Mechanical load triggers a metabolic–epigenetic switch that builds alveolar bone

Orthodontic tooth movement relies on mechanical force to remodel alveolar bone, yet how periodontal ligament (PDL) fibroblasts convert mechanical cues into signals that favor bone formation remains unclear. A new study shows that tensile force activates glycolysis in PDL fibroblasts, increasing glycolysis and driving histone H3 lysine 18 lactylation (H3K18la). H3K18la enrichment at the promoter of C-X-C motif chemokine ligand 1 (CXCL1) enhances its transcription and secretion. Fibroblast-derived CXCL1 then acts through C-X-C motif chemokine receptor 2 (CXCR2) on macrophages, boosting mitochondrial oxidative phosphorylation (OXPHOS) and promoting pro-resolving M2 macrophage polarization. In mice, blocking glycolysis or CXCR2 impaired M2 infiltration and reduced tension-side bone formation, identifying a glycolysis–H3K18la–CXCL1 axis that couples mechanical load to a bone-building immune niche.

Bone adapts to mechanical force through coupled formation and resorption, a principle central to orthodontics. Periodontal ligament (PDL) fibroblasts are the principal mechanosensing cells in the periodontal ligament and can release inflammatory mediators that initiate aseptic immune responses during orthodontic tooth movement (OTM). However, how these cells translate mechanical force into metabolic and epigenetic changes that shape the local immune microenvironment remains poorly defined. Glycolysis and its end product lactate can influence histone lactylation, but whether this metabolic–epigenetic link operates in PDL fibroblasts under mechanical load was unknown. Because of these gaps, there is a need to investigate how force-induced glycolysis and histone lactylation in PDL fibroblasts regulate periodontal immune niches and alveolar bone remodeling during OTM.

Researchers at West China Hospital of Stomatology, Sichuan University, reported (DOI: 10.1038/s41368-026-00465-0) on 02 October 2026 in the  International Journal of Oral Science that tensile force drives metabolic–epigenetic reprogramming in PDL fibroblasts. Using single-cell RNA sequencing, cyclic stretch, cleavage under targets and tagmentation (CUT&Tag), macrophage co-culture, periodontal injection of a glycolysis inhibitor and C-X-C motif chemokine receptor 2 (CXCR2) knockout mice, they traced how glycolysis and H3 lysine 18 lactylation (H3K18la) shape the periodontal immune niche and alveolar bone remodeling during OTM.

The study found that OTM upregulated glycolysis-related genes in PDL fibroblasts on the tension side. Cyclic stretch enhanced glycolytic proton efflux and lactate accumulation in human PDL fibroblasts, accompanied by higher global lactylation and H3K18la. CUT&Tag showed H3K18la enrichment at the CXCL1 promoter; exogenous lactate increased CXCL1, whereas the glycolysis inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) reduced H3K18la level and CXCL1 secretion. Single-cell data showed increased C-X-C motif chemokine ligand 1 (CXCL1) expression in PDL fibroblasts after OTM. Co-culture with stretched fibroblasts increased CD206⁺ macrophages, and the CXCR2 antagonist SB225002 reversed this effect. In macrophages, CXCL1 enhanced OXPHOS and M2 polarization through CXCR2. Seahorse analysis showed higher basal and maximal respiration and adenosine triphosphate (ATP) production in CXCL1-treated macrophages, blocked by SB225002. In vivo, 3PO reduced F4/80⁺CXCR2⁺ macrophage infiltration and osteocalcin⁺ bone formation. Cxcr2 knockout mice showed fewer F4/80⁺CD206⁺ M2 macrophages, fewer osteocalcin⁺ cells and more tartrate-resistant acid phosphatase-positive osteoclasts on the tension side, confirming that the CXCL1/CXCR2 axis supports a pro-resolving niche for bone deposition.

The authors said the work identifies a mechanical–metabolic–epigenetic pathway in PDL fibroblasts that converts tensile force into a specific chemokine signal. They said H3K18la enrichment at the CXCL1 promoter provides a mechanistic link between glycolysis and immune-cell recruitment, and that interrupting this axis blunts the pro-resolving macrophage response needed for tension-side bone formation. They added that the findings offer a framework for understanding how mechanical load shapes periodontal immune niches and may guide strategies to support bone remodeling in orthodontic settings.

Clinically, the glycolysis–H3K18la–CXCL1–CXCR2 axis may inform strategies to enhance alveolar bone formation during orthodontic treatment, especially in patients with impaired bone remodeling. The authors cautioned that 3PO can affect multiple cell types and that CXCR2 is broadly expressed, so cell-type-specific studies are needed before targeting this pathway. Future work should test whether manipulating fibroblast metabolism can improve bone regeneration in orthodontics and periodontics, and whether the axis behaves similarly under inflammatory conditions such as diabetes or periodontitis. Such studies could help translate the findings into safer, more selective approaches for patients who need faster or more reliable orthodontic bone remodeling.

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References

DOI

10.1038/s41368-026-00465-0

Original Source URL

https://www.nature.com/articles/s41368-026-00465-0

Funding Information

National Natural Science Foundation of China (82301115); Natural Science Foundation of Sichuan Province (2025ZNSFSC1584); China Postdoctoral Science Foundation (2023M742459). 

About  International Journal of Oral Science 

 International Journal of Oral Science  (ISSN 1674-2818) was founded in 2009 and aims to publish all aspects of oral science and interdisciplinary fields, including fundamental, applied and clinical research. Covered areas include oral microbiology, oral and maxillofacial oncology, cariology, oral inflammation and infection, dental stem cells and regenerative medicine, craniofacial surgery, dental materials, oral biomechanics, oral, dental and maxillofacial genetic and developmental diseases.