Astleford-Hopper Kristina, Saavedra Flavia, Bittner-Eddy Peter, Stein Clara, Auger Jennifer, Clark Rachel, Abrahante Llorens Juan E, Binstadt Bryce A, Thumbigere-Math Vivek, Mansky Kim C
Oral Biology Graduate Program, University of Minnesota School of Dentistry, Minneapolis, MN 55455, USA.
Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Cells. 2025 Jul 19;14(14):1111. doi: 10.3390/cells14141111.
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 , , and 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.
破骨细胞起源于髓系前体细胞，对生理性骨重塑至关重要，但在牙周炎和类风湿关节炎等炎症性疾病中也介导病理性骨丢失。赖氨酸特异性去甲基化酶（LSD1/KDM1A）是一种组蛋白去甲基化酶，通过对H3K4me1/2和H3K9me1/2进行去甲基化来调节染色质景观，从而调控决定细胞命运所必需的基因表达。我们之前证明，髓系特异性缺失LSD1（LSD1LysM-Cre）会破坏破骨细胞分化，在生理条件下导致骨体积分数（BV/TV）增加。在本研究中，我们发现LSD1LysM-Cre雌性小鼠在结扎诱导的牙周炎和K/BxN血清转移关节炎模型中同样对炎症性骨丢失具有抗性。对结扎诱导的牙周炎的LSD1LysM-Cre小鼠下颌来源的前破骨细胞进行的大量RNA测序显示，参与炎症、脂质代谢和免疫反应的基因上调。值得注意的是，即使在TGF-β和TNF共同刺激下，LSD1缺失也会阻断破骨细胞生成，这是一种替代的不依赖RANKL的分化途径。LSD1LysM-Cre前破骨细胞中、和的上调表明，LSD1对于抑制否则会阻碍破骨细胞定向分化的炎症和代谢程序至关重要。这些发现确立了LSD1作为整合炎症和代谢信号以调节破骨细胞分化和骨吸收的关键表观遗传守门人的地位。对LSD1的治疗性抑制可能在保留生理性骨重塑的同时选择性减轻炎症性骨丢失。
