Iron-dependent KDM4D activity controls the quiescence-activity balance of MSCs via the PI3K-Akt-Foxo1 pathway

Area of Science:

• Biochemistry
• Cell Biology
• Bone Metabolism

Background:

• Iron deficiency is a widespread nutritional issue impacting organ function.
• Emerging evidence links iron deficiency to bone metabolism dysfunction, but mechanisms are unclear.
• Iron-dependent enzymes regulate cell processes, yet their role in mesenchymal stem cell (MSC) activation under iron deficiency is unknown.

Purpose of the Study:

• To investigate the role of histone demethylase activity in iron deficiency-induced inhibition of quiescent MSC activation.
• To identify key molecular players involved in this process.

Main Methods:

• Investigated KDM4D's role in MSC activation under iron deficiency.
• Assessed H3K9me3 demethylase activity and heterochromatin formation near the PIK3R3 promoter.
• Utilized iron-deficient mouse models to evaluate bone marrow MSC activation and bone mass.
• Examined the PI3K-Akt-Foxo1 pathway's involvement.

Main Results:

• Identified KDM4D as crucial for quiescent MSC activation.
• Iron deficiency significantly decreased KDM4D's H3K9me3 demethylase activity.
• Increased heterochromatin near the PIK3R3 promoter suppressed its expression via the PI3K-Akt-Foxo1 pathway, inhibiting MSC activation.
• Iron-deficient mice showed impaired MSC activation and reduced bone mass.

Conclusions:

• Iron deficiency inhibits MSC activation by reducing KDM4D activity, leading to PIK3R3 downregulation and PI3K-Akt-Foxo1 pathway disruption.
• This mechanism contributes to bone loss in iron deficiency.
• Targeting the PI3K-Akt-Foxo1 pathway offers a potential therapeutic strategy for iron deficiency-induced bone loss.