Female Mice Lacking LSD1 in Myeloid Cells Are Resistant to Inflammatory Bone Loss

Area of Science:

• Epigenetics
• Immunology
• Bone Biology

Background:

• Osteoclasts are key to bone remodeling and pathological bone loss in diseases like periodontitis and rheumatoid arthritis.
• Lysine-specific demethylase (LSD1/KDM1A) regulates gene expression by modifying histone methylation, influencing cell fate.
• Previous studies showed myeloid-specific LSD1 deletion disrupts osteoclast differentiation under physiological conditions.

Purpose of the Study:

• To investigate the role of LSD1 in inflammatory bone loss.
• To determine if LSD1 deletion confers resistance to inflammatory bone loss in mouse models.
• To elucidate the molecular mechanisms by which LSD1 regulates osteoclastogenesis in inflammation.

Main Methods:

• Utilized myeloid-specific LSD1 knockout (LSD1LysM-Cre) female mice.
• Induced periodontitis and K/BxN serum-transfer arthritis models.
• Performed bulk RNA-sequencing on preosteoclasts from affected mice.

Main Results:

• LSD1LysM-Cre mice were resistant to inflammatory bone loss in both models.
• RNA-seq revealed upregulation of inflammation and lipid metabolism genes in LSD1-deficient preosteoclasts.
• LSD1 deletion inhibited osteoclastogenesis, even under TGF-β and TNF co-stimulation (RANKL-independent pathway).
• Upregulation of NLRP3, HIF1α, and ACOD1 suggests LSD1 represses inflammatory and metabolic programs hindering osteoclast commitment.

Conclusions:

• LSD1 acts as an epigenetic regulator integrating inflammatory and metabolic signals for osteoclast differentiation.
• LSD1 is essential for pathological bone resorption in inflammatory conditions.
• Therapeutic inhibition of LSD1 could treat inflammatory bone loss while preserving normal bone remodeling.