Transcription factor C/EBPbeta isoform ratio regulates osteoclastogenesis through MafB

Area of Science:

• Bone Biology
• Cell Signaling
• Molecular Endocrinology

Background:

• Osteoblast and osteoclast imbalance drives bone diseases.
• CCAAT/enhancer-binding protein beta (C/EBPbeta) isoforms are critical regulators of bone homeostasis.
• The mammalian target of rapamycin (mTOR) pathway influences cellular processes, including translation.

Purpose of the Study:

• To investigate how translationally controlled C/EBPbeta isoforms affect bone mass.
• To elucidate the role of the mTOR pathway in regulating C/EBPbeta isoform expression and osteoclastogenesis.
• To determine the downstream targets of C/EBPbeta isoforms in osteoclast differentiation.

Main Methods:

• Utilized C/EBPbeta mutant mouse models (null and LIP knock-in).
• Administered rapamycin, an mTOR inhibitor, to wild-type and mutant mice.
• Performed ectopic expression of C/EBPbeta isoforms (LAP and LIP) in monocytes.
• Assessed osteoclastogenesis, bone resorption, and MafB expression (promoter activity and gene expression).

Main Results:

• mTOR inhibition by rapamycin increased the LAP/LIP ratio and inhibited osteoclastogenesis in wild-type but not in C/EBPbeta-deficient or LIP-overexpressing cells.
• C/EBPbeta mutant mice showed increased bone resorption and reduced MafB expression.
• Ectopic LAP and LIP expression differentially regulated MafB promoter activity and gene expression, significantly impacting osteoclastogenesis.

Conclusions:

• The mTOR pathway regulates osteoclast formation by modulating the C/EBPbeta isoform ratio (LAP vs. LIP).
• This C/EBPbeta isoform modulation is crucial for controlling osteoclastogenesis, partly through regulating MafB expression.
• Targeting the mTOR-C/EBPbeta-MafB axis presents a potential therapeutic strategy for bone diseases characterized by impaired bone remodeling.