synthesis in mice.
• Ascorbate plays dual roles in bone health: an antioxidant suppressing osteoclast activity and a cofactor promoting osteoblast differentiation.
• Mouse models reveal mechanisms linking suboptimal ASC availability to osteoporosis development, relevant to human bone health.