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

## TL;DR

Female mice lacking LSD1 in myeloid cells are less likely to experience bone loss from inflammation, suggesting LSD1 could be a target for treating inflammatory bone diseases.

## Contribution

This study identifies LSD1 as an epigenetic regulator that integrates inflammatory and metabolic signals to control osteoclast differentiation.

## Key findings

- LSD1LysM-Cre female mice are resistant to inflammatory bone loss in periodontitis and arthritis models.
- LSD1 deletion blocks osteoclastogenesis even under TGF-β and TNF co-stimulation.
- Upregulation of Nlrp3, Hif1α, and Acod1 suggests LSD1 represses inflammatory and metabolic programs in osteoclasts.

## Abstract

Osteoclasts, which are derived from myeloid precursors, are essential for physiologic bone remodeling but also mediate pathological bone loss in inflammatory diseases such as periodontitis and rheumatoid arthritis. Lysine-specific demethylase (LSD1/KDM1A) is a histone demethylase that modulates the chromatin landscape via demethylation of H3K4me1/2 and H3K9me1/2, thereby regulating the expression of genes essential for deciding cell fate. We previously demonstrated that myeloid-specific deletion of LSD1 (LSD1LysM-Cre) disrupts osteoclast differentiation, leading to enhanced BV/TV under physiological conditions. In this study, we show that LSD1LysM-Cre female mice are similarly resistant to inflammatory bone loss in both ligature-induced periodontitis and K/BxN serum-transfer arthritis models. Bulk RNA-seq of mandibular-derived preosteoclasts from LSD1LysM-Cre mice with ligature-induced periodontitis revealed the upregulation of genes involved in inflammation, lipid metabolism, and immune response. Notably, LSD1 deletion blocked osteoclastogenesis even under TGF-β and TNF co-stimulation, which is an alternative RANKL-independent differentiation pathway. Upregulation of Nlrp3, Hif1α, and Acod1 in LSD1LysM-Cre preosteoclasts suggests that LSD1 is essential for repressing inflammatory and metabolic programs that otherwise hinder osteoclast commitment. These findings establish LSD1 as a critical epigenetic gatekeeper integrating inflammatory and metabolic signals to regulate osteoclast differentiation and bone resorption. Therapeutic inhibition of LSD1 may selectively mitigate inflammatory bone loss while preserving physiological bone remodeling.