H3K18la in periodontal ligament fibroblasts regulates immune niches and alveolar bone remodeling under mechanical loads

Abstract

The metabolism and remodeling of alveolar bone are highly active, which dynamically respond to mechanical force. However, the mechanism of how alveolar bone responds to mechanical force remains elusive. Orthodontics is essentially a physiological process of mechanical force–driven alveolar bone remodeling. Here, we demonstrated that orthodontic tension promoted the expression of glycolysis-related genes in periodontal ligament (PDL) fibroblasts. The mechanoactivated glycolysis subsequently enhanced lactylation on histone H3 lysine 18 (H3K18la) in PDL fibroblasts. CUT&Tag analysis revealed that H3K18la was enriched at the promoter region of CXCL1 to upregulate its transcription. 3PO inhibited glycolysis and attenuated stretching force–induced H3K18la and CXCL1 levels in PDL fibroblasts. CXCL1 subsequently augmented oxidative phosphorylation in macrophages and promoted M2 macrophage polarization. Additionally, in vivo inhibition of glycolysis by periodontal injection of 3PO disrupted the CXCL1-mediated CXCR2⁺ macrophage infiltration and inhibited bone formation during orthodontic tooth movement. Furthermore, the blockade of the CXCL1/CXCR2 axis in vivo, using Cxcr2 knockout (Cxcr2^–/^–) mice, impaired tension–induced M2 macrophage polarization in PDL, disrupting the pro-resolving microenvironment conducive to bone formation during orthodontic tooth movement. Overall, the results reveal that the tension–induced glycolysis–H3K18la axis in PDL fibroblasts plays a critical role in creating the pro-resolving periodontal immune niche and facilitating alveolar bone formation during orthodontic tooth movement.

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Funding

National Natural Science Foundation of China (National Science Foundation of China)(82301115)

Department of Science and Technology of Sichuan Province (Sichuan Provincial Department of Science and Technology)(2025ZNSFSC1584)

China Postdoctoral Science Foundation(2023M742459)

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