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.

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.

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